Pyroptosis and Its Role in Autoimmune Disease: A Potential Therapeutic Target

Abstract

Autoimmune diseases are a group of heterogeneous diseases with diverse clinical manifestations that can be divided into systemic and organ-specific. The common etiology of autoimmune diseases is the destruction of immune tolerance and the production of autoantibodies, which attack specific tissues and/or organs in the body. The pathogenesis of autoimmune diseases is complicated, and genetic, environmental, infectious, and even psychological factors work together to cause aberrant innate and adaptive immune responses. Although the exact mechanisms are unclear, recently, excessive exacerbation of pyroptosis, as a bond between innate and adaptive immunity, has been proven to play a crucial role in the development of autoimmune disease. Pyroptosis is characterized by pore formation on cell membranes, as well as cell rupture and the excretion of intracellular contents and pro-inflammatory cytokines, such as IL-1β and IL-18. This overactive inflammatory programmed cell death disrupts immune system homeostasis and promotes autoimmunity. This review examines the molecular structure of classical inflammasomes, including NLRP3, AIM2, and P2X7-NLRP3, as the switches of pyroptosis, and their molecular regulation mechanisms. The sophisticated pyroptosis pathways, including the canonical caspase-1-mediated pathway, the noncanonical caspase-4/5/11-mediated pathway, the emerging caspase-3-mediated pathway, and the caspase-independent pathway, are also described. We highlight the recent advances in pyroptosis in autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, Sjögren’s syndrome and dermatomyositis, and attempt to identify its potential advantages as a therapeutic target or prognostic marker in these diseases.

Evidence of pyroptosis and ferroptosis extensively involved in autoimmune diseases at the single-cell transcriptome level

“…For example, Talaromyces marneffei can activate pyroptosis mediated by AIM2-caspase-1/-4-GSDMD in hepatocytes [99]. Moreover, some researchers have begun to pay attention to pyroptosis and ferroptosis in autoimmune diseases and drugs toxicity [100][101][102][103][104]. Our results provide pyroptosis/ ferroptosis-associated signatures in several autoimmune diseases at the single-cell level, which provide extremely precise target information for the application of novel therapeutic approaches.…”

SARS-CoV-2 induces “cytokine storm” hyperinflammatory responses in RA patients through pyroptosis

“…In recent years the mechanism of pyroptosis has been shown to play a key role in the development of autoimmune diseases. In the course of the pro-inflammatory process, activation of the pyroptosis pathway causes host cells to release large amounts of pro-inflammatory cytokines and directs innate immune cells to the site of injury ( 119 ), which ultimately results in an overreactive immune response akin to a “cytokine storm” that sustains an ongoing autoimmune disease ( 189 , 190 ).…”

Metabolic alterations of the immune system in the pathogenesis of autoimmune diseases

“…Another mechanism of mROS-triggered myeloid cell death during infection and inflammation is pyroptosis, which is a lytic process induced in inflammasome-activated cells to counteract inflammatory processes. Once activated, the inflammasome ( Box 1 ) leads the cells to acquire pores in the cell membrane that allow the secretion of synthesized proinflammatory cytokines such as active IL-1β and IL-18, perpetuating the inflammatory process [ 34 ]. In SLE, inflammasome activity is perturbed and, together with increased mROS production, might contribute to the pathogenesis of the disease through increased generation of autoantigens by pyroptosis and enhanced synthesis of proinflammatory cytokines [ 35 ].…”