Elsevier

Seminars in Immunology

Volume 28, Issue 2, April 2016, Pages 174-186
Seminars in Immunology

Neutrophils in animal models of autoimmune disease

https://doi.org/10.1016/j.smim.2016.04.001Get rights and content

Highlights

  • Studies in animal models have revealed that neutrophils play complex roles in all phases of autoimmune diseases.

  • Neutrophils modulate autoimmune responses through interactions with other cells.

  • Neutrophil functions such as NETosis, cytokine production, superoxide production and release of antimicrobial peptides have distinct roles in modulating autoimmune diseases.

Abstract

Neutrophils have traditionally been thought to play only a peripheral role in the genesis of many autoimmune and inflammatory diseases. However, recent studies in a variety of animal models suggest that these cells are central to the initiation and propagation of autoimmunity. The use of mouse models, which allow either deletion of neutrophils or the targeting of specific neutrophil functions, has revealed the many complex ways these cells contribute to autoimmune/inflammatory processes. This includes generation of self antigens through the process of NETosis, regulation of T-cell and dendritic cell activation, production of cytokines such as BAFF that stimulate self-reactive B-cells, as well as indirect effects on epithelial cell stability. In comparing the many different autoimmune models in which neutrophils have been examined, a number of common underlying themes emerge – such as a role for neutrophils in stimulating vascular permeability in arthritis, encephalitis and colitis. The use of animal models has also stimulated the development of new therapeutics that target neutrophil functions, such as NETosis, that may prove beneficial in human disease. This review will summarize neutrophil contributions in a number of murine autoimmune/inflammatory disease models.

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.

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