State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang Universitygrid.13402.34, Hangzhou, China.
Jinan Microecological Biomedicine Shandong Laboratory, Jinan, China.
Microbiol Spectr. 2022 Oct 26;10(5):e0171722. doi: 10.1128/spectrum.01717-22. Epub 2022 Aug 16.
Autoimmune hepatitis (AIH) is a progressive inflammation-associated liver injury. Pyroptosis is a novel inflammatory programmed cell death wherein gasdermin D (GSDMD) serves as the executioner. Our work challenged mice with concanavalin A (ConA) to try to unveil the actual role of GSDMD in AIH. After ConA injection, mice exhibited more severe liver damage characterized by a lower survival rate, more extensive hepatocyte necrosis and apoptosis, and higher serum transaminase levels, indicating the protection of GSDMD in ConA-induced AIH. Furthermore, the mice exhibited higher hepatic expression and serum levels of inflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], and interleukin-17A [IL-17A]) and more infiltration of macrophages and neutrophils after ConA treatment than did wild-type (WT) mice. mice with AIH showed increased hepatic l-glutamine levels but decreased glycerophospholipid metabolites levels. L-glutamine levels showed positive correlations while glycerophospholipid metabolites showed negative associations with liver injury indexes and inflammation markers. We further observed a destroyed intestinal barrier in mice after ConA injection as indicated by decreased transcriptional expressions of , , , and . ConA-treated mice also exhibited higher serum LPS binding protein (LBP) concentrations and hepatic and mRNA levels. Further fecal 16S rRNA gene sequencing demonstrated decreased relative abundances of and but increased relative abundances of and in mice with AIH. was negatively correlated with liver injury and inflammation indexes and positively associated with , , and levels. was positively related to liver injury and inflammatory cytokines and negatively correlated with gut barrier indexes. Our study provides the first direct clues to the protective role of gasdermin D (GSDMD) in autoimmune hepatitis (AIH). We demonstrated that knockout exacerbated concanavalin A (ConA)-induced AIH in mice. It may be due to the destroyed intestinal barrier and changes in certain intestinal microbes and hepatic metabolites resulting in increased liver injury and inflammation in ConA-treated mice. This finding suggested a nonnegligible role of GSDMD in AIH and also confirmed its physiological nonpyroptosis effects on the host. The role of GSDMD in autoimmune liver diseases or other liver diseases is complex and intriguing, deserving deep investigation.
自身免疫性肝炎（AIH）是一种进展性炎症相关的肝损伤。细胞焦亡是一种新的炎症程序性细胞死亡，其中 gasdermin D（GSDMD）作为执行者。我们的工作通过用伴刀豆球蛋白 A（ConA）对 小鼠进行攻击，试图揭示 GSDMD 在 AIH 中的实际作用。注射 ConA 后， 小鼠表现出更严重的肝损伤，表现为生存率降低、更广泛的肝细胞坏死和凋亡以及更高的血清转氨酶水平，表明 GSDMD 对 ConA 诱导的 AIH 具有保护作用。此外，与野生型（WT）小鼠相比， 小鼠在 ConA 处理后表现出更高的肝内炎症细胞因子（γ干扰素[IFN-γ]、肿瘤坏死因子α[TNF-α]和白细胞介素-17A[IL-17A]）表达和血清水平以及更多的巨噬细胞和中性粒细胞浸润。AIH 小鼠的肝内 L-谷氨酰胺水平升高，但甘油磷脂代谢物水平降低。L-谷氨酰胺水平呈正相关，而甘油磷脂代谢物水平与肝损伤指标和炎症标志物呈负相关。我们进一步观察到 ConA 注射后 小鼠的肠道屏障被破坏，表现为转录表达的 、 、 和 降低。ConA 处理的 小鼠也表现出更高的血清脂多糖结合蛋白（LBP）浓度和肝内 和 mRNA 水平。进一步的粪便 16S rRNA 基因测序表明，AIH 小鼠的 和 相对丰度降低，但 和 相对丰度增加。 与肝损伤和炎症指标呈负相关，与 、 和 水平呈正相关。 与肝损伤和炎症细胞因子呈正相关，与肠道屏障指标呈负相关。我们的研究首次直接揭示了 GSDMD 在自身免疫性肝炎（AIH）中的保护作用。我们证明了 knockout 加剧了 ConA 诱导的 AIH 小鼠。这可能是由于破坏的肠道屏障和某些肠道微生物和肝代谢物的变化导致 ConA 处理的 小鼠肝损伤和炎症增加。这一发现表明 GSDMD 在 AIH 中具有不可忽视的作用，并证实了其对宿主的生理非细胞焦亡作用。GSDMD 在自身免疫性肝病或其他肝病中的作用是复杂而有趣的，值得深入研究。
