TSPO is involved in the regulation of GSDMD-mediated inflammatory bowel disease and macrophage pyroptosis

Title: TSPO is involved in the regulation of GSDMD-mediated inflammatory bowel disease and macrophage pyroptosis Journal: Cells 2022, 11(5), 856 Link: http://doi.org/10.3390/cells11050856

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Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease of the intestine characterized by persistent inflammation of the colonic mucosa and submucosa. Inflammatory bowel disease is often associated with inflammasome activation and cytokine release, which are associated with pyroptosis. Pyroptosis is a type of programmed cell death that usually occurs in inflammation. When cells are stimulated by inflammatory signals, the downstream inflammasome complex NLRP3 is activated and caspase-1 is activated to spline GSDMD into N-terminal GSDMD fragments (P30). Free GSDMD (P30) can be targeted into the plasma membrane, forming toxic pores that allow inflammatory factors to penetrate into the extracellular space. The increasing pore structure can cause osmotic pressure imbalance in the cell, resulting in cell swelling and loss of plasma membrane integrity, and cell death. Recent studies have shown that pyroptosis effector proteins can also target mitochondrial membranes. 18-kDa (TSPO) is one of the mitochondrial outer membranes, and TSPO expression is highly upregulated in many inflammatory diseases and colon cancer, such as IBD and colon cancer. However, the molecular mechanism of TSPO in inflammation and pyroptosis is still unknown.The research team from the Chinese Academy of Medical Sciences used TSPO knockout and wild-type mice to establish dextran sodium sulfate(DSS) -induced acute and chronic colitis mouse models. The results showed that TSPO-KO mice had more severe colitis damage compared with WT mice. In the experiment, the author found that TSPO deficiency resulted in the presence of more M1 macrophages in the colon. NLRP3 was overactivated as well as IL-1 β expression was significantly increased in TSPO-KO mice,. Western blot assay showed that caspase-1 and ASC were significantly reduced in TSPO-KO macrophage cells, and the level of pyroptosis effector GSDMD was significantly increased. Using multiple immunohistochemistry, TSPO was found to inhibit pyroptosis by interacting with mitochondria-targeted GSDMD in the process of pyroptosis induced by LPS and ATP.Taken together, this study reveals the molecular mechanism of TSPO in inflammation and pyroptosis, that is, TSPO expression is rapidly upregulated in response to inflammation, and TSPO interacts with pyroptosis effector GSDMD to provide cell protection and inhibit cell death.