Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Immunity. 2021 Oct 12;54(10):2273-2287.e6. doi: 10.1016/j.immuni.2021.09.004.
Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterol metabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell response. Mice lacking cholesterol 25-hydroxylase (CH25H), the enzyme generating 25-HC, had higher frequencies of immunoglobulin A (IgA)-secreting antigen-specific B cells upon immunization or infection. 25-HC did not affect class-switch recombination but rather restrained plasma cell (PC) differentiation. 25-HC was produced by follicular dendritic cells and increased in response to dietary cholesterol. Mechanistically, 25-HC restricted activation of the sterol-sensing transcription factor SREBP2, thereby regulating B cell cholesterol biosynthesis. Ectopic expression of SREBP2 in germinal center B cells induced rapid PC differentiation, whereas SREBP2 deficiency reduced PC output in vitro and in vivo. High-cholesterol diet impaired, whereas Ch25h deficiency enhanced, the IgA response against Salmonella and the resulting protection from systemic bacterial dissemination. Thus, a 25-HC-SREBP2 axis shapes the humoral response at the intestinal barrier, providing insight into the effect of high dietary cholesterol in intestinal immunity.
高胆固醇饮食会改变肠道免疫。在这里，我们研究了胆固醇代谢产物 25-羟胆固醇（25-HC）如何影响肠道 B 细胞反应。缺乏胆固醇 25-羟化酶（CH25H）的小鼠，该酶产生 25-HC，在免疫或感染时产生更高频率的分泌抗原特异性 IgA 的 B 细胞。25-HC 不影响类别转换重组，而是抑制浆细胞（PC）分化。25-HC 由滤泡树突状细胞产生，并响应膳食胆固醇而增加。从机制上讲，25-HC 限制了固醇感应转录因子 SREBP2 的激活，从而调节 B 细胞胆固醇生物合成。生殖中心 B 细胞中 SREBP2 的异位表达诱导快速 PC 分化，而 SREBP2 缺乏减少了体外和体内的 PC 输出。高胆固醇饮食会损害，而 Ch25h 缺乏会增强，针对沙门氏菌的 IgA 反应以及由此产生的全身细菌播散的保护作用。因此，25-HC-SREBP2 轴在肠道屏障处塑造了体液反应，为了解高膳食胆固醇对肠道免疫的影响提供了线索。
