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.

Loss of melanocytes induced by activated CD8+ T cells is the pathological hallmark of vitiligo. Melanocyte-specific CD8+ T cells are recruited to the skin via chemokines, thereby releasing perforin, granzyme, and other cytotoxic substances that destroy the melanocytes. However, the mechanism of CD8+ T cells to adhere to melanocytes is unknown. Previous transcriptome sequencing results published by our group showed that the occluding (OCLN) gene was significantly upregulated in CD8+ T cells from skin lesions of vitiligo. Occludin is a crucial component of the tight junction between cells; in cells without tight junction, occludin mediates the adhesion of two cells in the form of a self-ligand. This study demonstrated that OCLN gene expression was elevated in the CD8+ T cells of vitiligo patients, and occludin mediates the adherence of CD8+ T cells to melanocytes. Besides, pathological changes in vitiligo skin lesions reveal that CD8+ T cells continuously persist in the skin lesions, which is related to the persistence of the disease. In this regard, we found that fibroblasts from vitiligo patients significantly express occludin, which may participate in the continuous retention of CD8+ T cells in the skin lesions. The pathogenesis of vitiligo is closely related to oxidative stress, and our data suggest that overexpression of hypoxia-inducible factor-1α (HIF-1α) increases the expression of occludin. Besides, ChIP-qPCR of CD8+ T cells revealed that HIF-1α directly binds to the OCLN promoter. Thus, occludin upregulation promotes the adhesion of CD8+ T cells and melanocytes via the HIF-1α signaling pathway. Our study results suggested a critical role for OCLN in the occurrence, progression, and maintenance of vitiligo. Therefore, inhibiting the expression of OCLN gene may be a potential targeted treatment strategy.

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