Neutrophils in animal models of autoimmune disease
Introduction
Neutrophils are the most abundant cell in the immune system. Between 1011 and 1012 neutrophils are made each day in the human bone marrow, which comprises ∼50% of the total cellular content of the marrow, including a large pool of fully mature cells that is poised for release into the circulation in response to immune challenge [1]. The role of neutrophils in host defense against pathogen infection has been extensively studied in many disease contexts. However, current research indicates that neutrophils are also involved in regulating other aspects of immunity. Thus it is now clear that neutrophils are both effectors and modulators of host immune responses [2], [3]. It is also evident that dysfunction of either of these neutrophil roles can lead to immune-based diseases, including a variety of autoimmune and autoinflammatory conditions.
That neutrophils contribute at all to autoimmune disease pathogenesis is somewhat of a novel concept. Clearly, as effector cells, their contribution to tissue injury in inflammatory diseases, for example in immune complex-mediated diseases such as rheumatoid arthritis or glomerulonephritis, has long been appreciated. But the concept that neutrophil dysfunction, in either effector or regulatory properties, could initiate autoimmune disease is a new idea [4], [5]. Indeed, the entire autoimmunity field is undergoing a conceptual shift with the realization that dysregulation of any one of a number of innate immune cell types (especially dendritic cells) can be a primary driver of autoimmunity [6], [7]. Hence, determination of the mechanisms by which neutrophils affect adaptive immune cells is among the most dynamic areas of research in autoimmunity [8].
As effector cells, neutrophils respond to infectious pathogens through a myriad of molecular receptors that recognize pathogen-associated molecules. Activation of neutrophils through FcRs (that recognize Ig opsonized pathogens), integrins or C-type lectin receptors induces phagocytosis of bacteria or fungi, which in concert with stimulation of Toll-like receptors (TLRs), G-protein coupled receptors (such as the formyl peptide receptors) or various intracellular pathogen sensing molecules (such as NOD receptors), leads to stimulation of superoxide production as well as release of granules containing antimicrobial proteases and peptides [9]. Additionally, during host defense reactions neutrophils undergo a distinct form of cell death, referred to as NETosis, which leads to extracellular release of chromatin (which is often decorated with anti-microbial peptides released from granules) that forms a meshwork to trap extracellular pathogens [10]. Defects in any one of these effector functions, such as lack of integrin signaling or impairment of superoxide formation, leads to various forms of immunodeficiency. Importantly, these same defects in effector function can also contribute to autoimmune disease [11]. For example, patients with chronic granulomatous disease (CGD), caused by mutations in genes encoding subunits of the NADPH oxidase resulting in reduced or absent superoxide production, often develop autoimmune disease (colitis), which may be due to changes in the intestinal microbiome that favor outgrowth of proinflammatory organisms. Similarly, the process of NETosis is now recognized as a major source of self (or auto) antigens that drive autoimmunity in diseases such as systemic lupus erythematous or rheumatoid arthritis [12]. Thus the antimicrobial role of neutrophils underlies aspects of their contribution to autoimmune disease.
As regulatory cells, neutrophils have been found to modulate the function of T-cells, B-cells and dendritic cells, which in turn directly affects autoimmune disease pathogenesis. The regulatory mechanisms utilized by neutrophils includes direct effects, via the production of cytokines such as IL-1, IL-6, IL-10 (in murine neutrophils only), TNF and BAFF that affect other immune cells, as well as indirect effects, through production of superoxides or consumption of nutrients (amino acids or even oxygen) that limit function of neighboring immune cells [13], [14]. Both stimulatory and inhibitory roles for neutrophils, based on their ability to produce various cytokines or indirectly affect other immune cells, have been described in a variety of autoimmune or autoinflammatory processes. Thus, the most productive way to summarize the contributions of neutrophils to any given autoimmune disease is to review the current evidence for each disease individually.
This review will focus on the current evidence linking murine neutrophils to a wide variety of murine autoimmune and autoinflammatory disease models. We will focus on mechanisms by which neutrophils contribute to disease pathogenesis beyond just induction of tissue injury through effector mechanisms (superoxide or protease release) normally operative in host defense reactions. The majority of evidence will involve neutrophil depletion or use of genetic knockout mice in any given disease model. As the reader will see, there are many complex ways neutrophils are involved in autoimmune diseases that were previously just thought to arise from defects in T or B-cell tolerance mechanisms.
Section snippets
Neutrophils in systemic lupus erythematosus
There is a wealth of literature demonstrating a pathogenic role for neutrophils in various rheumatologic diseases, in particular systemic lupus erythematosus (SLE). Most of this data is based on human observations, which paints a picture of abnormal neutrophils contributing to both inflammatory states in SLE (through production of disease inducing cytokines such as IL-1β or BAFF) as well as being the source of many auto-antigens in the disease (mainly through NETosis). However, the picture is a
Experimental autoimmune encephalomyelitis (EAE)
The mouse EAE model has been used extensively to replicate the autoimmune pathogenesis in human multiple sclerosis [68]. EAE is initiated by immunization of mice with myelin protein or peptides, which leads to development of self-reactive CD4+ Th17 cells that infiltrate the CNS leading to demyelination and neuronal injury. Myeloid cell infiltration into the CNS is a major component of the EAE model and is also seen in human multiple sclerosis lesions [69]. Indeed, early reports demonstrated
Neutrophils in autoimmune uveitis
The uvea is the middle layer of the eye, consisting of the iris, the ciliary body and the choroidea. Inflammation of this layer is associated with several autoimmune diseases (e.g. ankylosing spondylitis, Behcet’s disease, etc.) and is the leading cause of blindness in Western societies [79]. Experimental autoimmune uveoretinitis (EAU) can be triggered in mice by immunization with the interphotoreceptor retinoid-binding protein (IRBP). Wild type mice develop leukocytosis with marked
Models of autoimmune bullous diseases
Two major autoimmune bullous skin diseases have been modeled in mice: bullous pemphigoid (BP) and epidermolysis bullosa acquisita (EBA). BP results from development of pathogenic autoantibodies recognizing hemidesmosomal proteins BP180 or BP320, while EBA is caused by development of autoantibodies recognizing collagen VII [81]. Deposition of these autoantibodies along the dermal/epidermal border produces a neutrophil-dominant inflammatory reaction that leads to separation of the epidermis from
Type 1 diabetes mellitus
Type 1 diabetes mellitus is a T cell-mediated autoimmune disorder that requires insulin replacement therapy for the entire life of patients suffering from the disease. The major mouse model for this disease is the non obese diabetic (NOD) model; these mice develop an inflammatory autoimmunity against their pancreatic islet (insulin producing) β-cells [100]. Early in the disease process the pancreatic islets of NOD mice develop a transient influx of neutrophils [101]. This influx is reduced by
Roles for neutrophils in non-classical autoinflammatory-like disease models
Autoinflammation and autoimmunity share many common features such as chronicity or self-destruction by immune cells; however, autoinflammatory conditions lack autoantibodies, autoreactive lymphocytes and MHC allele-correlations. According to the Immunological disease continuum view, there is a smooth transition from classical autoinflammatory diseases like the monogenic Familial Mediterranean Fever (FMF) to classical autoimmune diseases like systemic lupus erythematosus (SLE) with intermediate
Novel therapeutic approaches targeting neutrophils
Given the wealth of new information revealing novel functions for neutrophils in various autoimmune and inflammatory diseases, the potential for new therapeutics is obvious. Perhaps the most interesting therapeutic target is neutrophil NETosis. Indeed, as described above, blockade of NETosis using PAD inhibitors has been successful in mouse models of lupus and arthritis. The PAD inhibitors may also be useful to modulate neutrophil-mediated inflammation in other diseases such as atherosclerosis,
Conclusions
A number of the mechanisms by which neutrophils contribute to autoimmune and inflammatory disease pathology are summarized in Fig. 1. These mechanisms emphasize that neutrophils are involved in disease pathogenesis in many ways other than simply inducing tissue injury through release of proteases and ROS. Indeed, as summarized in Table 1, Table 2, there are examples where neutrophil-derived mechanisms both exacerbate autoimmune disease as well as examples of neutrophils protecting the host from
Conflict of interest
The authors declare no financial or commercial conflict of interest.
Acknowledgments
The authors thank Clare Abram for careful reading of the manuscript. This work is supported by grants from the National Institutes of Health (RO1 AI068150, AI065495 and AI113272) to C.A.L., and the János Bolyai Research Scholarship of the Hungarian Academy of Sciences to T. N.
References (149)
- et al.
Neutrophil kinetics in health and disease
Trends Immunol.
(2010) - et al.
The role of neutrophils in autoimmune diseases
Immunol. Lett.
(2012) - et al.
Distinct roles for neutrophils and dendritic cells in inflammation and autoimmunity in motheaten mice
Immunity
(2013) - et al.
Social networking of human neutrophils within the immune system
Blood
(2014) - et al.
Neutrophil cell surface receptors and their intracellular signal transduction pathways
Int. Immunopharmacol.
(2013) - et al.
Neutrophils regulate humoral autoimmunity by restricting interferon-gamma production via the generation of reactive oxygen species
Cell Rep.
(2015) - et al.
Clearance deficiency and systemic lupus erythematosus (SLE)
J. Autoimmun.
(2007) - et al.
A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis
Cell Rep.
(2014) - et al.
Epigenome profiling reveals significant DNA demethylation of interferon signature genes in lupus neutrophils
J. Autoimmun.
(2015) - et al.
Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity
Blood
(2011)
Neutrophil myeloperoxidase regulates T-cell-driven tissue inflammation in mice by inhibiting dendritic cell function
Blood
L10. Animal models of ANCA-associated vasculitis: effector mechanisms and experimental therapies
Presse Med.
Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity
Blood
FcgammaRIIB regulates T-cell autoreactivity, ANCA production, and neutrophil activation to suppress anti-myeloperoxidase glomerulonephritis
Kidney Int.
Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo
Blood
A key role for G-cSF-induced neutrophil production and trafficking during inflammatory arthritis
Blood
The K/BxN mouse: a model of human inflammatory arthritis
Trends Mol. Med.
Enhancement of antibody-induced arthritis via Toll-like receptor 2 stimulation is regulated by granulocyte reactive oxygen species
Am. J. Pathol.
GM-cSF in neuroinflammation: licensing myeloid cells for tissue damage
Trends Immunol.
G-cSF and neutrophils are nonredundant mediators of murine experimental autoimmune uveoretinitis
Am. J. Pathol.
Interleukin-17 causes neutrophil mediated inflammation in ovalbumin-induced uveitis in DO11.10 mice
Cytokine
Modern diagnosis of autoimmune blistering skin diseases
Autoimmun. Rev.
Neutrophil elastase cleaves the murine hemidesmosomal protein BP180/type XVII collagen and generates degradation products that modulate experimental bullous pemphigoid
Matrix Biol.
The C5a receptor on mast cells is critical for the autoimmune skin-blistering disease bullous pemphigoid
J. Biol. Chem.
The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion
J. Invest. Dermatol.
Critical role of neutrophils for the generation of psoriasiform skin lesions in flaky skin mice
J. Invest. Dermatol.
Neutrophil-derived proteases escalate inflammation through activation of IL-36 family cytokines
Cell Rep.
Unprocessed interleukin-36alpha regulates psoriasis-like skin inflammation in cooperation with interleukin-1
J. Invest. Dermatol.
The multifaceted functions of neutrophils
Annu. Rev. Pathol.
Diverse novel functions of neutrophils in immunity, inflammation, and beyond
J. Exp. Med.
Role of neutrophils in systemic autoimmune diseases
Arthritis Res. Ther.
Hyperactivated MyD88 signaling in dendritic cells through specific deletion of Lyn kinase, causes severe autoimmunity and inflammation
Proc. Natl. Acad. Sci. U. S. A.
At the Bench: neutrophil extracellular traps (NETs) highlight novel aspects of innate immune system involvement in autoimmune diseases
J. Leukoc. Biol.
Early-onset autoimmune disease as a manifestation of primary immunodeficiency
Front. Immunol.
Citrullination of autoantigens implicates NETosis in the induction of autoimmunity
Ann. Rheum. Dis.
Neutrophils contribute to excess serum BAFF levels and promote CD4+ T cell and B cell responses in lupus-prone mice
PLoS One
The role of neutrophils in the pathogenesis of systemic lupus erythematosus
Curr. Opin. Rheumatol.
Neutrophil extracellular traps and systemic lupus erythematosus
J. Clin. Cell. Immunol.
Superoxide anion production by neutrophils is associated with prevalent clinical manifestations in systemic lupus erythematosus
Clin. Rheumatol.
Breaking immunological tolerance in systemic lupus erythematosus
Front. Immunol.
Neutrophil extracellular traps kill bacteria
Science
PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps
J. Exp. Med.
Neutrophils activate plasmacytoid dendritic cells by releasing self-dNA-peptide complexes in systemic lupus erythematosus
Sci. Transl. Med.
Neutrophil extracellular trap-associated protein activation of the NLRP3 inflammasome is enhanced in lupus macrophages
J. Immunol.
Neutrophil-mediated IFN activation in the bone marrow alters B cell development in human and murine systemic lupus erythematosus
J. Immunol.
Myeloid cells BAFF, and IFN-gamma establish an inflammatory loop that exacerbates autoimmunity in Lyn-deficient mice
J. Exp. Med.
Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9
J. Exp. Med.
Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus
J. Clin. Invest.
Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice
Ann. Rheum. Dis.
Neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: an additional proatherogenic mechanism in systemic lupus erythematosus
Arthritis Rheumatol
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