美国马萨诸塞大学Andrea Reboldi课题组发现，胆固醇代谢物25-羟基胆固醇抑制转录调节因子SREBP2并限制肠道IgA浆细胞的分化。这一研究成果于2021年10月12日发表在国际学术期刊《免疫》上。

研究人员揭示了胆固醇代谢物25-羟基胆固醇（25-HC）如何影响肠道B细胞反应。缺乏胆固醇25-羟化酶（CH25H，即产生25-HC的酶）的小鼠，在免疫或感染时有更高频率的免疫球蛋白A（IgA）分泌的抗原特异性B细胞。25-HC不影响类别转换重组，而是抑制了浆细胞（PC）的分化。25-HC由滤泡树突状细胞产生，并在饮食中胆固醇的作用下增加。从机制上讲，25-HC限制了甾醇感应转录因子SREBP2的激活，从而调节了B细胞胆固醇的生物合成。

生发中心B细胞中SREBP2的异位表达诱导了快速的PC分化，而SREBP2的缺乏则减少了体外和体内的PC输出。高胆固醇饮食损害了对沙门氏菌的IgA反应，而Ch25h缺乏则增强了对系统性细菌传播的保护。因此，25-HC-SREBP2轴塑造了肠道屏障的体液反应，揭示了对高膳食胆固醇在肠道免疫中的影响。

据悉，高胆固醇的饮食改变了肠道免疫力。

附：英文原文

Title: The cholesterol metabolite 25-hydroxycholesterol restrains the transcriptional regulator SREBP2 and limits intestinal IgA plasma cell differentiation

Author: Bruno C. Trindade, Simona Ceglia, Alyssa Berthelette, Fiona Raso, Kelsey Howley, Jagan R. Muppidi, Andrea Reboldi

Issue&Volume: 2021/10/12

Abstract: Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterolmetabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell response. Micelacking cholesterol 25-hydroxylase (CH25H), the enzyme generating 25-HC, had higherfrequencies of immunoglobulin A (IgA)-secreting antigen-specific B cells upon immunizationor infection. 25-HC did not affect class-switch recombination but rather restrainedplasma cell (PC) differentiation. 25-HC was produced by follicular dendritic cellsand increased in response to dietary cholesterol. Mechanistically, 25-HC restrictedactivation of the sterol-sensing transcription factor SREBP2, thereby regulating Bcell cholesterol biosynthesis. Ectopic expression of SREBP2 in germinal center B cellsinduced rapid PC differentiation, whereas SREBP2 deficiency reduced PC output in vitro and in vivo. High-cholesterol diet impaired, whereas Ch25h deficiency enhanced, the IgA responseagainst Salmonella and the resulting protection from systemic bacterial dissemination. Thus, a 25-HC-SREBP2axis shapes the humoral response at the intestinal barrier, providing insight intothe effect of high dietary cholesterol in intestinal immunity.

DOI: 10.1016/j.immuni.2021.09.004

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00389-7