ReviewPromotion of trained innate immunity by nanoparticles
Introduction
The vertebrate immune system has been traditionally divided into innate and adaptive arms based on their levels of specificity for antigen recognition. Activation of innate defenses relies on germ-line encoded receptors (pattern recognition receptors; PRRs) which recognize a discrete number of evolutionarily conserved patterns associated with microbes (MAMPs) or damage/danger associated molecular patterns (DAMPs). Signal transduction triggered by MAMPs and DAMPs leads to swift activation of innate cells including macrophages, monocytes and neutrophils among other myeloid cells, which act as the first line of defense [1,2]. Adaptive immunity is a more recent evolutionary trait of vertebrates and relies on clonally distributed receptors expressed by T and B cells (TCR and BCR), which can recognize virtually any type of antigen. The specificity of TCRs and BCRs is determined by unique genetic mechanisms that operate during lymphocyte development in the bone marrow and thymus. These allow for the generation of millions of variants of the genes encoding the T and B cell receptor molecules so that each pathogen can be specifically recognized, while autoreactive clones are eliminated [1,2].
In addition to its exquisite specificity and wide recognition of antigens, adaptive immunity is characterized by long-lived responses known as immunological memory. Adaptive memory allows for a faster and more efficient response to subsequent encounters with the same pathogen [3]. Until recently, immunological memory was thought to be the exclusive hallmark of adaptive responses. However, several studies have shown that organisms lacking adaptive immunity such as plants and invertebrates, can mediate a certain level of protection against reinfection [4,5]. In mammals, protection against re-challenge has been demonstrated independently from adaptive immunity. For instance, exposure to mild Candida albicans infection confers protection against lethal re-challenge in mice lacking a thymus and therefore T cells, or RAG1-/- mice which cannot produce functional T or B cells [6,7]. In this scenario, macrophages were required to mediate protection [8]. Interestingly, protection against heterologous challenges in the absence of functional adaptive responses has also been observed. Administration of the Toll Like Receptor (TLR) 5 agonist flagellin, a MAMP absent in Streptococcus pneumoniae, protected SCID mice lacking T and B cells against pneumococcal pneumonia [9] and the Bacillus Calmette-Guérin (BCG) vaccine confers protection against heterologous lethal candidiasis in RAG1-/- and athymic mice [10,11]. On the other hand, following an initial exposure, myeloid cells can also dampen their response to subsequent stimuli. This is the case with lipopolysaccharide (LPS)-induced tolerance in macrophages, characterized by reduced inflammatory cytokine production and enhanced expression of anti-inflammatory genes like interleukin (IL-)10 upon re-exposure to endotoxin [[12], [13], [14]].
These studies demonstrate that like the adaptive system, innate immunity can adapt to environmental challenges and modify the subsequent response to homologous or more notably, heterologous secondary challenges. The long-term functional reprogramming of innate cells that leads to this modified response is known as ‘trained immunity’ [15]. In essence, trained immunity allows for the generation of ‘innate immune memory’, which may be regarded as the predecessor of the more refined adaptive memory that appeared later on in evolution [3].
Much of the evidence for trained immunity in humans originated from epidemiological studies in cohorts immunized with live vaccines including BCG, measles, smallpox or polio that found non-specific protective effects against other infections than the vaccine target [[16], [17], [18], [19]]. Immunological studies found that the BCG vaccine induces reprogramming of innate cells including monocytes and natural killer (NK) cells that mediate long-lasting protection against heterologous challenges [11,20,21]. On the other hand, this effect has not been observed with non-living vaccines [22,23]. Trained immunity has also been found to play a role in autoimmune disorders in which an exacerbated trained immune phenotype could contribute to disease pathogenesis, for instance in atherosclerotic cardiovascular disease [24,25]. This suggests that depending on the context, the effects of trained immunity may be beneficial or detrimental for the host. In recent years there has been impressive progress in the characterization of the molecular mechanisms that promote trained immunity. Among these, important roles for epigenetic modifications, long non-coding RNA (lncRNA), microRNA (miRNA) and metabolic reprogramming have been found and reviewed recently [26]. Understanding how different stimuli activate these mechanisms, leading to specific programs of trained immunity, i.e. potentiation of the response or induction of tolerance, is important to predict responses to infections, vaccination, and to open new treatment avenues for autoimmune diseases and cancer.
The last three decades have seen a significant growth in the use of biomaterials and nanotechnology for biomedical and pharmaceutical applications. Biomaterials and particulates are being developed as drug delivery systems, vaccine adjuvants, biosensors, theragnostics and scaffolds for wound healing, among other medical uses. Exposure to particles also originates from erosion of wearables such as prosthetics [27] or inhalation of pollutants [28]. Whether derived from intentional or accidental exposure, particles are sensed by innate cells which respond to them in different ways largely determined by the physicochemical characteristics of the particles [29]. While innate responses to particles have been extensively studied, this work has focused principally on primary responses. Trained immunity was first described as a phenomenon triggered by microbial-derived molecules. However, endogenously generated particles such as oxidized low-density lipoprotein (ox-LDL) [30,31] and monosodium urate (MSU) crystals [32] have also been shown to induce trained immunity. In line with this, it has been suggested that other non-biological stressors including exogenous particles could lead to innate memory and modify innate responses to subsequent stimuli [33]. Using pristine graphene (pGr), an interesting material for biomedical applications, we recently demonstrated that particulate biomaterials can induce trained immunity in macrophages. We showed that while primary exposure to pGr does not induce inflammatory cytokine secretion, it modifies their response to secondary stimulation with TLR ligands. By inducing chromatin remodeling, pGr modifies the long-term response of macrophages to TLR stimulation [34].
Here we briefly revisit the effects caused by primary exposure of innate cells to particulates, concentrating on macrophages, monocytes and dendritic cells, and delve into the latest evidence in the field of innate training induced by biomaterials, with an emphasis on micro and nanoparticles. We analyse the mechanisms whereby particles can induce innate training and discuss how specific characteristics of particles could influence induction of innate memory. Finally, we review the implications of innate training in the context of particulate adjuvants, nanocarriers and nanovaccines and reflect on the unanswered questions and the future of the field.
Section snippets
Innate immunity during primary exposure to nanomaterials
Engineered biomaterials and nanoparticles are sensed by and interact with the cellular and humoral components of the immune system eliciting diverse type of responses. Innate immunity constitutes the first line of defense against microbes and also environmental insults such as particles, implants, vaccines and drug carriers. Due to the constant exposure to insults, barrier tissues including mucosae and the skin harbor populations of resident immune cells which respond to them. Regardless of the
Mechanisms of trained immunity: epigenetic and metabolic reprogramming
The key attribute that distinguishes trained immunity from innate activation is that trained immunity is a state of long-term functional reprogramming that leads to altered responsiveness, independent of the continued presence of the stimulus by which it was evoked. Both innate activation and trained immunity can be evoked by exposure to exogenous (microbial-derived molecules, environmental compounds, vaccines) [13,21] or endogenously generated (LDL, urate crystals) stimuli [32,50]. Innate
Trained immunity induced by particles
In recent years it has been hypothesized that similar to microbial or endogenous stimuli, exogenous particulates could induce innate memory [33]. Limited but increasing evidence indicates that engineered particles and nanomaterials can promote epigenetic and metabolic reprogramming of cells, which are the hallmark of innate training [77]. In 2020, our group demonstrated for the first time that pristine graphene induces an innate memory phenotype in macrophages associated with specific histone
Particulate adjuvants, heterologous effects of vaccination and trained immunity
Traditionally the protective effects of vaccination have been attributed to the long-lived antigen-specific adaptive immune responses induced by immunization, namely antigen-specific antibodies and T cell responses. However, the ability of BCG and other live vaccines to induce heterologous protection against non-related diseases, has highlighted the important role of non-specific immunity as means to boost protection against pathogens [16,17,103]. BCG became the case study for this phenomenon
Conclusion
The use of nanoparticles and biomaterials has increased significantly in recent decades, with wide application as diagnostic tools, drug delivery systems, implants/prosthetics and vaccine adjuvants. Despite existing methods for evaluating the safety of biomaterials and particles, their ability to induce epigenetic changes leading to long-term effects on the immune system and more generally on human health, have not been assessed systematically. In addition to those used in medicine, it is
Funding
This work was supported by the Health Research Board grant number HRB-EIA-2019-004 awarded to NMW and Science Foundation Ireland grant number 19/FFP/6484, awarded to ECL.
References (123)
- et al.
Innate and adaptive immune memory: an evolutionary continuum in the host’s response to pathogens
Cell Host Microbe
(2019) Specific memory within innate immune systems
Trends Immunol.
(2005)- et al.
Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes
Cell Host Microbe
(2012) - et al.
Trained immunity: a memory for innate host defense
Cell Host Microbe
(2011) - et al.
BCG-induced trained immunity in NK cells: role for non-specific protection to infection
Clin. Immunol.
(2014) - et al.
Treatment with statins does not revert trained immunity in patients with familial hypercholesterolemia
Cell Metab.
(2019) Innate immunity to inhaled particles: a new paradigm of collective recognition
Curr. Opin. Toxicol.
(2018)- et al.
Nanoparticle-based theragnostics: integrating diagnostic and therapeutic potentials in nanomedicine
J. Control. Release
(2010) - et al.
Harnessing nanoparticles for immune modulation
Trends Immunol.
(2015) - et al.
Nanoparticle interaction with plasma proteins as it relates to particle biodistribution, biocompatibility and therapeutic efficacy
Adv. Drug Deliv. Rev.
(2009)