Inflammasomes and autoimmunity

Abstract

The NOD-like receptor (NLR) family members are cytosolic sensors of microbial components and danger signals. A subset of NLRs control inflammasome assembly that results in caspase-1 activation and, in turn, IL-1β and IL-18 production. Excessive inflammasome activation can cause autoinflammatory disorders, including the hereditary periodic fevers. Autoinflammatory and autoimmune diseases form a disease spectrum of aberrant, immune-mediated inflammation against self, through innate and adaptive immunity. However, the role of inflammasomes in autoimmune disease is less clear than in autoinflammation, despite the numerous effects IL-1β and IL-18 can have on shaping adaptive immunity. We summarize the role of inflammasomes in autoimmune disorders, highlight the need for a better understanding of inflammasomes in these conditions and offer suggestions for future research directions.

Figure 1. Activation of the inflammasome

The various inflammasomes are activated by a wide spectrum of DAMPs and PAMPs. NLRP3 activation and inflammasome formation is depicted as an example. Once activated, the inflammasome-forming NLR undergoes a conformational change, allowing for NLR binding to ASC via the pyrin domains (PYD). ASC acts an adaptor protein, and binds to pro-caspase-1 through caspase recruitment domains (CARD). This large complex is termed the inflammasome and provides the platform for the autoactivation of caspase-1 by proteolytic cleavage. Active caspase-1 (p20/p10) then cleaves pro-forms of IL-1β and IL-18, allowing for their secretion and biological activity.

Figure 2. The influence of inflammasome activation on adaptive immunity

Activation of the inflammasome results in the cleavage of proIL-1β and proIL-18 into their biologically active forms, IL-1β and IL-18, which can shape adaptive immune responses in a number of ways. IL-18, formerly known as IFNγ-inducing factor, enhances Th1 cell proliferation and production of IFNγ; IL-1β can enhance naïve T cell survival and proliferation, via upregulation of the IL-2 receptor. Additionally, a role for IL-1R signaling in Th17 cell differentiation and homeostasis has recently been reported. Humoral responses can also be enhanced by IL-1β, either directly via increased B cell proliferation or indirectly by upregulation of co-stimulatory molecules on T cells. Therefore, activation of the inflammasome can significantly affect an adaptive immune response through the cleavage of IL-18 and IL-1β.