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Review

Immune Thrombosis: Exploring the Significance of Immune Complexes and NETosis

by
José Perdomo
1,* and
Halina H. L. Leung
2
1
Haematology Research Group, Faculty Medicine and Health, Central Clinical School, University of Sydney, Sydney, NSW 2006, Australia
2
Haematology Research Unit, St George & Sutherland Clinical Campuses, Faculty of Medicine & Health, School of Clinical Medicine, University of New South Wales, Kogarah, NSW 2217, Australia
*
Author to whom correspondence should be addressed.
Biology 2023, 12(10), 1332; https://doi.org/10.3390/biology12101332
Submission received: 20 August 2023 / Revised: 26 September 2023 / Accepted: 11 October 2023 / Published: 12 October 2023
(This article belongs to the Special Issue Neutrophil Extracellular Traps in Disease and Immunity)
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Abstract

:

Simple Summary

While neutrophil extracellular traps (NETs) are released by neutrophils as part of immune processes, there is extensive evidence of the involvement of NETs in pathological developments such as thrombosis. Immune complexes, formed by antibodies against diverse antigens, can trigger NETs formation, which induces a generation of neutrophil–platelet aggregates, platelet activation, vascular damage, and thrombus formation. Thromboses associated with autoimmune diseases and severe infections are thought to be caused by immune complex-induced NETs formation. Here, we explore the impact of immune complexes on NETs-associated thrombosis.

Abstract

Neutrophil extracellular traps (NETs) are major contributors to inflammation and autoimmunity, playing a key role in the development of thrombotic disorders. NETs, composed of DNA, histones, and numerous other proteins serve as scaffolds for thrombus formation and promote platelet activation, coagulation, and endothelial dysfunction. Accumulating evidence indicates that NETs mediate thrombosis in autoimmune diseases, viral and bacterial infections, cancer, and cardiovascular disease. This article reviews the role and mechanisms of immune complexes in NETs formation and their contribution to the generation of a prothrombotic state. Immune complexes are formed by interactions between antigens and antibodies and can induce NETosis by the direct activation of neutrophils via Fc receptors, via platelet activation, and through endothelial inflammation. We discuss the mechanisms by which NETs induced by immune complexes contribute to immune thrombotic processes and consider the potential development of therapeutic strategies. Targeting immune complexes and NETosis hold promise for mitigating thrombotic events and reducing the burden of immune thrombosis.

1. Introduction

Morphological changes in neutrophils, distinct from apoptosis or necrosis, upon treatment with phorbol 12-myristate 13-acetate (PMA) were described by Takei et al. in 1996 [1]. This process was later termed neutrophil extracellular traps (NETs) formation and was initially reported as a host defence mechanism against infection [2]. NETs formation has evolved into a mechanism with wide implications in biological processes and in the pathology of diabetes, cancer, autoimmunity, atherosclerosis, infections, and thrombosis. Two distinct types of NETosis have been described: a slow form of cell death that may take hours and is known as lytic or suicidal NETosis and vital NETosis, a fast process whereby neutrophils release nuclear material but remain viable and functional [3]. In fact, enucleated neutrophils are known to retain chemotactic and phagocytic functions [4].
Lytic NETosis depends on NADPH and reactive oxygen species (ROS) activity which triggers histone citrullination via peptidyl arginine deiminase (PAD4), while vital NETosis does not involve NADPH and relies on increases in intracellular calcium [5]. A sub-category of lytic NETosis, termed noncanonical NETosis, has been proposed more recently [6]. This form of NETosis is elicited in the presence of cytosolic Gram-negative bacteria and involves noncanonical inflammasomes and caspase 4/5 activation. Histone citrullination mediated by PAD4 is also present in noncanonical NETosis [7]. Both lytic and vital NETosis, however, involve nuclear the decondensation and subsequent release of chromatin into the extracellular space. Chromatin serves as the backbone for numerous NET components including histones, myeloperoxidase, elastase, and cathepsin-G [8]. Therefore, the consequences of NETs formation—antibacterial activity, inflammation, vascular occlusion—can be attributed to the activity of the diverse components of these DNA structures.
Since the description of NETs induction by PMA and bacteria [1,2], numerous stimuli of NETs formation such as viruses [9], cholesterol crystals [10], activated platelets [11,12], cytokines [13], autoantibodies [14], and immune complexes (ICs) [15,16,17] have been described. Unsurprisingly, an attendant number of neutrophil receptors have been associated with various stimuli. Activated platelets induce NETosis via the PSGL1 receptor [15,18] or via high-mobility group protein B1-RAGE interaction [19], bacteria and viruses through pattern recognition receptors and Fc receptors [20,21] and ICs via Fc receptors [15,16,22] (Figure 1).

2. Immune Complexes and Fc Receptors

The adaptive immune response results in the production of antibodies against antigens, leading to the formation of antigen–antibody complexes. The generation of antibodies that bind to different epitopes on the antigen leads to the formation of ICs. The role of ICs in conditions such a serum sickness, vasculitis, and rheumatic disease has been documented for decades [23]. ICs have a higher affinity for Fc receptors and are normally cleared by the liver (by sinusoidal endothelial cells and Kupffer cells) and spleen via interaction with Fc receptors expressed on monocytes/macrophages and neutrophils. Neutrophils express both low- (FcγRIIA, FcγRIIB, and FcγRIIIB) and high- affinity (FcRn and FcγRI, which is expressed on activated neutrophils) IgG Fc receptors. FcαRI, a receptor for IgA, is also present on human neutrophils [24]. High-affinity receptors such as FcγRI bind IgG monomers, while the low affinity receptors have an avidity for IgG ICs or opsonised cells. IgG subclasses display distinct Fc receptor binding affinities. IgG1 and IgG3 interact with FcγRI, FcγRIIA/B, FcγRIIIB, and FcRn, while IgG2 fails to recognise FcγRI, FcγRIIB, and FcγRIIIB [25]. Some IgG2 and IgG4 ICs also recognise complement receptors on neutrophils [26].
The recognition of ICs by Fc receptors leads to cellular signalling. For example, the clustering of FcγRIIA via interaction with ICs induces a phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) by Src kinases [27], leading to Syk signalling involving PI3K and PLCγ. This triggers diverse responses including phagocytosis and receptor internalisation, cytokine production, and oxidative burst. Murine neutrophils expressing human FcγRIIA and FcγRIIIB are able to uptake ICs, but only FcγRIIA and not FcγRIIIB transgenic mice formed NETs in response to ICs in vivo [28]. In human neutrophils, however, FcγRIIIB has been found to be involved in NETs formation [29].
Circulating ICs resulting from excessive antibody production or clearance failure can be deposited on tissues, causing inflammation, and as such are involved in the pathology of multiple conditions including autoimmune diseases such as arthritis and lupus erythematosus. Drug-mediated reactions such as heparin-induced thrombocytopenia (HIT) and vaccine-induced thrombotic thrombocytopenia (VITT) and infections including influenza and SARS-CoV-2 are facilitated by circulating ICs. In fact, the induction of platelet release via IC activity has been known since the 1950s [30].
Since the topic of this review is the contribution of NETs to thrombotic processes, the role of ICs on other Fc-expressing granulocytes is not discussed in detail. However, it should be noted that ICs also induce processes analogous to NETosis in monocytes [31]. Monocyte extracellular traps (ETs) possess a procoagulant activity, suggesting a role for these monocyte-derived structures in thrombosis (reviewed by Han et al. [32]). The more generalised nature of ET formation and its association with thrombosis is exemplified by observations of ETs of macrophage, mast cell, and eosinophil origin in coronary thrombi [33].
IgG, and more specifically IgG1, is the most common type of immunoglobulin in human serum [25]. IgG ICs have been more widely described, and it is reasonable to assume that IgG ICs are also the most abundant. Lupus erythematosus is an extensively studied autoimmune disease characterised by the presence of autoantibodies against numerous endogenous antigens including dsDNA, ribonucleoprotein, phospholipids, histones, and β2-glycoprotein I. Most of these autoantibodies are of the IgG class [34]. DNA-containing Ics found in lupus patients signal through FcγRIIA and induce ROS production in neutrophils [35]. This is reminiscent of ROS-dependent neutrophil activation, NETosis, and thrombosis induced by FcγRIIA-activating HIT Ics [36].
ADAMTS-13 Ics in thrombotic thrombocytopenic purpura are correlated with relapse [37] and markers of NETosis such as histone/DNA complexes, cell-free DNA, and citrullinated histones are present in plasma from these patients [38], suggesting a contribution of ICs in the inductions of NETosis and thrombosis in this condition. IgG ICs are also present in granulomatosis (antineutrophil cytoplasmic antibodies [39]), SARS-CoV-2 infection [40], rheumatoid arthritis [41], HIT, and VITT [15,16] (Table 1).
Thrombosis is also driven by IgA ICs (Table 1). Antibody specificity and signalling is dependent on the isotype, where IgG binds to FcγR while IgA binds to FcαR. In the context of IgG signalling, unlike low-affinity FcγRs, only high-affinity FcγRs (i.e., FcγR1) can bind monomeric IgG. All FcγRs can, however, bind to IgG aggregates or immune complexes containing IgG [42]. Similarly, monomeric IgA binds poorly to FcαR1, while large IgA complexes bind with a high avidity, leading to phagocytosis, antigen presentation [43], cytokine release [44], reactive oxygen species production [45], and NETosis [46,47,48].
The proinflammatory IgA immune complex-mediated FcαR signalling is a key pathogenic feature in IgA vasculitis (or Henoch–Schönlein purpura), an inflammatory condition where the immune system attacks the lining of blood vessels. Recently, Mayer-Hain et al. showed the requirement of neutrophil prestimulation by polymeric IgA or IgA ICs to lower the threshold for neutrophil activation. This step is critical for neutrophils to become activated and undergo NETosis upon binding to activated endothelial cells, resulting in vessel wall damage [46]. Interestingly, neutrophils isolated from IgA vasculitis patients spontaneously underwent NETosis, and NETs were proximal to endothelial cells and IgA-coated neutrophils in tissue sections of these patients [46]. A significant reduction in vessel damage in a mouse model of vasculitis was observed following NET inhibition, suggesting that NETosis is key a mediator of vasculitis pathogenesis. Although uncommon, cases of coagulation abnormalities and thrombosis have been documented in IgA vasculitis [49]. Altogether, IgA ICs prestimulate neutrophils and NETosis is a key mediator of vessel wall damage in IgA vasculitis.
The presence of IgA autoantibodies is also associated with increased disease severity, enhanced cartilage damage, and worse disease prognosis in rheumatoid arthritis [50,51,52]. The activation of neutrophils by IgA ICs, present in rheumatoid arthritis patients’ plasma and synovial fluid, leads them to undergo NETosis and secrete chemoattractants that amplify neutrophil recruitment [47] and promotes cartilage damage via neutrophil elastase [48]. IgA IC-induced NETosis can be blocked by anti-FcαR1 monoclonal antibody [47], suggesting FcαR1 inhibitors could potentially reduce cartilage damage and disability in rheumatoid arthritis patients. In antiphospholipid syndrome (APS), β2-glycoprotein I/IgA IC is strongly linked to thrombosis following transplantation [53]. NETosis is likely to be of pathological significance since NETs are known to contribute to thrombosis in APS [54].
NETosis has been well documented in bacterial (e.g., Staphylococcus aureus [55]) and viral (e.g., influenza A, HIV, SARS-CoV-2 [21]) infections. NETs exert both antimicrobial [56] and antiviral [21] activity. IgA-bacteria ICs activate FcαRI and enhance the phagocytosis of IgA-opsonized bacteria [57]. Interestingly, the phagocytosis of S. aureus is more efficient in the presence of IgA [58]. Both bacterial and viral IgA IC-induced NETosis are dependent on FcαRI and NADPH oxidase [21,58]. A lower virus titre is required to trigger NETosis in the presence of IgA compared to virus alone, and NETosis is independent of phagocytosis. Unlike NETosis induced by virus alone, IgA-virus ICs-induced NETosis does not require toll-like receptor signalling [21]. Although NETosis plays a protective role in infection, the release of reactive oxygen species, proteolytic enzymes and inflammatory mediators can enhance neutrophil infiltration and elicit tissue damage. This can result in the enhancement of disease pathogenesis in conditions such as respiratory syncytial virus [59], rhinovirus [60], influenza [61], and COVID-19 [62,63,64].
Table 1. Fc receptors implicated in IgG- and IgA-immune complex-mediated NETosis.
Table 1. Fc receptors implicated in IgG- and IgA-immune complex-mediated NETosis.
ConditionFc Receptor InvolvedReceptor Binding SpecificityAntigen-Antibody ComplexReference
Influenza AFcαR1 (CD89)IgAInfluenza—IgAStacey et al. [21]
Human immunodeficiency virus (HIV)FcαR1 (CD89)IgAHIV—IgAStacey et al. [21]
SARS-CoV-2FcαR1 (CD89)
FcγRIIA (CD32a)		IgA
IgG		SARS-CoV2—IgA
Spike protein—IgG		Stacey et al. [21]
Bye et al. [65]
Staphylococcus aureusFcαR1 (CD89)IgAS. aureus—IgAAleyd et al. [58]
VasculitisFcαR1 (CD89)IgAAggregated vasculitis—IgAMayer-Hain et al. [46]
Rheumatoid arthritisFcαR1 (CD89), FcγRI (CD64), FcγRIIA (CD32a)IgA, IgGRheumatoid factor—IgA/IgG, citrullinated protein—anticitrullinated protein antibody (ACPA) IgG, cyclic citrullinated peptide—IgA/IgG, antineutrophil cytoplasmic antibodies (ANCA)—IgA/IgGMathsson et al. [41]; Aleyd et al. [47];
Kempers et al. [66]
Granulomatosis with polyangiitis (Wegener’s granulomatosis)FcαR1 (CD89), FcγRIIIB (CD16b)IgA, IgGAntineutrophil cytoplasmic antibodies (ANCA)—IgA/IgGKelley et al. [39]
Heparin-induced thrombocytopenia (HIT)FcγRIIA (CD32a)IgGHeparin—PF4 -HIT IgGKelton et al. [67]; Chong et al. [68]
Vaccine-induced thrombotic thrombocytopenia (VITT)FcγRIIA (CD32a)IgGPF4—VITT IgGGreinacher et al. [69]
Autoimmune inflammatory disorderFcγRIIA (CD32a), FcγRIIIB (CD16b)IgGBovine serum albumin (BSA)—IgG, human serum albumin (HAS)—IgG, cross linking—FcγRIIIBAleman et al. [29]; Behnen et al. [22]
Systemic lupus erythematosus (SLE)FcγRIIA (CD32a)IgGDNA—IgGBonegio et al. [35]; Bruneau et al. [70]; Patiño-Trives et al. [71]; Dema and Charles [34].

3. Mechanisms of Neutrophil Activation

The expression of Fc receptors by neutrophils is indicative of the role of these receptors in NETs formation. Chen and colleagues first showed that the engagement of FcγRIIA by soluble ICs resulted in NETosis in transgenic mice [28]. In this setting, FcγRIIIb acted in the removal of ICs by internalization but did not lead to neutrophil activation. Nevertheless, Alemán et al. showed that FcγRIIIB cross-linking with a monoclonal antibody induced NETs formation in human neutrophils [29]. FcγRIIIB-mediated activation involved ERK1 and transforming growth factor-β-activated kinase 1 phosphorylation [29]. The same authors demonstrated that neither cross-linking of FcγRIIA with the IV.3 monoclonal antibody nor activation with PMA induced transforming growth factor-β-activated kinase 1 phosphorylation, despite the induction of ERK1 phosphorylation by PMA [29]. This illustrates the various signalling pathways that lead to NETs formation following neutrophil activation. Immobilised ICs also induced NETs via FcγRIIIB in a NADPH-dependent manner involving the Src/Syk pathway [22], suggesting a role in NETs formation for both FcγRIIA and FcγRIIIB (Figure 1). These observations did not define whether both receptors are required or if there is a main receptor implicated in NETosis. In the case of ICs from HIT patients, however, Xiao et al. showed neutrophil activation via FcγRIIA without the involvement of FcγRIIIB [72]. Consistent with these findings, IgG ICs from HIT and VITT patients were shown to engage FcγRIIA exclusively to promote NETs formation and thrombosis [15,16]. HIT IC-FcγRIIA interaction led to ROS production in both platelets and neutrophils. The potential clinical relevance of these findings was supported by observations of increased ROS production in activated neutrophils (known as low-density granulocytes) from patients with active HIT. Moreover, ROS inhibition abrogated NETs formation in human blood and was sufficient to block thrombosis in a mouse model of HIT [36].
Platelets have long been considered significant contributors of thrombosis. This led to the development and wide use of various antiplatelet drugs as primary and secondary prevention of recurring thrombotic complications, particularly following myocardial infarction and ischemic stroke. Platelets can be activated by various stimuli such as immune complexes [16], viruses (e.g., SARS-CoV-2) [73], and vascular injury [74] resulting in either a direct or indirect activation of neutrophils. With the former, activated platelets can bind and activate neutrophils via various corresponding receptors such as P-selectin/PSGL1, GP1bα/Mac-1, αIIβ3/Mac-1, ICAM-2/Mac-1, CD40L/CD40, and GPIIb/IIIa/SLC44A2 [75,76] although P-selectin/PSGL1 has been the most prominent interaction found to be involved in direct platelet-induced NETosis [15,18] (Figure 1). Crosstalk between platelets and neutrophils enhance the thrombotic process as neutrophils become activated and consequently undergo NETosis [15], while NETs in turn can promote platelet activation [77,78,79], further perpetuating the thrombotic condition. Circulating neutrophil/platelet complexes have been found associated with inflammation, thrombosis, and sepsis [15,16,80,81]. Platelets can also secrete molecules that activate neutrophils to undergo NETosis such as HMGB1, considered a critical mediator of thrombosis and further promoting platelet aggregation [19,82,83].
The glycocalyx of the vascular endothelium provides an anticoagulant separation barrier between blood and tissues. Endothelial inflammation (thromboinflammation) involves the upregulation of adhesion molecules including E-selectin, P-selectin, and intracellular adhesion molecule-1 (ICAM-1) [84], which are critical in the development of thrombotic diseases including stroke and cardiovascular events. Neutrophils are attracted to damaged endothelium, attach via integrins such as Mac-1 [85], and stimulate further inflammation, the formation of neutrophil-platelet aggregates and promote atherosclerosis [86]. NETs stimulate endothelial inflammation through the activity of NETs components such as cathepsin G [87]. In vitro, purified NETs were shown to induce endothelial cell activation [87] in the absence of neutrophils. Franck at al. found that PAD4 deficiency (or DNAse I treatment) prevented endothelial injury and caused a reduction in thrombus formation. This endothelial cell death and detachment was promoted by NETs and mediated by complement activity [88]. Complement function, however, may be dispensable for NETs-mediated damage since ICs can induce vascular inflammation via Fc receptors in the absence of complement [89]. The role of NETs in the endothelium is also supported by observations of inflammation and occlusion in COVID-19 patients associated with NETs formation [90]. Platelets also attach to damaged endothelium and contribute to neutrophil recruitment and further NETs formation and inflammation [84].

4. Immune Complexes, NETs, and Immune Thrombosis

Thrombosis is the immediate cause of stroke, myocardial infarction, embolism, and deep vein thrombosis. As such, it is one of the principal causes of morbidity and mortality worldwide. More recently, a subtype of thrombus formation in blood vessels resulting from the activity of leukocytes, platelets, and the endothelium has become known as immunothrombosis [91] or thromboinflammation. A common example of immunothrombosis occurs in cases of systemic infection, where generalised inflammation, leukocyte, and platelet activation lead to thrombosis, which contributes to multiple organ failure. NETs contribute to thrombosis by promoting thrombin generation through tissue factor activity, the activation of factor XII and the interaction and activation of platelets via histone activity. NETs also contribute to thrombus stability by providing a DNA scaffold and inhibiting fibrinolysis. The presence of NETs in coronary artery [92,93], stroke [94] and infection-related thrombi [90] provides compelling evidence for the involvement of neutrophils in distinct types of thrombosis (Table 2).
An early example of IgG ICs generating NETs was provided by Kelley et al. [39]. The authors showed that antineutrophil cytoplasmic antibodies (ANCA) induced NETs via interaction with Fc receptors [39]. Some ANCA antibodies, such as anti PR3 antibodies, may also induce NETs formation independently of Fc interaction [95]. Patients with ANCA antibodies present with vasculitis and have increased incidence of venous thromboembolism [96] and arterial thrombotic events. In fact, NETs formation not only contributes to inflammation in ANCA vasculitis, but also generates autoantigens, such as myeloperoxidase, that contribute to a further development of ANCA antibodies [97].
Autoantibodies from APS patients, such as anti β2-glycoprotein I antibodies, induce NETs release mediated by TLR4 signalling [54] and NETs formation was required for thrombosis in a mouse model of APS [98]. Likewise, an enhanced risk of cardiovascular events in lupus erythematosus patients is associated with the presence of complexes such as DNA/anti-dsDNA antibody ICs. Importantly, these ICs induced NETs formation in a Fc receptor-dependent manner and stimulated endothelial cell activation in vitro [71]. Patients with rheumatoid arthritis are at higher risk of deep vein thrombosis and embolism. Some ICs associated with this disease activate FcγRIIA and induce the expression of TNF-α [41]. This is likely associated with endothelial inflammation and induce NETs formation.
Experimental evidence for the role of ICs in thrombosis has been provided by our studies of HIT and VITT IC-mediated thrombosis [15,16,36]. These studies demonstrated that IgG ICs activate both platelets and neutrophils via FcγRIIA interaction. An important observation from these studies is the indispensable requirement of neutrophils in IC-mediated thrombosis. Ex vivo, thrombosis was inhibited when using neutrophil-depleted blood, despite the presence of platelets. In vivo, ICs were unable to induce thrombosis in the absence of NETosis. Together, the data suggest that IC-induced NETosis is required for thrombosis in HIT and VITT. Unexpectedly, the absence of platelets did not preclude thrombus formation in the HIT mouse model. The interaction of ICs with FcγRIIA on platelets caused thrombocytopenia in HIT and VITT but did not lead to thrombus formation when neutrophil activity was inhibited [15,16]. In this context, other Fc receptors were dispensable since blockage of FcγRIIA was sufficient to prevent NETs formation, thrombocytopenia and thrombosis.
NETs formation is also common in viral infections and is critical in the pathology of COVID-19 [99,100,101,102]. IgG-spike protein complexes can activate platelets via FcγRIIA [65], which is indicative of IC formation. In fact, IgG ICs have been associated with the inflammatory response and disease severity [103]. The involvement of NETs in COVID-19-related thrombosis is supported by observations of neutrophils and NETs in pulmonary thrombi [63]. The induction of NETs in the context of COVID-19 is mediated, at least in part, by platelet–neutrophil interactions [63].
Table 2. Various NETs formation-associated stimuli.
Table 2. Various NETs formation-associated stimuli.
ConditionCommentsReferences
CardiovascularAMI patients. Neutrophils are activated in acute coronary syndrome. NETs are formed at culprit lesion site.
Stroke patients. Neutrophils and NETs markers detected in retrieved stroke thrombi. NETs are associated with severity and mortality.
DVT patients. Elevated levels of activated neutrophils and circulating nucleosomes increase risk of DVT.
DVT mouse model. NETs promote thrombus formation.		[19,78,94,104,105,106,107,108,109,110]
DiabetesType I diabetes patients and mice. Type II diabetes patients. Platelet/neutrophil aggregates present. Neutrophils are primed to undergo NETosis.
Homocysteine elevated in diabetic patients and correlates with NETosis.		[111,112,113,114]
AutoimmunityAPS patients. APS antibodies promote NETs and thrombosis.
HIT patients and mouse model. NETs are essential for thrombosis.
VITT patients and mouse model. NETs mediate thrombosis.
Rheumatoid arthritis patients. NETs mediate cartilage damage.
Psoriasis patients. NETs promote inflammation.
Lupus erythematosus. Anti-DNA antibodies promote NETosis. Association with endothelial disfunction and cardiovascular disease.		[15,16,47,54,71,115,116,117]
CancerPancreatic adenocarcinoma. NETs contribute to cell migration and invasion.
Gastric cancer patients. NETs are involved in metastasis.
Breast cancer patients and mouse model. NETs contribute to cancer-associated thrombosis.
Chronic myelogenous leukemia mouse model. Neutrophils in CML mice more susceptible to NET formation.		[118,119,120,121,122,123]
InfectionSepsis patients and mouse model. NETs and NETs components promote coagulation and death.
Influenza A patients. Virus-IgA complexes stimulate NETosis and inactivate viruses. NETs induce inflammation.
HIV-1 patients. Virus-IgA complexes stimulate NETosis and inactivate viruses. NETs induce inflammation.
SARS-CoV2. NETs mediate severe COVID-19 pathology.
CHIKV patients. NETs limit viral load.
Hantaan virus. Strong NETs stimulation. May contribute to kidney and lung damage.
Dengue virus. Viral exosomes induce NETs and promote proinflammatory cytokine release.
S. aureus. NETs promote intravascular coagulation.
A. fumigatus
C. albicans. NETs mediate fungal killing.
E. coli. NETs promote intravascular coagulation.		[2,21,99,100,101,102,124,125,126,127,128,129,130,131,132,133]
AMI, acute myocardial infarction; DVT, deep vein thrombosis; APS, antiphospholipid syndrome; HIT, heparin-induced thrombocytopenia; VITT, vaccine-induced thrombotic thrombocytopenia; CHIKV, Chikungunya virus.

5. NETs Targeting in Immune Thrombosis

Several pathways of NETs formation have already been targeted both pharmacologically and genetically. NETs formation has been prevented by inhibitors of PAD4 (CI-amidine, GSK-484), MPO (PF-1355), elastase (AZD9668), ROS and NOX (DPI), and other compounds (reviewed in [134]). The usefulness of these inhibitors is tempered by certain shortcomings. For instance, PAD4 mice are more susceptible to infection, and the inhibition of ROS production may also have detrimental effects on infections. NETs breakdown with DNase I reduces thrombosis but releases harmful NETs products such as histones and MPO that may cause further tissue damage. Other drugs in clinical use that may inhibit NETosis, albeit more indirectly, include heparin, metformin, clopidogrel, and anti-IL-1β antibody [135]. All these therapies, however, are directed to either NETs themselves, NETs components or signalling pathways. Targeted therapies that would prevent Fc receptor interaction with pathogenic ICs are likely to be more effective and with potentially fewer side effects. Fc receptor blockage has been proposed, and therapies have been developed, for several immune conditions. For instance, intravenous immunoglobulins work, in part, by the overloading and blockage of Fc receptors [136]. Similarly, Fc receptor blockage using Fc fragments has also been used to treat immune thrombocytopenia (ITP) [137]. Even though toxicity was observed following the use of anti-FcγRIIIA blocking antibody in ITP, this was due to the high affinity of the antibody causing receptor cross-linking. This can be overcome by the engineering of antibody fragments with a lower binding affinity [138]. The blockage of FcγRIIA by the monoclonal antibody IV.3 has been shown to completely prevent NETosis and thrombosis mediated by FcγRIIA-activating ICs in vitro and in mouse models of thrombosis [15,16]. This represents a proof-of-concept of the viability of Fc receptor inhibition to prevent immune thrombosis. Recently, an FcRn-blocking antibody fragment (modified Fc fragment) was approved for use for the treatment of myasthenia gravis, an autoimmune neuromuscular disease [139]. This is promising for the future development of Fc blocking agents to prevent IC-mediated cell activation.

6. Conclusions

The conventional concept of thrombosis surmises that thrombi are formed due to platelet and coagulation activation. The partial efficacy of anticoagulants and antiplatelets suggest that additional aspects are involved. The pathogenesis of immune thrombosis has evolved significantly over recent decades, with the discovery of NETosis illustrating that mechanisms of thrombosis are multicellular and complex. The growing recognition of NETs involvement in conditions such as infection, cardiovascular disease, cancer, diabetes, and autoimmunity has resulted in an improved understanding of disease mechanisms and the discovery of potential biomarkers and novel therapies. Various NETs inhibitors have been studied in a multitude of conditions, including recently developed oral PAD4 inhibitors. Due to the involvement of autoantibodies and ICs in immune thrombosis, further studies are needed to design therapies that can prevent the interaction of these complexes to receptors on platelets and neutrophils to prevent cell activation and the development of NETosis, thus hindering one of the initial steps of thrombus formation. By continuing to examine the interactions between ICs, Fc receptors, and NETs, more effective treatments are likely to emerge with the aim of reducing thrombotic burden in patients with immune thrombosis.

Author Contributions

J.P. and H.H.L.L. contributed to all aspects of this manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the New South Wales Health Cardiovascular Collaborative Grant to H.H.L.L.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Not available.

References

  1. Takei, H.; Araki, A.; Watanabe, H.; Ichinose, A.; Sendo, F. Rapid killing of human neutrophils by the potent activator phorbol 12-myristate 13-acetate (PMA) accompanied by changes different from typical apoptosis or necrosis. J. Leukoc. Biol. 1996, 59, 229–240. [Google Scholar] [CrossRef] [PubMed]
  2. Brinkmann, V.; Reichard, U.; Goosmann, C.; Fauler, B.; Uhlemann, Y.; Weiss, D.S.; Weinrauch, Y.; Zychlinsky, A. Neutrophil extracellular traps kill bacteria. Science 2004, 303, 1532–1535. [Google Scholar] [CrossRef]
  3. Pilsczek, F.H.; Salina, D.; Poon, K.K.H.; Fahey, C.; Yipp, B.G.; Sibley, C.D.; Robbins, S.M.; Green, F.H.Y.; Surette, M.G.; Sugai, M.; et al. A Novel Mechanism of Rapid Nuclear Neutrophil Extracellular Trap Formation in Response to Staphylococcus aureus. J. Immunol. 2010, 185, 7413–7425. [Google Scholar] [CrossRef] [PubMed]
  4. Malawista, S.E.; Van Blaricom, G.; Breitenstein, M.G. Cryopreservable neutrophil surrogates. Stored cytoplasts from human polymorphonuclear leukocytes retain chemotactic, phagocytic, and microbicidal function. J. Clin. Investig. 1989, 83, 728–732. [Google Scholar] [CrossRef] [PubMed]
  5. Yipp, B.G.; Kubes, P. NETosis: How vital is it? Blood 2013, 122, 2784–2794. [Google Scholar] [CrossRef] [PubMed]
  6. Burgener, S.S.; Schroder, K. Neutrophil Extracellular Traps in Host Defense. Cold Spring Harb. Perspect. Biol. 2020, 12, a037028. [Google Scholar] [CrossRef]
  7. Chen, K.W.; Monteleone, M.; Boucher, D.; Sollberger, G.; Ramnath, D.; Condon, N.D.; von Pein, J.B.; Broz, P.; Sweet, M.J.; Schroder, K. Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps. Sci. Immunol. 2018, 3, eaar6676. [Google Scholar] [CrossRef]
  8. Csomós, K.; Kristóf, E.; Jakob, B.; Csomós, I.; Kovács, G.; Rotem, O.; Hodrea, J.; Bagoly, Z.; Muszbek, L.; Balajthy, Z.; et al. Protein cross-linking by chlorinated polyamines and transglutamylation stabilizes neutrophil extracellular traps. Cell Death Dis. 2016, 7, e2332. [Google Scholar] [CrossRef]
  9. Zhu, Y.; Chen, X.; Liu, X. NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond. Front. Immunol. 2022, 13, 838011. [Google Scholar] [CrossRef]
  10. Warnatsch, A.; Ioannou, M.; Wang, Q.; Papayannopoulos, V. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 2015, 349, 316–320. [Google Scholar] [CrossRef]
  11. Jung, C.J.; Yeh, C.Y.; Hsu, R.B.; Lee, C.M.; Shun, C.T.; Chia, J.S. Endocarditis pathogen promotes vegetation formation by inducing intravascular neutrophil extracellular traps through activated platelets. Circulation 2015, 131, 571–581. [Google Scholar] [CrossRef]
  12. Carestia, A.; Kaufman, T.; Rivadeneyra, L.; Landoni, V.I.; Pozner, R.G.; Negrotto, S.; D’Atri, L.P.; Gómez, R.M.; Schattner, M. Mediators and molecular pathways involved in the regulation of neutrophil extracellular trap formation mediated by activated platelets. J. Leukoc. Biol. 2016, 99, 153–162. [Google Scholar] [CrossRef] [PubMed]
  13. Yalcinkaya, M.; Fotakis, P.; Liu, W.; Endo-Umeda, K.; Dou, H.; Abramowicz, S.; Xiao, T.; Libby, P.; Wang, N.; Tall, A.R.; et al. Cholesterol accumulation in macrophages drives NETosis in atherosclerotic plaques via IL-1β secretion. Cardiovasc. Res. 2023, 119, 969–981. [Google Scholar] [CrossRef] [PubMed]
  14. Garcia-Romo, G.S.; Caielli, S.; Vega, B.; Connolly, J.; Allantaz, F.; Xu, Z.; Punaro, M.; Baisch, J.; Guiducci, C.; Coffman, R.L.; et al. Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 2011, 3, 73ra20. [Google Scholar] [CrossRef] [PubMed]
  15. Perdomo, J.; Leung, H.H.L.; Ahmadi, Z.; Yan, F.; Chong, J.J.H.; Passam, F.H.; Chong, B.H. Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia. Nat. Commun. 2019, 10, 1322. [Google Scholar] [CrossRef] [PubMed]
  16. Leung, H.H.L.; Perdomo, J.; Ahmadi, Z.; Zheng, S.S.; Rashid, F.N.; Enjeti, A.; Ting, S.B.; Chong, J.J.H.; Chong, B.H. NETosis and thrombosis in vaccine-induced immune thrombotic thrombocytopenia. Nat. Commun. 2022, 13, 5206. [Google Scholar] [CrossRef]
  17. Holm, S.; Kared, H.; Michelsen, A.E.; Kong, X.Y.; Dahl, T.B.; Schultz, N.H.; Nyman, T.A.; Fladeby, C.; Seljeflot, I.; Ueland, T.; et al. Immune complexes, innate immunity, and NETosis in ChAdOx1 vaccine-induced thrombocytopenia. Eur. Heart J. 2021, 42, 4064–4072. [Google Scholar] [CrossRef]
  18. Etulain, J.; Martinod, K.; Wong, S.L.; Cifuni, S.M.; Schattner, M.; Wagner, D.D. P-selectin promotes neutrophil extracellular trap formation in mice. Blood 2015, 126, 242–246. [Google Scholar] [CrossRef]
  19. Maugeri, N.; Campana, L.; Gavina, M.; Covino, C.; De Metrio, M.; Panciroli, C.; Maiuri, L.; Maseri, A.; D’Angelo, A.; Bianchi, M.E.; et al. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extracellular traps. J. Thromb. Haemost. 2014, 12, 2074–2088. [Google Scholar] [CrossRef]
  20. Chen, T.; Li, Y.; Sun, R.; Hu, H.; Liu, Y.; Herrmann, M.; Zhao, Y.; Muñoz, L.E. Receptor-Mediated NETosis on Neutrophils. Front. Immunol. 2021, 12, 775267. [Google Scholar] [CrossRef]
  21. Stacey, H.D.; Golubeva, D.; Posca, A.; Ang, J.C.; Novakowski, K.E.; Zahoor, M.A.; Kaushic, C.; Cairns, E.; Bowdish, D.M.E.; Mullarkey, C.E.; et al. IgA potentiates NETosis in response to viral infection. Proc. Natl. Acad. Sci. USA 2021, 118, e2101497118. [Google Scholar] [CrossRef] [PubMed]
  22. Behnen, M.; Leschczyk, C.; Möller, S.; Batel, T.; Klinger, M.; Solbach, W.; Laskay, T. Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcγRIIIB and Mac-1. J. Immunol. 2014, 193, 1954–1965. [Google Scholar] [CrossRef] [PubMed]
  23. Cochrane, C.G.; Koffler, D. Immune complex disease in experimental animals and man. Adv. Immunol. 1973, 16, 185–264. [Google Scholar] [CrossRef] [PubMed]
  24. Otten, M.A.; van Egmond, M. The Fc receptor for IgA (FcalphaRI, CD89). Immunol. Lett. 2004, 92, 23–31. [Google Scholar] [CrossRef]
  25. Vidarsson, G.; Dekkers, G.; Rispens, T. IgG subclasses and allotypes: From structure to effector functions. Front. Immunol. 2014, 5, 520. [Google Scholar] [CrossRef]
  26. Voice, J.K.; Lachmann, P.J. Neutrophil Fc gamma and complement receptors involved in binding soluble IgG immune complexes and in specific granule release induced by soluble IgG immune complexes. Eur. J. Immunol. 1997, 27, 2514–2523. [Google Scholar] [CrossRef]
  27. Mkaddem, S.B.; Murua, A.; Flament, H.; Titeca-Beauport, D.; Bounaix, C.; Danelli, L.; Launay, P.; Benhamou, M.; Blank, U.; Daugas, E.; et al. Lyn and Fyn function as molecular switches that control immunoreceptors to direct homeostasis or inflammation. Nat. Commun. 2017, 8, 246. [Google Scholar] [CrossRef]
  28. Chen, K.; Nishi, H.; Travers, R.; Tsuboi, N.; Martinod, K.; Wagner, D.D.; Stan, R.; Croce, K.; Mayadas, T.N. Endocytosis of soluble immune complexes leads to their clearance by FcγRIIIB but induces neutrophil extracellular traps via FcγRIIA in vivo. Blood 2012, 120, 4421–4431. [Google Scholar] [CrossRef]
  29. Alemán, O.R.; Mora, N.; Cortes-Vieyra, R.; Uribe-Querol, E.; Rosales, C. Transforming Growth Factor-β-Activated Kinase 1 Is Required for Human FcγRIIIb-Induced Neutrophil Extracellular Trap Formation. Front. Immunol. 2016, 7, 277. [Google Scholar] [CrossRef]
  30. Humphrey, J.H.; Jaques, R. The release of histamine and 5-hydroxytryptamine (serotonin) from platelets by antigen-antibody reactions (in vitro). J. Physiol. 1955, 128, 9–27. [Google Scholar] [CrossRef]
  31. Granger, V.; Faille, D.; Marani, V.; Noël, B.; Gallais, Y.; Szely, N.; Flament, H.; Pallardy, M.; Chollet-Martin, S.; de Chaisemartin, L. Human blood monocytes are able to form extracellular traps. J. Leukoc. Biol. 2017, 102, 775–781. [Google Scholar] [CrossRef] [PubMed]
  32. Han, Z.; Liu, Q.; Li, H.; Zhang, M.; You, L.; Lin, Y.; Wang, K.; Gou, Q.; Wang, Z.; Zhou, S.; et al. The role of monocytes in thrombotic diseases: A review. Front. Cardiovasc. Med. 2023, 10, 1113827. [Google Scholar] [CrossRef]
  33. Pertiwi, K.R.; de Boer, O.J.; Mackaaij, C.; Pabittei, D.R.; de Winter, R.J.; Li, X.; van der Wal, A.C. Extracellular traps derived from macrophages, mast cells, eosinophils and neutrophils are generated in a time-dependent manner during atherothrombosis. J. Pathol. 2019, 247, 505–512. [Google Scholar] [CrossRef]
  34. Dema, B.; Charles, N. Autoantibodies in SLE: Specificities, Isotypes and Receptors. Antibodies 2016, 5, 2. [Google Scholar] [CrossRef] [PubMed]
  35. Bonegio, R.G.; Lin, J.D.; Beaudette-Zlatanova, B.; York, M.R.; Menn-Josephy, H.; Yasuda, K. Lupus-Associated Immune Complexes Activate Human Neutrophils in an FcγRIIA-Dependent but TLR-Independent Response. J. Immunol. 2019, 202, 675–683. [Google Scholar] [CrossRef] [PubMed]
  36. Leung, H.H.L.; Perdomo, J.; Ahmadi, Z.; Yan, F.; McKenzie, S.E.; Chong, B.H. Inhibition of NADPH oxidase blocks NETosis and reduces thrombosis in heparin-induced thrombocytopenia. Blood Adv. 2021, 5, 5439–5451. [Google Scholar] [CrossRef]
  37. Mancini, I.; Ferrari, B.; Valsecchi, C.; Pontiggia, S.; Fornili, M.; Biganzoli, E.; Peyvandi, F. ADAMTS13-specific circulating immune complexes as potential predictors of relapse in patients with acquired thrombotic thrombocytopenic purpura. Eur. J. Intern. Med. 2017, 39, 79–83. [Google Scholar] [CrossRef]
  38. Sui, J.; Lu, R.; Halkidis, K.; Kocher, N.K.; Cao, W.; Marques, M.B.; Zheng, X.L. Plasma levels of S100A8/A9, histone/DNA complexes, and cell-free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura. J. Thromb. Haemost. 2021, 19, 370–379. [Google Scholar] [CrossRef]
  39. Kelley, J.M.; Monach, P.A.; Ji, C.; Zhou, Y.; Wu, J.; Tanaka, S.; Mahr, A.D.; Johnson, S.; McAlear, C.; Cuthbertson, D.; et al. IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis. Proc. Natl. Acad. Sci. USA 2011, 108, 20736–20741. [Google Scholar] [CrossRef]
  40. Mazzitelli, I.; Bleichmar, L.; Ludueña, M.G.; Pisarevsky, A.; Labato, M.; Chiaradia, V.; Finocchieto, P.; Paulin, F.; Hormanstorfer, M.; Baretto, M.C.; et al. Immunoglobulin G Immune Complexes May Contribute to Neutrophil Activation in the Course of Severe Coronavirus Disease 2019. J. Infect. Dis. 2021, 224, 575–585. [Google Scholar] [CrossRef]
  41. Mathsson, L.; Lampa, J.; Mullazehi, M.; Rönnelid, J. Immune complexes from rheumatoid arthritis synovial fluid induce FcγRIIa dependent and rheumatoid factor correlated production of tumour necrosis factor-α by peripheral blood mononuclear cells. Arthritis Res. Ther. 2006, 8, R64. [Google Scholar] [CrossRef] [PubMed]
  42. Bruhns, P.; Iannascoli, B.; England, P.; Mancardi, D.A.; Fernandez, N.; Jorieux, S.; Daeron, M. Specificity and affinity of human Fc gamma receptors and their polymorphic variants for human IgG subclasses. Blood 2009, 113, 3716–3725. [Google Scholar] [CrossRef] [PubMed]
  43. Chen, Y.W.; Lang, M.L.; Wade, W.F. Protein kinase C-alpha and -delta are required for FcalphaR (CD89) trafficking to MHC class II compartments and FcalphaR-mediated antigen presentation. Traffic 2004, 5, 577–594. [Google Scholar] [CrossRef] [PubMed]
  44. Wu, J.M.; Ji, C.Y.; Xie, F.L.; Langefeld, C.D.; Qian, K.; Gibson, A.W.; Edberg, J.C.; Kimberly, R.P. Fc alpha RI (CD89) Alleles determine the proinflammatory potential of serum IgA. J. Immunol. 2007, 178, 3973–3982. [Google Scholar] [CrossRef]
  45. Lang, M.L.; Kerr, M.A. Characterization of Fc alpha R-triggered Ca2+ signals: Role in neutrophil NADPH oxidase activation. Biochem. Biophys. Res. Commun. 2000, 276, 749–755. [Google Scholar] [CrossRef]
  46. Mayer-Hain, S.; Gebhardt, K.; Neufeld, M.; Ehrchen, J.M.; Molyneux, K.; Barratt, J.; Nattkemper, E.; Gerloff, D.; Roth, J.; Vogl, T.; et al. Systemic Activation of Neutrophils by Immune Complexes Is Critical to IgA Vasculitis. J. Immunol. 2022, 209, 1048–1058. [Google Scholar] [CrossRef]
  47. Aleyd, E.; Al, M.; Tuk, C.W.; van der Laken, C.J.; van Egmond, M. IgA Complexes in Plasma and Synovial Fluid of Patients with Rheumatoid Arthritis Induce Neutrophil Extracellular Traps via FcαRI. J. Immunol. 2016, 197, 4552–4559. [Google Scholar] [CrossRef] [PubMed]
  48. Carmona-Rivera, C.; Carlucci, P.M.; Goel, R.R.; James, E.; Brooks, S.R.; Rims, C.; Hoffmann, V.; Fox, D.A.; Buckner, J.H.; Kaplan, M.J. Neutrophil extracellular traps mediate articular cartilage damage and enhance cartilage component immunogenicity in rheumatoid arthritis. JCI Insight 2020, 5, 139388. [Google Scholar] [CrossRef] [PubMed]
  49. Mosalem, O.; Garcilazo, N.H.; Saleh, Y.; Abu Rous, F. Pulmonary embolism as the primary presentation of IgA vasculitis. BMJ Case Rep. 2020, 13, e235884. [Google Scholar] [CrossRef]
  50. He, Y.T.; Zha, Q.L.; Liu, D.Y.; Lu, A.P. Relations between serum IgA level and cartilage erosion in 436 cases of rheumatoid arthritis. Immunol. Investig. 2007, 36, 285–291. [Google Scholar] [CrossRef]
  51. Teitsson, I.; Withrington, R.H.; Seifert, M.H.; Valdimarsson, H. Prospective-Study of Early Rheumatoid-Arthritis.1. Prognostic Value of Iga Rheumatoid-Factor. Ann. Rheum. Dis. 1984, 43, 673–678. [Google Scholar] [CrossRef] [PubMed]
  52. Karimifar, M.; Moussavi, H.; Babaei, M.; Akbari, M. The association of immunoglobulin A, immunoglobulin G and anti-cyclic citrullinated peptide antibodies with disease activity in seronegative rheumatoid arthritis patients. J. Res. Med. Sci. 2014, 19, 823–826. [Google Scholar]
  53. Serrano, M.; Martínez-Flores, J.A.; Pérez, D.; García, F.; Cabrera-Marante, O.; Pleguezuelo, D.; Paz-Artal, E.; Morales, J.M.; González, E.; Serrano, A. β(2)-Glycoprotein I/IgA Immune Complexes: A Marker to Predict Thrombosis after Renal Transplantation in Patients with Antiphospholipid Antibodies. Circulation 2017, 135, 1922–1934. [Google Scholar] [CrossRef]
  54. Yalavarthi, S.; Gould, T.J.; Rao, A.N.; Mazza, L.F.; Morris, A.E.; Núñez-Álvarez, C.; Hernández-Ramírez, D.; Bockenstedt, P.L.; Liaw, P.C.; Cabral, A.R.; et al. Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: A newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol. 2015, 67, 2990–3003. [Google Scholar] [CrossRef] [PubMed]
  55. Fuchs, T.A.; Abed, U.; Goosmann, C.; Hurwitz, R.; Schulze, I.; Wahn, V.; Weinrauch, Y.; Brinkmann, V.; Zychlinsky, A. Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 2007, 176, 231–241. [Google Scholar] [CrossRef]
  56. Remijsen, Q.; Kuijpers, T.W.; Wirawan, E.; Lippens, S.; Vandenabeele, P.; Vanden Berghe, T. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ. 2011, 18, 581–588. [Google Scholar] [CrossRef]
  57. Bakema, J.E.; van Egmond, M. The human immunoglobulin A Fc receptor FcalphaRI: A multifaceted regulator of mucosal immunity. Mucosal Immunol. 2011, 4, 612–624. [Google Scholar] [CrossRef] [PubMed]
  58. Aleyd, E.; van Hout, M.W.; Ganzevles, S.H.; Hoeben, K.A.; Everts, V.; Bakema, J.E.; van Egmond, M. IgA enhances NETosis and release of neutrophil extracellular traps by polymorphonuclear cells via Fcα receptor I. J. Immunol. 2014, 192, 2374–2383. [Google Scholar] [CrossRef] [PubMed]
  59. Cortjens, B.; de Boer, O.J.; de Jong, R.; Antonis, A.F.; Sabogal Pineros, Y.S.; Lutter, R.; van Woensel, J.B.; Bem, R.A. Neutrophil extracellular traps cause airway obstruction during respiratory syncytial virus disease. J. Pathol. 2016, 238, 401–411. [Google Scholar] [CrossRef]
  60. Toussaint, M.; Jackson, D.J.; Swieboda, D.; Guedan, A.; Tsourouktsoglou, T.D.; Ching, Y.M.; Radermecker, C.; Makrinioti, H.; Aniscenko, J.; Bartlett, N.W.; et al. Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation. Nat. Med. 2017, 23, 681–691. [Google Scholar] [CrossRef]
  61. Narasaraju, T.; Yang, E.; Samy, R.P.; Ng, H.H.; Poh, W.P.; Liew, A.A.; Phoon, M.C.; van Rooijen, N.; Chow, V.T. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am. J. Pathol. 2011, 179, 199–210. [Google Scholar] [CrossRef]
  62. Barnes, B.J.; Adrover, J.M.; Baxter-Stoltzfus, A.; Borczuk, A.; Cools-Lartigue, J.; Crawford, J.M.; Dassler-Plenker, J.; Guerci, P.; Huynh, C.; Knight, J.S.; et al. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J. Exp. Med. 2020, 217, e20200652. [Google Scholar] [CrossRef] [PubMed]
  63. Middleton, E.A.; He, X.Y.; Denorme, F.; Campbell, R.A.; Ng, D.; Salvatore, S.P.; Mostyka, M.; Baxter-Stoltzfus, A.; Borczuk, A.C.; Loda, M.; et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 2020, 136, 1169–1179. [Google Scholar] [CrossRef]
  64. Radermecker, C.; Detrembleur, N.; Guiot, J.; Cavalier, E.; Henket, M.; d’Emal, C.; Vanwinge, C.; Cataldo, D.; Oury, C.; Delvenne, P.; et al. Neutrophil extracellular traps infiltrate the lung airway, interstitial, and vascular compartments in severe COVID-19. J. Exp. Med. 2020, 217, e20201012. [Google Scholar] [CrossRef]
  65. Bye, A.P.; Hoepel, W.; Mitchell, J.L.; Jégouic, S.; Loureiro, S.; Sage, T.; Vidarsson, G.; Nouta, J.; Wuhrer, M.; de Taeye, S.; et al. Aberrant glycosylation of anti-SARS-CoV-2 spike IgG is a prothrombotic stimulus for platelets. Blood 2021, 138, 1481–1489. [Google Scholar] [CrossRef]
  66. Kempers, A.C.; Nejadnik, M.R.; Rombouts, Y.; Ioan-Facsinay, A.; van Oosterhout, M.; Jiskoot, W.; Huizinga, T.W.J.; Toes, R.E.M.; Scherer, H.U. Fc gamma receptor binding profile of anti-citrullinated protein antibodies in immune complexes suggests a role for FcγRI in the pathogenesis of synovial inflammation. Clin. Exp. Rheumatol. 2018, 36, 284–293. [Google Scholar]
  67. Kelton, J.G.; Sheridan, D.; Santos, A.; Smith, J.; Steeves, K.; Smith, C.; Brown, C.; Murphy, W.G. Heparin-induced thrombocytopenia: Laboratory studies. Blood 1988, 72, 925–930. [Google Scholar] [CrossRef]
  68. Chong, B.H.; Fawaz, I.; Chesterman, C.N.; Berndt, M.C. Heparin-induced thrombocytopenia: Mechanism of interaction of the heparin-dependent antibody with platelets. Br. J. Haematol. 1989, 73, 235–240. [Google Scholar] [CrossRef]
  69. Greinacher, A.; Selleng, K.; Mayerle, J.; Palankar, R.; Wesche, J.; Reiche, S.; Aebischer, A.; Warkentin, T.E.; Muenchhoff, M.; Hellmuth, J.C.; et al. Anti-platelet factor 4 antibodies causing VITT do not cross-react with SARS-CoV-2 spike protein. Blood 2021, 138, 1269–1277. [Google Scholar] [CrossRef] [PubMed]
  70. Bruneau, C.D.; Edmonds, J.P.; Hughes, G.R.; Aarden, L. Detection and characterization of DNA-anti-DNA complexes in a patient with systemic lupus erythematosus. Clin. Exp. Immunol. 1977, 28, 433–436. [Google Scholar] [PubMed]
  71. Patiño-Trives, A.M.; Pérez-Sánchez, C.; Pérez-Sánchez, L.; Luque-Tévar, M.; Ábalos-Aguilera, M.C.; Alcaide-Ruggiero, L.; Arias-de la Rosa, I.; Román-Rodríguez, C.; Seguí, P.; Espinosa, M.; et al. Anti-dsDNA Antibodies Increase the Cardiovascular Risk in Systemic Lupus Erythematosus Promoting a Distinctive Immune and Vascular Activation. Arterioscler. Thromb. Vasc. Biol. 2021, 41, 2417–2430. [Google Scholar] [CrossRef] [PubMed]
  72. Xiao, Z.; Visentin, G.P.; Dayananda, K.M.; Neelamegham, S. Immune complexes formed following the binding of anti-platelet factor 4 (CXCL4) antibodies to CXCL4 stimulate human neutrophil activation and cell adhesion. Blood 2008, 112, 1091–1100. [Google Scholar] [CrossRef] [PubMed]
  73. Zhang, S.; Liu, Y.; Wang, X.; Yang, L.; Li, H.; Wang, Y.; Liu, M.; Zhao, X.; Xie, Y.; Yang, Y.; et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J. Hematol. Oncol. 2020, 13, 120. [Google Scholar] [CrossRef] [PubMed]
  74. Li, Z.; Delaney, M.K.; O’Brien, K.A.; Du, X. Signaling during platelet adhesion and activation. Arterioscler. Thromb. Vasc. Biol. 2010, 30, 2341–2349. [Google Scholar] [CrossRef]
  75. Mereweather, L.J.; Constantinescu-Bercu, A.; Crawley, J.T.B.; Salles, C., II. Platelet-Neutrophil Crosstalk in Thrombosis. Int. J. Mol. Sci. 2023, 24, 1266. [Google Scholar] [CrossRef]
  76. Hirsch, J.; Uzun, G.; Zlamal, J.; Singh, A.; Bakchoul, T. Platelet-neutrophil interaction in COVID-19 and vaccine-induced thrombotic thrombocytopenia. Front. Immunol. 2023, 14, 1186000. [Google Scholar] [CrossRef]
  77. von Brühl, M.L.; Stark, K.; Steinhart, A.; Chandraratne, S.; Konrad, I.; Lorenz, M.; Khandoga, A.; Tirniceriu, A.; Coletti, R.; Köllnberger, M.; et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J. Exp. Med. 2012, 209, 819–835. [Google Scholar] [CrossRef]
  78. Brill, A.; Fuchs, T.A.; Savchenko, A.S.; Thomas, G.M.; Martinod, K.; De Meyer, S.F.; Bhandari, A.A.; Wagner, D.D. Neutrophil extracellular traps promote deep vein thrombosis in mice. J. Thromb. Haemost. 2012, 10, 136–144. [Google Scholar] [CrossRef]
  79. Fuchs, T.A.; Brill, A.; Duerschmied, D.; Schatzberg, D.; Monestier, M.; Myers, D.D., Jr.; Wrobleski, S.K.; Wakefield, T.W.; Hartwig, J.H.; Wagner, D.D. Extracellular DNA traps promote thrombosis. Proc. Natl. Acad. Sci. USA 2010, 107, 15880–15885. [Google Scholar] [CrossRef]
  80. Page, C.; Pitchford, S. Neutrophil and platelet complexes and their relevance to neutrophil recruitment and activation. Int. Immunopharmacol. 2013, 17, 1176–1184. [Google Scholar] [CrossRef]
  81. Kirschenbaum, L.A.; Adler, D.; Astiz, M.E.; Barua, R.S.; Saha, D.; Rackow, E.C. Mechanisms of platelet-neutrophil interactions and effects on cell filtration in septic shock. Shock 2002, 17, 508–512. [Google Scholar] [CrossRef] [PubMed]
  82. Stark, K.; Philippi, V.; Stockhausen, S.; Busse, J.; Antonelli, A.; Miller, M.; Schubert, I.; Hoseinpour, P.; Chandraratne, S.; von Brühl, M.L.; et al. Disulfide HMGB1 derived from platelets coordinates venous thrombosis in mice. Blood 2016, 128, 2435–2449. [Google Scholar] [CrossRef] [PubMed]
  83. Vogel, S.; Bodenstein, R.; Chen, Q.; Feil, S.; Feil, R.; Rheinlaender, J.; Schäffer, T.E.; Bohn, E.; Frick, J.S.; Borst, O.; et al. Platelet-derived HMGB1 is a critical mediator of thrombosis. J. Clin. Investig. 2015, 125, 4638–4654. [Google Scholar] [CrossRef] [PubMed]
  84. Dehghani, T.; Panitch, A. Endothelial cells, neutrophils and platelets: Getting to the bottom of an inflammatory triangle. Open Biol. 2020, 10, 200161. [Google Scholar] [CrossRef]
  85. Dupuy, A.; Aponte-Santamaría, C.; Yeheskel, A.; Hortle, E.; Oehlers, S.H.; Gräter, F.; Hogg, P.J.; Passam, F.H.; Chiu, J. Mechano-Redox Control of Mac-1 De-Adhesion by PDI Promotes Directional Movement under Flow. Circ. Res. 2023, 132, e151–e168. [Google Scholar] [CrossRef]
  86. Gaul, D.S.; Stein, S.; Matter, C.M. Neutrophils in cardiovascular disease. Eur. Heart J. 2017, 38, 1702–1704. [Google Scholar] [CrossRef]
  87. Folco, E.J.; Mawson, T.L.; Vromman, A.; Bernardes-Souza, B.; Franck, G.; Persson, O.; Nakamura, M.; Newton, G.; Luscinskas, F.W.; Libby, P. Neutrophil Extracellular Traps Induce Endothelial Cell Activation and Tissue Factor Production through Interleukin-1α and Cathepsin G. Arterioscler. Thromb. Vasc. Biol. 2018, 38, 1901–1912. [Google Scholar] [CrossRef]
  88. Franck, G.; Mawson, T.L.; Folco, E.J.; Molinaro, R.; Ruvkun, V.; Engelbertsen, D.; Liu, X.; Tesmenitsky, Y.; Shvartz, E.; Sukhova, G.K.; et al. Roles of PAD4 and NETosis in Experimental Atherosclerosis and Arterial Injury: Implications for Superficial Erosion. Circ. Res. 2018, 123, 33–42. [Google Scholar] [CrossRef]
  89. Sylvestre, D.; Clynes, R.; Ma, M.; Warren, H.; Carroll, M.C.; Ravetch, J.V. Immunoglobulin G-mediated inflammatory responses develop normally in complement-deficient mice. J. Exp. Med. 1996, 184, 2385–2392. [Google Scholar] [CrossRef]
  90. Leppkes, M.; Knopf, J.; Naschberger, E.; Lindemann, A.; Singh, J.; Herrmann, I.; Stürzl, M.; Staats, L.; Mahajan, A.; Schauer, C.; et al. Vascular occlusion by neutrophil extracellular traps in COVID-19. eBioMedicine 2020, 58, 102925. [Google Scholar] [CrossRef]
  91. Engelmann, B.; Massberg, S. Thrombosis as an intravascular effector of innate immunity. Nat. Rev. Immunol. 2013, 13, 34–45. [Google Scholar] [CrossRef] [PubMed]
  92. Stakos, D.A.; Kambas, K.; Konstantinidis, T.; Mitroulis, I.; Apostolidou, E.; Arelaki, S.; Tsironidou, V.; Giatromanolaki, A.; Skendros, P.; Konstantinides, S.; et al. Expression of functional tissue factor by neutrophil extracellular traps in culprit artery of acute myocardial infarction. Eur. Heart J. 2015, 36, 1405–1414. [Google Scholar] [CrossRef] [PubMed]
  93. Chilingaryan, Z.; Deshmukh, T.; Leung, H.H.L.; Perdomo, J.; Emerson, P.; Kurup, R.; Chong, B.H.; Chong, J.J.H. Erythrocyte interaction with neutrophil extracellular traps in coronary artery thrombosis following myocardial infarction. Pathology 2022, 54, 87–94. [Google Scholar] [CrossRef]
  94. Laridan, E.; Denorme, F.; Desender, L.; François, O.; Andersson, T.; Deckmyn, H.; Vanhoorelbeke, K.; De Meyer, S.F. Neutrophil extracellular traps in ischemic stroke thrombi. Ann. Neurol. 2017, 82, 223–232. [Google Scholar] [CrossRef] [PubMed]
  95. Kessenbrock, K.; Krumbholz, M.; Schönermarck, U.; Back, W.; Gross, W.L.; Werb, Z.; Gröne, H.J.; Brinkmann, V.; Jenne, D.E. Netting neutrophils in autoimmune small-vessel vasculitis. Nat. Med. 2009, 15, 623–625. [Google Scholar] [CrossRef] [PubMed]
  96. Borowiec, A.; Hadzik-Błaszczyk, M.; Kowalik, I.; Rusinowicz, T.; Krupa, R.; Jankowski, J.; Kandyba, P.; Józefik, E.; Gawałkiewicz, A.; Życińska, K. High incidence of venous thromboembolism but not of coronary artery disease in granulomatosis with polyangiitis in first years after diagnosis. Sarcoidosis Vasc. Diffus. Lung Dis. 2019, 36, 202–208. [Google Scholar] [CrossRef]
  97. Misra, D.P.; Thomas, K.N.; Gasparyan, A.Y.; Zimba, O. Mechanisms of thrombosis in ANCA-associated vasculitis. Clin. Rheumatol. 2021, 40, 4807–4815. [Google Scholar] [CrossRef]
  98. Meng, H.; Yalavarthi, S.; Kanthi, Y.; Mazza, L.F.; Elfline, M.A.; Luke, C.E.; Pinsky, D.J.; Henke, P.K.; Knight, J.S. In Vivo Role of Neutrophil Extracellular Traps in Antiphospholipid Antibody–Mediated Venous Thrombosis. Arthritis Rheumatol. 2017, 69, 655–667. [Google Scholar] [CrossRef]
  99. Janiuk, K.; Jablonska, E.; Garley, M. Significance of NETs Formation in COVID-19. Cells 2021, 10, 151. [Google Scholar] [CrossRef]
  100. Veras, F.P.; Pontelli, M.C.; Silva, C.M.; Toller-Kawahisa, J.E.; de Lima, M.; Nascimento, D.C.; Schneider, A.H.; Caetite, D.; Tavares, L.A.; Paiva, I.M.; et al. SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology. J. Exp. Med. 2020, 217, e20201129. [Google Scholar] [CrossRef]
  101. Arcanjo, A.; Logullo, J.; Menezes, C.C.B.; de Souza Carvalho Giangiarulo, T.C.; Dos Reis, M.C.; de Castro, G.M.M.; da Silva Fontes, Y.; Todeschini, A.R.; Freire-de-Lima, L.; Decote-Ricardo, D.; et al. The emerging role of neutrophil extracellular traps in severe acute respiratory syndrome coronavirus 2 (COVID-19). Sci. Rep. 2020, 10, 19630. [Google Scholar] [CrossRef] [PubMed]
  102. Narasaraju, T.; Tang, B.M.; Herrmann, M.; Muller, S.; Chow, V.T.K.; Radic, M. Neutrophilia and NETopathy as Key Pathologic Drivers of Progressive Lung Impairment in Patients With COVID-19. Front. Pharmacol. 2020, 11, 870. [Google Scholar] [CrossRef] [PubMed]
  103. Kolb, P.; Giese, S.; Voll, R.E.; Hengel, H.; Falcone, V. Immune complexes as culprits of immunopathology in severe COVID-19. Med. Microbiol. Immunol. 2023, 212, 185–191. [Google Scholar] [CrossRef]
  104. Conteduca, V.; Scarpi, E.; Wetterskog, D.; Brighi, N.; Ferroni, F.; Rossi, A.; Romanel, A.; Gurioli, G.; Bleve, S.; Gianni, C.; et al. Plasma tumor DNA is associated with increased risk of venous thromboembolism in metastatic castration-resistant cancer patients. Int. J. Cancer 2022, 150, 1166–1173. [Google Scholar] [CrossRef]
  105. de Boer, O.J.; Li, X.; Teeling, P.; Mackaay, C.; Ploegmakers, H.J.; van der Loos, C.M.; Daemen, M.J.; de Winter, R.J.; van der Wal, A.C. Neutrophils, neutrophil extracellular traps and interleukin-17 associate with the organisation of thrombi in acute myocardial infarction. Thromb. Haemost. 2013, 109, 290–297. [Google Scholar] [CrossRef] [PubMed]
  106. Mangold, A.; Alias, S.; Scherz, T.; Hofbauer, M.; Jakowitsch, J.; Panzenbock, A.; Simon, D.; Laimer, D.; Bangert, C.; Kammerlander, A.; et al. Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size. Circ. Res. 2015, 116, 1182–1192. [Google Scholar] [CrossRef]
  107. Mutua, V.; Gershwin, L.J. A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics. Clin. Rev. Allergy Immunol. 2021, 61, 194–211. [Google Scholar] [CrossRef]
  108. Valles, J.; Lago, A.; Santos, M.T.; Latorre, A.M.; Tembl, J.I.; Salom, J.B.; Nieves, C.; Moscardo, A. Neutrophil extracellular traps are increased in patients with acute ischemic stroke: Prognostic significance. Thromb. Haemost. 2017, 117, 1919–1929. [Google Scholar] [CrossRef]
  109. van Montfoort, M.L.; Stephan, F.; Lauw, M.N.; Hutten, B.A.; Van Mierlo, G.J.; Solati, S.; Middeldorp, S.; Meijers, J.C.; Zeerleder, S. Circulating nucleosomes and neutrophil activation as risk factors for deep vein thrombosis. Arterioscler. Thromb. Vasc. Biol. 2013, 33, 147–151. [Google Scholar] [CrossRef]
  110. Wang, Y.; Luo, L.; Braun, O.O.; Westman, J.; Madhi, R.; Herwald, H.; Morgelin, M.; Thorlacius, H. Neutrophil extracellular trap-microparticle complexes enhance thrombin generation via the intrinsic pathway of coagulation in mice. Sci. Rep. 2018, 8, 4020. [Google Scholar] [CrossRef]
  111. Carestia, A.; Frechtel, G.; Cerrone, G.; Linari, M.A.; Gonzalez, C.D.; Casais, P.; Schattner, M. NETosis before and after Hyperglycemic Control in Type 2 Diabetes Mellitus Patients. PLoS ONE 2016, 11, e0168647. [Google Scholar] [CrossRef] [PubMed]
  112. Joshi, M.B.; Baipadithaya, G.; Balakrishnan, A.; Hegde, M.; Vohra, M.; Ahamed, R.; Nagri, S.K.; Ramachandra, L.; Satyamoorthy, K. Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps. Sci. Rep. 2016, 6, 36362. [Google Scholar] [CrossRef] [PubMed]
  113. Popp, S.K.; Vecchio, F.; Brown, D.J.; Fukuda, R.; Suzuki, Y.; Takeda, Y.; Wakamatsu, R.; Sarma, M.A.; Garrett, J.; Giovenzana, A.; et al. Circulating platelet-neutrophil aggregates characterize the development of type 1 diabetes in humans and NOD mice. JCI Insight 2022, 7, e153993. [Google Scholar] [CrossRef]
  114. Wong, L.S.; Demers, M.; Martinod, K.; Gallant, M.; Wang, Y.; Goldfine, A.B.; Kahn, C.R.; Wagner, D.D. Diabetes primes neutrophils to undergo NETosis, which impairs wound healing. Nat. Med. 2015, 21, 815–819. [Google Scholar] [CrossRef]
  115. Gollomp, K.; Kim, M.; Johnston, I.; Hayes, V.; Welsh, J.; Arepally, G.M.; Kahn, M.; Lambert, M.P.; Cuker, A.; Cines, D.B.; et al. Neutrophil accumulation and NET release contribute to thrombosis in HIT. JCI Insight 2018, 3, 99445. [Google Scholar] [CrossRef] [PubMed]
  116. Hu, S.C.; Yu, H.; Yen, F.; Lin, C.; Chen, G.; Lan, C. Neutrophil extracellular trap formation is increased in psoriasis and induces human β-defensin-2 production in epidermal keratinocytes. Sci. Rep. 2016, 6, 31119. [Google Scholar] [CrossRef]
  117. Shao, S.; Fang, H.; Dang, E.; Xue, K.; Zhang, J.; Li, B.; Qiao, H.; Cao, T.; Zhuang, Y.; Shen, S.; et al. Neutrophil Extracellular Traps Promote Inflammatory Responses in Psoriasis via Activating Epidermal TLR4/IL-36R Crosstalk. Front. Immunol. 2019, 10, 746. [Google Scholar] [CrossRef]
  118. Demers, M.; Krause, D.S.; Schatzberg, D.; Martinod, K.; Voorhees, J.R.; Fuchs, T.A.; Scadden, D.T.; Wagner, D.D. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc. Natl. Acad. Sci. USA 2012, 109, 13076–13081. [Google Scholar] [CrossRef]
  119. Jin, W.; Yin, H.; Li, H.; Yu, X.J.; Xu, H.X.; Liu, L. Neutrophil extracellular DNA traps promote pancreatic cancer cells migration and invasion by activating EGFR/ERK pathway. J. Cell Mol. Med. 2021, 25, 5443–5456. [Google Scholar] [CrossRef]
  120. Leal, A.C.; Mizurini, D.M.; Gomes, T.; Rochael, N.C.; Saraiva, E.M.; Dias, M.S.; Werneck, C.C.; Sielski, M.S.; Vicente, C.P.; Monteiro, R.Q. Tumor-Derived Exosomes Induce the Formation of Neutrophil Extracellular Traps: Implications For The Establishment of Cancer-Associated Thrombosis. Sci. Rep. 2017, 7, 6438. [Google Scholar] [CrossRef]
  121. Lecot, P.; Sarabi, M.; Pereira Abrantes, M.; Mussard, J.; Koenderman, L.; Caux, C.; Bendriss-Vermare, N.; Michallet, M.C. Neutrophil Heterogeneity in Cancer: From Biology to Therapies. Front. Immunol. 2019, 10, 2155. [Google Scholar] [CrossRef]
  122. Snoderly, H.T.; Boone, B.A.; Bennewitz, M.F. Neutrophil extracellular traps in breast cancer and beyond: Current perspectives on NET stimuli, thrombosis and metastasis, and clinical utility for diagnosis and treatment. Breast Cancer Res. 2019, 21, 145. [Google Scholar] [CrossRef]
  123. Zhu, T.; Zou, X.; Yang, C.; Li, L.; Wang, B.; Li, R.; Li, H.; Xu, Z.; Huang, D.; Wu, Q. Neutrophil extracellular traps promote gastric cancer metastasis by inducing epithelial-mesenchymal transition. Int. J. Mol. Med. 2021, 48, 127. [Google Scholar] [CrossRef]
  124. Ellett, F.; Jorgensen, J.; Frydman, G.H.; Jones, C.N.; Irimia, D. Neutrophil Interactions Stimulate Evasive Hyphal Branching by Aspergillus fumigatus. PLoS Pathog. 2017, 13, e1006154. [Google Scholar] [CrossRef] [PubMed]
  125. Hiroki, C.H.; Toller-Kawahisa, J.E.; Fumagalli, M.J.; Colon, D.F.; Figueiredo, L.T.M.; Fonseca, B.; Franca, R.F.O.; Cunha, F.Q. Neutrophil Extracellular Traps Effectively Control Acute Chikungunya Virus Infection. Front. Immunol. 2019, 10, 3108. [Google Scholar] [CrossRef] [PubMed]
  126. McDonald, B.; Davis, R.P.; Kim, S.J.; Tse, M.; Esmon, C.T.; Kolaczkowska, E.; Jenne, C.N. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood 2017, 129, 1357–1367. [Google Scholar] [CrossRef] [PubMed]
  127. Raftery, M.J.; Lalwani, P.; Krautkrämer, E.; Peters, T.; Scharffetter-Kochanek, K.; Kruger, R.; Hofmann, J.; Seeger, K.; Kruger, D.H.; Schonrich, G. β2 integrin mediates hantavirus-induced release of neutrophil extracellular traps. J. Exp. Med. 2014, 211, 1485–1497. [Google Scholar] [CrossRef]
  128. Sung, P.S.; Huang, T.F.; Hsieh, S.L. Extracellular vesicles from CLEC2-activated platelets enhance dengue virus-induced lethality via CLEC5A/TLR2. Nat. Commun. 2019, 10, 2402. [Google Scholar] [CrossRef]
  129. Urban, C.F.; Ermert, D.; Schmid, M.; Abu-Abed, U.; Goosmann, C.; Nacken, W.; Brinkmann, V.; Jungblut, P.R.; Zychlinsky, A. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog. 2009, 5, e1000639. [Google Scholar] [CrossRef]
  130. Urban, C.F.; Reichard, U.; Brinkmann, V.; Zychlinsky, A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol. 2006, 8, 668–676. [Google Scholar] [CrossRef]
  131. Yipp, B.G.; Petri, B.; Salina, D.; Jenne, C.N.; Scott, B.N.; Zbytnuik, L.D.; Pittman, K.; Asaduzzaman, M.; Wu, K.; Meijndert, H.C.; et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat. Med. 2012, 18, 1386–1393. [Google Scholar] [CrossRef] [PubMed]
  132. Xu, J.; Zhang, X.; Pelayo, R.; Monestier, M.; Ammollo, C.T.; Semeraro, F.; Taylor, F.B.; Esmon, N.L.; Lupu, F.; Esmon, C.T. Extracellular histones are major mediators of death in sepsis. Nat. Med. 2009, 15, 1318–1321. [Google Scholar] [CrossRef] [PubMed]
  133. Yang, S.; Qi, H.; Kan, K.; Chen, J.; Xie, H.; Guo, X.; Zhang, L. Neutrophil Extracellular Traps Promote Hypercoagulability in Patients with Sepsis. Shock 2017, 47, 132–139. [Google Scholar] [CrossRef]
  134. Chamardani, T.M.; Amiritavassoli, S. Inhibition of NETosis for treatment purposes: Friend or foe? Mol. Cell. Biochem. 2022, 477, 673–688. [Google Scholar] [CrossRef] [PubMed]
  135. Ngo, A.T.P.; Gollomp, K. Building a better NET: Neutrophil extracellular trap targeted therapeutics in the treatment of infectious and inflammatory disorders. Res. Pract. Thromb. Haemost. 2022, 6, e12808. [Google Scholar] [CrossRef]
  136. Schwab, I.; Nimmerjahn, F. Intravenous immunoglobulin therapy: How does IgG modulate the immune system? Nat. Rev. Immunol. 2013, 13, 176–189. [Google Scholar] [CrossRef] [PubMed]
  137. Debré, M.; Bonnet, M.C.; Fridman, W.H.; Carosella, E.; Philippe, N.; Reinert, P.; Vilmer, E.; Kaplan, C.; Teillaud, J.L.; Griscelli, C. Infusion of Fc gamma fragments for treatment of children with acute immune thrombocytopenic purpura. Lancet 1993, 342, 945–949. [Google Scholar] [CrossRef]
  138. Yu, X.; Lazarus, A.H. Targeting FcγRs to treat antibody-dependent autoimmunity. Autoimmun. Rev. 2016, 15, 510–512. [Google Scholar] [CrossRef]
  139. Heo, Y.A. Efgartigimod: First Approval. Drugs 2022, 82, 341–348. [Google Scholar] [CrossRef]
Biology 12 01332 g001
Figure 1. Mechanisms of neutrophil activation. Summarised receptor signalling pathways implicated in NETosis. IC, immune complex; Act. platelet, activated platelets; HMB1, high-mobility group box 1; TAK1, transforming growth factor-β-activated kinase 1; RAGE, receptor for advanced glycation end-products; PSGL-1, P-selectin glycoprotein ligand-1; dotted arrows indicate intermediate signalling molecules not included in the Figure.
Figure 1. Mechanisms of neutrophil activation. Summarised receptor signalling pathways implicated in NETosis. IC, immune complex; Act. platelet, activated platelets; HMB1, high-mobility group box 1; TAK1, transforming growth factor-β-activated kinase 1; RAGE, receptor for advanced glycation end-products; PSGL-1, P-selectin glycoprotein ligand-1; dotted arrows indicate intermediate signalling molecules not included in the Figure.
Biology 12 01332 g001
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Perdomo, J.; Leung, H.H.L. Immune Thrombosis: Exploring the Significance of Immune Complexes and NETosis. Biology 2023, 12, 1332. https://doi.org/10.3390/biology12101332

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Perdomo J, Leung HHL. Immune Thrombosis: Exploring the Significance of Immune Complexes and NETosis. Biology. 2023; 12(10):1332. https://doi.org/10.3390/biology12101332

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Perdomo, José, and Halina H. L. Leung. 2023. "Immune Thrombosis: Exploring the Significance of Immune Complexes and NETosis" Biology 12, no. 10: 1332. https://doi.org/10.3390/biology12101332

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