The regulation of self-tolerance and the role of inflammasome molecules

Abstract

Inflammasome molecules make up a family of receptors that typically function to initiate a proinflammatory response upon infection by microbial pathogens. Dysregulation of inflammasome activity has been linked to unwanted chronic inflammation, which has also been implicated in certain autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and related animal models. Classical inflammasome activation-dependent events have intrinsic and extrinsic effects on both innate and adaptive immune effectors, as well as resident cells in the target tissue, which all can contribute to an autoimmune response. Recently, inflammasome molecules have also been found to regulate the differentiation and function of immune effector cells independent of classical inflammasome-activated inflammation. These alternative functions for inflammasome molecules shape the nature of the adaptive immune response, that in turn can either promote or suppress the progression of autoimmunity. In this review we will summarize the roles of inflammasome molecules in regulating self-tolerance and the development of autoimmunity.

Keywords: autoimmunity; immunoregulation; inflammasomes; inflammation; self-tolerance.

Figure 1

Inflammasome assembly and activation. Canonical activation of the inflammasome pathway begins with a primary signal, such as PAMPs, endogenous-derived DAMPs, or dsDNA, that are recognized by pattern recognition receptors (PRRs), such as toll-like receptors (TLRs). PRR activation induces NF-κB and subsequent expression of NLRP, pro-IL-1β and pro-IL-18, and post-translational events. Formation of the inflammasome complex occurs when the sensor protein, such as NLRP3, binds to ASC, driving caspase activation and inflammasome assembly. Caspase enzymes cleave pro-IL-1β and pro-IL-18 as well as the C terminus from gasdermin D, allowing the gasdermin D N-terminal domain to form pores necessary for pyroptosis. IL-1β and IL-18, as well as cellular contents are released to establish a proinflammatory response. In autoimmune disease, inflammasome activation can occur via activation in a noncanonical matter including agonist-induced ion flux and lysosomal and mitochondrial reactive oxygen species (ROS). The figure was prepared using Biorender software licensed to the UNC Lineberger Comprehensive Cancer Center.

Figure 2

The role of inflammasomes in multiple sclerosis (MS) and experimental autoimmune encephalitis (EAE). The autoimmune response for MS is believed to begin in the periphery. Activation of NLRP3 and NLRC4 inflammasome pathways in antigen-presenting cells (APC) enhance stimulation and differentiation of pathogenic CD4⁺ Th1/Th17 and CD8⁺ Tc1 subsets. On the other hand, NLRC3 activation in dendritic cells (DC) is protective against disease by inhibiting DC maturation. Secretion of IL-1β and IL-18 increase T cell expression of osteopontin (OPN), CCR2 (binding CCL7/8), and CXCR6 (binding CXCL16) to promote infiltration to the central nervous system (CNS). Upon activation and differentiation, CD4⁺ and CD8⁺ T cells, and B cells migrate to the CNS. In the CNS, peripheral DC, macrophages (MP), and monocytes (MO) further amplify inflammation. CNS resident cells such as microglia and astrocytes also promote inflammation. Lysophosphatidylcholine (LPC) activates NLRP3 and NLRC4, causing secretion of IL-1β and chemokines, leading to further inflammation and demyelination. NLRP9 expression is increased in microglia. NLRX1 and NLRP12 serve to down-regulate neuroinflammation and provide protection against disease as indicated by the red arrows. Reduction of NLRX1 and NLRP12 can lead to exacerbated disease states. Purinergic receptor (P2X7R). The figure was prepared using Biorender software licensed to the UNC Lineberger Comprehensive Cancer Center.

Figure 3

Events in dysregulated inflammasome activation in rheumatoid arthritis (RA). NLRP3 and NLRC4 activity are increased in monocytes (MO) and DC by Fc-receptor (FcR) binding of DNA-IgG immune complexes and complement component 1q (C1q) binding to pentraxin 3 (PTX3). Uptake of elevated levels of calciprotein particles (CPPs) in the joint by resident DC also leads to NLRP3 activation. Resulting pyroptosis and secretion of proinflammatory cytokines promote RA progression by favoring Th1 and Th17 differentiation and development of autoantibodies and RA factor producing plasma cells. NLRP3 activation is also increased in Th17 cells. Aberrant lysosomal processing of endocytosed dsDNA can lead to AIM2 activation in joint resident macrophages (MP). Neutrophils exhibit reduced expression of inflammasome molecules, which correlates with decreased disease severity. NLRP3, NLRC5 and AIM2 are associated with proinflammatory properties of fibroblast-like synoviocytes (FLS), while NLRP6 and NLRP12 serve protective roles, indicated by the red arrows. NLRP6 limits FLS cytokine production, and NLRP12 negatively regulates Th17 subset differentiation. Reduced expression of NLRP6 and NLRP12 leads to pathology. Matrix metalloproteinases (MMP). The figure was prepared using Biorender software licensed to the UNC Lineberger Comprehensive Cancer Center.

Figure 4

The roles of inflammasomes in type 1 diabetes (T1D). Under homeostasis, healthy intestinal epithelial cells maintain intestinal barrier function and regulate permeability to prevent passage of harmful elements such as microorganisms and toxins. AIM2 serves a protective function (indicated by the red arrow). Dysregulation of inflammasome function, such as AIM2 deficiency, leads to reduced production of IL-18, which is necessary for maintaining intestinal barrier function. Consequently, inflammasome dysregulation enhances intestinal permeability and triggers inflammation. On the other hand, NLRP3 is linked to dysbiosis within the gut microbiota, which can exacerbate T1D progression. In the pancreatic lymph node (PLN), upregulation of NLRP3 in APC promotes IL-1β production that ultimately drives differentiation of diabetogenic CD8⁺ Tc1, CD4⁺ Th1, and Th17 cells. In the pancreatic islets, NLRP3 hyperactivity in β cells induces release of cytokines and chemokines. These conditions combined with other immunomodulatory factors establish a positive feedback loop to further perpetuate pancreatic inflammation. Macrophage (MP), dendritic cell (DC), antigen-presenting cell (APC). The figure was prepared using Biorender software licensed to the UNC Lineberger Comprehensive Cancer Center.

Figure 5

The roles of inflammasomes in systemic lupus erythematosus (SLE). Upregulation of NLRP3 inflammasome in macrophages (MP) and DC by DNA or RNA immune complexes (IC) or small nuclear ribonucleoprotein (snRNP) leads to release of proinflammatory cytokines such as IL-1β, IL-18 and IFNα. Dysregulation of inflammasomes in APC also promotes Th17 and Tfh cell differentiation. Tfh cells and IFNα facilitate B cell maturation and autoantibody production. However, production of IFNα is regulated by AIM2-mediated pyroptosis (indicated by red arrows). Deposition of IC, infiltrating Th17 cells, and production of autoantibodies and cytokines all contribute to tissue damage. IL-18 activates NETosis in neutrophils and in turn upregulates NLRP3 and IL-1β and IL-18 secretion in macrophages via cathelicidin antimicrobial peptide (LL37)-driven K⁺ efflux mediated by the P2X7 receptor (P2X7R). These cytokines further induce pyroptosis and release of cellular and nuclear contents, leading to the production of anti-nuclear autoantibodies and further amplifying systemic inflammation. Inflammasome activation in cells of target tissues, such as kidney resident podocytes also contributes to disease pathology by producing IL-1β. The figure was prepared using Biorender software licensed to the UNC Lineberger Comprehensive Cancer Center.