Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School and Blavatnik Institute, Boston, Massachusetts 02115, United States.
Laboratory of Systems Pharmacology, Harvard Medical School and Blavatnik Institute, Boston, Massachusetts 02115, United States.
J Am Chem Soc. 2023 Nov 1;145(43):23422-23426. doi: 10.1021/jacs.3c09734. Epub 2023 Oct 23.
An systematic phenotypic screen of the mouse gut microbiome for metabolites with an immunomodulatory effect identified as one of only two members with an oversized effect on T-cell populations. Here we report the identification and characterization of a lipid, MiCL-1, as the responsible metabolite. MiCL-1 is an 18:1-16:0 cardiolipin, whose close relatives are found on concave lipid surfaces of both mammals and bacteria. MiCL-1 was synthesized to confirm the structural analysis and functionally characterized in cell-based assays. It has a highly restrictive structure-activity profile, as its chain-switched analog fails to induce responses in any of our assays. MiCL-1 robustly induces the production of pro-inflammatory cytokines like TNF-α, IL-6, and IL-23, but has no detectable effect on the anti-inflammatory cytokine IL-10. As is the case with other recently discovered immunomodulatory lipids, MiCL-1 requires functional TLR2 and TLR1 but not TLR6 in cell-based assays.
一项针对具有免疫调节作用的肠道微生物代谢产物的系统性表型筛选发现，只有两种成员对 T 细胞群体具有超大的影响。在这里，我们报告了一种脂质 MiCL-1 的鉴定和特征，它是负责的代谢物。MiCL-1 是一种 18:1-16:0 心磷脂，其近亲存在于哺乳动物和细菌的凹面脂质表面。合成了 MiCL-1 以确认结构分析，并在基于细胞的测定中进行了功能表征。它具有高度受限的结构-活性谱，因为其链交换类似物在我们的任何测定中都不能诱导反应。MiCL-1 可强烈诱导 TNF-α、IL-6 和 IL-23 等促炎细胞因子的产生，但对抗炎细胞因子 IL-10 没有可检测到的作用。与其他最近发现的免疫调节脂质一样，MiCL-1 在基于细胞的测定中需要功能性 TLR2 和 TLR1，但不需要 TLR6。
