Elsevier

Free Radical Biology and Medicine

Volume 125, September 2018, Pages 81-89
Free Radical Biology and Medicine

Review Article
The proinflammatory effects of macrophage-derived NADPH oxidase function in autoimmune diabetes

https://doi.org/10.1016/j.freeradbiomed.2018.04.581Get rights and content

Abstract

Type 1 diabetes (T1D) is an autoimmune disease culminating in the destruction of insulin-producing pancreatic β-cells. While ultimately a T cell-mediated disease, macrophages play an indispensable role in disease initiation and progression. Infiltrating macrophages generate an inflammatory environment by releasing NADPH oxidase-derived superoxide and proinflammatory cytokines. The synthesis of reactive oxygen species (ROS) is acknowledged as putative factors contributing to autoimmunity and β-cell damage in T1D. In addition to direct lysis, free radicals collectively participate in β-cell destruction by providing a redox-dependent third signal necessary for islet-reactive CD4 and CD8 T cell maturation and by inducing oxidative post-translational modifications of β-cell epitopes to further exacerbate autoimmune responses. This review will provide an overview of macrophage function and a synergistic cross-talk with redox biology that contributes to autoimmune dysregulation in T1D.

Introduction

Type 1 diabetes (T1D) is a polygenic autoimmune disease, characterized by the destruction of insulin-producing β-cells located in the islets of Langerhans in the pancreas. In 2011–2012, approximately 21.7 new cases of T1D per 100,000 U.S. children and adolescents less than 20 years of age were observed [1]. Currently, no cure exists and worldwide incidence is steadily climbing at a rate of 3% per year [2], [3]. Following β-cell demise, the resultant primary pathology is the inability to regulate the uptake of glucose, leading to systemic hyperglycemia. Secondary complications of T1D include cardiovascular disease, ketoacidosis, nephropathy, retinopathy, and increased risk of stroke and peripheral ischemia. T1D was first discovered to be autoimmune in the 1970's, and since that time a wealth of research has been expended to determine the cause of β-cell destruction. While exogenous insulin administration has improved overall survival and quality of life, unfortunately, an ultimate cure has proven to be elusive.

Similar to other autoimmune diseases, T1D is a chronic inflammatory-mediated disease, involving the generation of proinflammatory cytokines and reactive oxygen species (ROS) [4]. Islet-resident, as well as islet-infiltrating leukocytes contribute to this inflammatory milieu, resulting in both localized β-cell destruction and enhancement of the adaptive immune effector response of islet-specific autoreactive CD4 T cells and cytotoxic CD8 T cells. As the β-cells undergo damage and death, autoantigens are shed and phagocytosed by antigen-presenting cells (APC) including islet-resident and islet-infiltrating macrophages. These APCs further exacerbate β-cell destruction by synthesizing tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12p70), interleukin 1-beta (IL-1β), and ROS. Originally identified for their potent antimicrobial defense properties, ROS are now known to have extended roles in modulating immune responses. In conjunction with antigen presentation and costimulatory molecule expression, ROS and inflammatory cytokines serve to function as a “third signal” to mature autoreactive CD4 and CD8 T cell effector responses [5], [6]. Immune mechanisms leading to β-cell demise are dependent upon ROS signaling for efficacy.

Oxidative stress is prevalent in nearly all pathological conditions and is defined as an imbalance between cellular oxidants and reductants. Chronic oxidative stress and inflammation within the islet microenvironment can enhance autoreactive CD4 and CD8 T cell responses to further propagate β-cell destruction. The predominant source of endogenous cellular superoxide generation is the NADPH oxidase (NOX) complex, of which the NOX2 isoform is expressed primarily by neutrophils and macrophages [7]. B and T lymphocytes can be stimulated to produce NOX2-derived ROS, however at much lower levels than phagocytes [8], [9]. While CD4 and CD8 T cell participation is necessary for final β-cell destruction, early islet-resident macrophage responses can synthesize superoxide, reactive nitrogen species, proinflammatory cytokines, and Type I interferons (IFN-α/β) to initiate pancreatic β-cell death [10]. Therefore, while ultimately a T cell-mediated disease, macrophages are absolutely necessary for T1D initiation and progression [11], [12]. Coupled with the observations that pancreatic β-cells display a decrease in antioxidant defenses including superoxide dismutase (SOD), catalase, and glutathione peroxidase [13], [14], [15], [16], studies in T1D allow researchers the unique opportunity to further define how oxidative stress can influence autoimmunity.

This review will provide an overview of the relationship between NOX-derived superoxide, proinflammatory macrophage responses, and disease progression in T1D. We will first describe genetic associations of innate immune response genes that contribute to T1D susceptibility in both human subjects and mirrored in the non-obese diabetic (NOD) mouse, the most widely utilized spontaneous murine model of human T1D [17]. Importantly, some of these genetic defects are closely associated with dysregulated macrophage function and proinflammatory innate immune responses. Furthermore, we will relate how the discovery of a mutation in the p47phox subunit of the NOX complex provides a link between superoxide production, macrophage function, and T1D development. Part II will discuss the role of macrophage-derived superoxide to activate T cells. Importantly, we will describe the role of superoxide produced by macrophage-derived NOX, as a necessary component of the “third signal” required for T cell activation in T1D. In Part III, we discuss the role that ROS play in the oxidative post-translational modification (PTM) of autoantigens in T1D progression, and how oxidative PTMs may enhance autoimmune responses.

In both patients with T1D and the NOD mouse model, some of the polygenic susceptibility loci involved in spontaneous autoimmune diabetes progression include genes involved in the regulation of innate immune responses. In humans, approximately 60 genetic loci have been associated with predisposition to T1D. The strongest genetic locus associated with T1D is the Human Leukocyte Antigen (HLA) complex, located on chromosome 6p21 and termed the insulin-dependent diabetes mellitus locus (IDDM1). Genes in this region contain haplotypes of DR-DQ Class II HLA alleles [18]. These genes encode for major histocompatibility class II (MHC-II) receptors found on APCs such as dendritic cells, B cells, and macrophages, thus providing evidence for T1D as being autoimmune in origin. Similar to humans, the most significant genetic associations in the NOD mouse model are with the MHC alleles, specifically I-Ag7 [19]. Mechanistic studies defining how the I-Ag7 allele contributes to diabetes susceptibility include autoantigenic peptides displaying a low affinity, loose, and flexible interaction with the MHC complex [20], [21], [22], [23]. A weak autoantigen-MHC interaction may result in inefficient negative selection of autoreactive T cells in the thymus and inadvertently allow diabetogenic T cells to escape into the periphery [24], [25], [26].

The genetics underpinning T1D progression are complex. Innate immune-related genes associated with T1D susceptibility include IFIH1, which encode for the cytosolic helicase melanoma differentiation-associated protein 5 (MDA5) viral dsRNA sensor. Following the recognition of long dsRNA, MDA5 will initiate Type I and III interferon synthesis to prevent viral replication [27], [28]. Various single nucleotide polymorphisms (SNP) within IFIH1 have been shown to either increase or reduce the risk of T1D susceptibility due to altering the expression and function of MDA5 [29]. It was also shown that, a SNP within the macrophage activation gene, natural resistance associated macrophage protein 1 (NRAMP1) confers susceptibility in T1D patients [30], [31]. Recent mechanistic studies have shown that T1D-associated variants of NRAMP1 resulted in accelerated phagocytosis, phagosomal acidification, antigen presentation and T cell activation by DCs [32].

Other genes identified by genome-wide association studies (GWAS) include Src kinase-associated phosphoprotein 2 (SKAP2), an adaptor protein of the Src signaling pathway that contributes to macrophage responses and cytoskeletal reorganization [33]. Another innate immune gene identified by GWAS studies to be associated with T1D include CTSH, encoding for cathepsin H, a lysosomal cysteine protease involved in the degradation of lysosomal proteins for MHC-II antigen presentation [34]. Interestingly, CTSH was also recently shown to be involved in regulating pancreatic β-cell function in human T1D, as higher expression of CTSH in β-cells may protect against immune-mediated destruction [35]. Finally, TNF alpha induced protein 3 (TNFAIP3) is a potent negative regulator of the NF-κB signaling pathway and inhibitor of TNF-mediated apoptosis by functioning to deubiquitinate specific NF-κB signaling molecules [36]. The loss of TNFAIP3 can influence macrophage differentiation and function by enhancing CD40, CD80, CD86, MHC-II, TNF-α and IL-6 expression [37]. Taken together, in addition to genetic associations with pancreatic β-cell function and adaptive immune responses, these studies implicate innate immune responses as harboring genetic predispositions to T1D development.

Macrophages are cells of the innate immune system traditionally attributed to antigen presentation and antimicrobial defense. Macrophages also serve other key functions including maintaining tissue homeostasis, phagocytosis of apoptotic and necrotic cells, wound healing, and tissue repair [38]. Because of their multifaceted roles, macrophages polarize to specific subtypes upon stimulation by environmental triggers. Initially, macrophages were delineated into two broad subtypes; “classical” M1 macrophages and “alternatively-activated” M2 macrophages [39]. In recent years, the M1 and M2 macrophage nomenclature has been refined to depict the cytokine or activation standard used to polarize macrophages and induce multiple phenotypes including M(IL-4), M(Ig), M(IL-10), M(IFN-γ), M(LPS), etc. [40]. For the sake of simplicity, we will delineate only between M1 and M2 macrophages in this review article. Due to their role in the processing and presentation of β-cell antigens to autoreactive T cells, M1 macrophages are the principal macrophage subtype of focus in the context of T1D. Classically activated M1 macrophages are polarized from myeloid precursors upon stimulation by inflammatory signals, such as IFN-γ, or detection of pathogen-associated molecular patterns (PAMPS) including lipopolysaccharide (LPS), bacterial flagella, unmethylated CpG motifs, viral dsRNA, or granulocyte macrophage colony-stimulating factor (GM-CSF) stimulation [40]. M1 macrophage polarization pathways activated following stimulation include IFNGR1/IFNGR2-STAT1, Toll-like receptor-3 (TLR3), TLR4, NF-κB, and STAT5. The M2 macrophage pathways necessary for differentiation include IL-4R-STAT6, IL-10R1/IL-10R2-STAT3, and SP1.

Inflammatory macrophage responses are crucial for the development of autoimmune diabetes. Early studies showed that NOD mice deficient in macrophage function were resistant to T1D [41], [42]. Macrophages are the initial islet-infiltrating cells within NOD mice and humans, superseding CD4/CD8 T cells, NK cells, and B cells. Studies utilizing silica or cyclophosphamide to selectively deplete macrophages in NOD mice demonstrated an indispensable role for macrophages in T1D, as these mice failed to develop T1D [41], [42]. In the context of the NOD mouse, selective depletion of macrophages using liposomal dichloromethyl diphosphonate (lip-Cl2MDP) also severely diminished T cell autoreactivity. Specifically, macrophage-depleted NOD mice remained euglycemic following islet transplantation, and analysis of CD8 T cells revealed blunted perforin and Fas ligand (FasL) expression, indicating diminished CD8 T cell cytotoxicity [12]. Selective depletion of macrophages also abrogated Th1 CD4 T cell effector responses and elicited a concomitant increase in a T helper 2 (Th2) phenotype [12], [43]. The importance of macrophages and neutrophils in T1D were further demonstrated in antibody depletion studies with RB6–8C5 and 1A8, antibody clones that can deplete macrophages and neutrophils or neutrophils only, respectively. NOD mice treated with 1A8 did not exhibit a delay in spontaneous T1D, but NOD mice depleted of macrophages with RB6–8C5 were protected [11].

In T1D, macrophages secrete free radicals, such as superoxide (O2.−), hydrogen peroxide (H2O2), nitric oxide (NO), and peroxynitrite (ONOO-), acting in concert with proinflammatory cytokines, including Type I Interferons, IFN-γ, IL-1β, and TNF-α to promote β-cell destruction [44], [45]. Macrophage-derived proinflammatory cytokines and free radicals can also promote the effector response of diabetogenic T cells. Compared to macrophages isolated from diabetes-resistant Non-Obese Resistant (NOR) mice, incubation of NOD macrophages with LPS, CD40, or apoptotic cells resulted in enhanced production of proinflammatory cytokines such as TNF-α, IL-1β, and IL-12p70 [46]. This predisposition toward an inflammatory phenotype in NOD mice is partially explained by defects in the innate immune system, which contribute to dysregulated autoreactive CD4 and CD8 T cell responses in autoimmune diabetes. While T cells ultimately mediate the final stages of T1D disease progression, macrophages isolated from NOD mice were found to have dysregulated NF-κB signaling, resulting in increased production of proinflammatory cytokines and chemokines to facilitate β-cell cytotoxicity [49], [50].

In another study, it was shown that naïve T cells from macrophage-depleted NOD mice regained their β-cell cytotoxicity when adoptively transferred to macrophage-intact NOD mice. Macrophage-derived synthesis of TNF-α, IL-1β, and IL-12p70 induced the differentiation of CD8 T cells to become cytotoxic and the maturation of CD4 T cells to synthesize proinflammatory Th1 cytokines [43]. Finally, macrophages from NOD mice have shown defects in clearance of necrotic and apoptotic cells, leading to autoreactive immune responses [51]. The consequences of delayed phagocytosis of apoptotic cells may result in the absence of non-inflammatory signals, creating a necrotic and hyperinflammatory environment to inadvertently induce bystander T cell activation.

Accumulating evidence has implicated a role for environmental triggers for T1D progression [52]. While genetics play a role in T1D susceptibility, they are not the sole determinant, as monozygotic twins share only a 40% co-incidence rate over a 40-year timespan [53]. Furthermore, worldwide T1D incidence increases at a rate of 3% per year [2], [3] while in the US the rate is 3.5% with the number of T1D diagnoses to triple from 179,388 in 2010 to 587,488 in 2050 [54]. Population genetics alone cannot account for such increases. Therefore, environmental determinants may be involved in disease initiation, acceleration, or both. Viral infections have long been proposed to constitute such an environmental trigger [55], [56], [57], [58].

Coxsackievirus is a non-enveloped, positive-sense single stranded RNA virus that belongs to the Enterovirus genus of the Picornaviridae family [59]. Epidemiological data provided by the Diabetes Autoimmunity Study in the Young (DAISY) showed that T1D progression in predisposed children coincided with prior enterovirus infections [60]. Studies have shown that infection with Coxsackievirus strains B3 (CB3) or B4 (CB4) can accelerate T1D progression in NOD mice [61], [62]. One mechanism of virus-accelerated T1D is due to the phagocytosis of virus-infected β-cells by APCs and subsequent bystander activation of autoreactive T cells [63]. Established insulitis was a prerequisite for this observed acceleration of T1D incidence, which suggests that Coxsackievirus infections impact disease onset through increasing inflammation and breaking peripheral tolerance [64], [65]. Macrophages can transfer the diabetogenicity of CB4 infection, as adoptive transfer of macrophages from CB4-infected NOD.scid mice was able to trigger diabetes onset in T cell receptor-transgenic NOD.BDC-2.5 mouse [63].

In addition to a hyperinflammatory phenotype, NOD mice also show impaired macrophage differentiation from hematopoietic precursors. The macrophage growth factor colony-stimulating factor 1 (CSF-1) was unable to prime macrophages isolated from NOD mice to secrete IL-1 in response to LPS stimulation [47]. Serreze et al. hypothesize that the failure of NOD mice to develop functionally mature monocytes may have pathogenic significance in TD. Interestingly, they observed that NOD mice displayed a defect in the ability of IFN-γ to induce protein kinase C (PKC)-mediated pathways in multiple NOD-derived cell lines. One such IFN-γ-defective response is down-regulation of MHC class I expression [48]. Therefore, the compromised ability of macrophages to effectively process and present antigens or to provide costimulatory signals, may result in the inability to initiate tolerance, but still retain the ability to activate autoreactive T cells.

Macrophages in T1D display a heightened proinflammatory signature and under conditions of oxidative stress, the generation of free radicals can facilitate proinflammatory M1 macrophage differentiation. Consequently, scavenging of ROS can induce an alternatively-activated M2 macrophage phenotype. In one study utilizing recombinant thioredoxin-1 (Trx), a potent antioxidant protein, El Hadri et al. observed an increase in the inducible expression of anti-inflammatory M2 macrophage markers CD206 and IL-10 [66]. Furthermore, treatment of proinflammatory M1 macrophages with Trx blunted the expression of TNF-α in a mouse model of atherosclerosis and promoted M2 macrophage differentiation to heal atherosclerotic lesions [66]. In the context of T1D, our lab has shown an inducible M2 macrophage phenotype by sequestration of ROS, as treatment of NOD.Rag mice with a superoxide dismutase mimetic following transfer of BDC-2.5 T cells induced M2 macrophage recruitment to the pancreas while inhibiting M1 macrophage infiltration and delaying the adoptive transfer of T1D [67]. As such, M2 macrophages hold potential as a cell-based therapy in T1D. Indeed, a seminal study by Parsa et al. showed that adoptive transfer of polarized M2 macrophages to 16-week-old pre-diabetic NOD mice inhibited spontaneous development of T1D at a rate of 80% over vehicle control mice [68].

To examine the role of NOX-derived superoxide in macrophages in T1D, the Ncf1m1J mutation was introgressed into NOD mice [69]. NOD.Ncf1m1J mice do not express the p47phox subunit (Fig. 1), a key scaffolding protein involved in NOX assembly and superoxide synthesis in immune cells including macrophages [70]. NOD.Ncf1m1J mice lacking the ability to generate NOX-derived superoxide exhibit a delay in the incidence of spontaneous [11], [69], adoptive transfer [69], and virus-accelerated T1D [71]. To define the redox-dependent mechanism of protection afforded by NOD.Ncf1m1J mice, the activation of TLR signaling pathways in macrophages from NOD.Ncf1m1J mice was assessed. Following poly(I:C)- or LPS-stimulation to examine TLR3- and TLR4-dependent signaling, respectively, a decrease in proinflammatory cytokines and Type I interferon synthesis was observed in NOD.Ncf1m1J macrophages in contrast to NOD [69], [72]. Importantly, recent published studies from our lab show that CB3-infected NOD.Ncf1m1J mice remained resistant to virus-induced diabetes [71], and this protection was partly due to the induction of a decreased proinflammatory M1 macrophage phenotype in NOD.Ncf1m1J mice. Our studies show that loss of superoxide production in NOD.Ncf1m1J mice induced phenotypic skewing of macrophages from a proinflammatory M1 to an anti-inflammatory M2 phenotype during spontaneous and adoptive transfer of T1D [67]. Importantly, induction of a proinflammatory antiviral response in macrophages is highly dependent on NOX-derived superoxide synthesis and contributes to CB3-accelerated T1D.

Adoptive transfer of a highly diabetogenic BDC-2.5 CD4 T cell clone [73], [74] showed a reduction in proinflammatory M1 macrophage infiltration in NOD.Ncf1m1J mice. Compared to NOD control mice, BDC-2.5 CD4 T cells failed to recruit macrophages to the pancreas of NOD.Ncf1m1J mice, which ultimately remained diabetes-free [11]. Studies by Padgett et al. showed that islet-resident macrophages from NOD.Ncf1m1J mice during spontaneous T1D progression display an enhanced alternatively-activated M2 phenotype in contrast to a proinflammatory M1 macrophage phenotype [67]. In addition to blunted inflammatory macrophage response, T cell responses were also affected by the Ncf1m1J mutation. CD8 T cell responses were less robust, as characterized by diminished release of perforin, granzyme, and proinflammatory cytokines including IFN-γ and TNF-α [11]. NOD.Ncf1m1J CD4 T cells were skewed away from a pathogenic, β-cell destructive Th1 phenotype and displayed a Th17 cytokine response [69]. While T cell responses from NOD mice containing the Ncf1m1J mutation exhibit a decreased proinflammatory phenotype and are inefficient in mediating pancreatic β-cell destruction, we provide evidence that ultimately it is the decreased proinflammatory M1 macrophage phenotype that is mainly responsible for delaying autoimmune diabetes in NOD.Ncf1m1J mice [11], [69]. In addition to their role in synthesizing proinflammatory effector molecules to damage β-cells, macrophages have an indispensable role as APCs to efficiently activate diabetogenic CD4 and CD8 T cells. The inability of macrophages to produce NOX-derived superoxide may also affect the ability of these innate immune cells to properly stimulate autoreactive T cells.

Section snippets

Role of macrophages in T cell activation

During the progression of T1D, β-cell antigens are phagocytosed by islet-resident macrophages. These macrophages along with DCs can act as APCs to activate CD4 and CD8 T cells to become proinflammatory effector T cells and to differentiate into cytotoxic T cells toward β-cells, respectively. Successful T cell activation requires at least three signals consisting of the T cell receptor (TCR) interacting with its MHC-bound cognate peptide on APCs (signal 1), engagement of costimulatory molecules

The role of NOX in the modification of putative T1D autoantigens

T1D is an organ-specific autoimmune disease, but with the exception of insulin, many of the autoantigens associated with disease progression are not solely expressed by the pancreatic β-cell including glutamic acid decarboxylase-65 (GAD65), zinc transporter 8 (ZnT8), tyrosine phosphatase-like protein insulinoma antigen-2 (IA-2), and heat-shock protein (Hsp60) [96]. One potential molecular mechanism to explain this difference in organ-specific autoimmunity versus systemic autoimmunity is due to

Summary and future directions

The goal of this review article was to emphasize the complex relationship between oxidative stress, NOX-derived superoxide produced by macrophages, and T1D disease progression. While ultimately considered a T cell-mediated autoimmune disease, macrophages nevertheless play an indispensable role in T1D. Studies utilizing the NOD.Ncf1m1J mouse model of autoimmune diabetes provide evidence that superoxide synthesis is necessary for mediating autoimmune responses in T1D, as NOD.Ncf1m1J mice exhibit

Acknowledgements

This work was supported by a JDRF Postdoctoral Fellowship (3-PDF-2018-592-A-N) to JMF and an NIH/NIDDK R01 Award (DK099550), an American Diabetes Association Career Development Award (7-12-CD-11), and a JDRF Award (1-SRA-2015-42-A-N) to HMT.

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