Dysfunctional T Follicular Helper Cells Cause Intestinal and Hepatic Inflammation in NASH.
Dysfunctional T Follicular Helper Cells Cause Intestinal and Hepatic Inflammation in NASH.
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功能失调的滤泡辅助 T 细胞会导致 NASH 中的肠道和肝脏炎症。
DOI：
10.1101/2023.06.07.544061
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Revelo,XavierS
中科院分区：
文献类型：
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作者：
Wang,Haiguang;Barrow,Fanta;Fredrickson,Gavin;Florczak,Kira;Nguyen,Huy;Parthiban,Preethy;Herman,Adam;Adeyi,Oyedele;Staley,Christopher;Ikramuddin,Sayeed;Ruan,Hai-Bin;Jameson,StephenC;Revelo,XavierS
以肝脏炎症和细胞损伤为特征的非酒精性脂肪性肝炎（NASH）是非酒精性脂肪性肝病最严重的形式，也是肝移植增长最快的适应症。肠道免疫系统是局部和全身炎症的中心调节剂。特别地，派伊尔集合淋巴结（PP）含有T滤泡辅助（Tfh）细胞，其支持产生高亲和力肠IgA和维持肠内稳态所需的生发中心（GC）反应。然而，我们对NASH发病过程中调节粘膜免疫的机制的理解是不完整的。在这里，使用类似于人类疾病关键特征的临床前小鼠模型，我们发现了Tfh细胞在NASH发病机制中的重要作用。我们发现，喂食高脂肪高碳水化合物（HFHC）饮食的小鼠具有发炎的肠道微环境，其特征在于PP增大，Tfh细胞扩增。令人惊讶的是，NASH小鼠PP中的Tfh细胞显示出功能障碍的证据，沿着有缺陷的GC应答和减少的IgA + B细胞。喂食HFHC饮食的Tfh缺陷小鼠表现出肠道通透性受损，肝脏炎症增加，NASH加重，表明Tfh细胞在维持肠道-肝脏稳态中的基本作用。从机制上讲，HFHC饮食喂养导致Tfh细胞中转录因子KLF2表达的异常增加，这抑制了其功能。因此，CD4 T细胞中KLF2表达降低的转基因小鼠显示出改善的Tfh细胞功能和改善的NASH，包括HFHC喂养后的肝脂肪变性、炎症和纤维化。总的来说，这些发现强调了Tfh细胞作为参与NASH期间肠-肝轴炎症调节的关键肠道免疫细胞。
Nonalcoholic steatohepatitis (NASH), characterized by hepatic inflammation and cellular damage, is the most severe form of nonalcoholic fatty liver disease and the fastest-growing indication for a liver transplant. The intestinal immune system is a central modulator of local and systemic inflammation. In particular, Peyer’s patches (PPs) contain T follicular helper (Tfh) cells that support germinal center (GC) responses required for the generation of high-affinity intestinal IgA and the maintenance of intestinal homeostasis. However, our understanding of the mechanisms regulating mucosal immunity during the pathogenesis of NASH is incomplete. Here, using a preclinical mouse model that resembles the key features of human disease, we discovered an essential role for Tfh cells in the pathogenesis of NASH. We have found that mice fed a high-fat high-carbohydrate (HFHC) diet have an inflamed intestinal microenvironment, characterized by enlarged PPs with an expansion of Tfh cells. Surprisingly, the Tfh cells in the PPs of NASH mice showed evidence of dysfunction, along with defective GC responses and reduced IgA+ B cells. Tfh-deficient mice fed the HFHC diet showed compromised intestinal permeability, increased hepatic inflammation, and aggravated NASH, suggesting a fundamental role for Tfh cells in maintaining gut-liver homeostasis. Mechanistically, HFHC diet feeding leads to an aberrant increase in the expression of the transcription factor KLF2 in Tfh cells which inhibits its function. Thus, transgenic mice with reduced KLF2 expression in CD4 T cells displayed improved Tfh cell function and ameliorated NASH, including hepatic steatosis, inflammation, and fibrosis after HFHC feeding. Overall, these findings highlight Tfh cells as key intestinal immune cells involved in the regulation of inflammation in the gut-liver axis during NASH.