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Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell–mediated inflammation in the skin
发表日期:2021-10-12

Cholesterol metabolite curbs T cell enthusiasm

Interleukin-27 (IL-27) is a cytokine with known immunoregulatory effects based on prior studies of IL-27–deficient mice, but the mechanisms contributing to IL-27’s suppressive effects are still poorly understood. Takahashi et al. identified the gene encoding cholesterol 25-hydroxylase (Ch25h), the enzyme that converts cholesterol to 25-hydroxycholesterol (25OHC), as strongly and selectively induced in T cells stimulated with IL-27 versus other combinations of cytokines. Extracellular 25OHC selectively impaired in vitro growth of activated T cells through impairment of cholesterol biosynthesis while sparing quiescent T cells. In autoreactive T cells capable of inducing dermatitis after adoptive transfer, genetic absence of Ch25h or the IL-27 receptor resulted in more severe skin disease. These findings identify IL-27–induced 25OHC as immunomodulatory cholesterol metabolite with therapeutic potential in autoimmune and inflammatory diseases.

根据先前对 IL-27 缺陷小鼠的研究,白细胞介素 27 (IL-27) 是一种具有已知免疫调节作用的细胞因子,但对 IL-27 抑制作用的机制仍知之甚少。高桥等人鉴定了编码胆固醇 25-羟化酶 ( Ch25h )的基因,该酶将胆固醇转化为 25-羟基胆固醇 (25OHC),与其他细胞因子组合相比,在用 IL-27 刺激的 T 细胞中强烈且选择性地诱导。细胞外 25OHC 通过损害胆固醇生物合成选择性地损害活化 T 细胞的体外生长,同时保留静止 T 细胞。在过继转移后能够诱发皮炎的自身反应性 T 细胞中,Ch25h 的遗传缺失或 IL-27 受体导致更严重的皮肤病。这些发现将 IL-27 诱导的 25OHC 作为免疫调节胆固醇代谢物,在自身免疫和炎症性疾病中具有治疗潜力。

血清培养基瓶
 血清培养基瓶

Abstract

Interleukin-27 (IL-27) is an immunoregulatory cytokine whose essential function is to limit immune responses. We found that the gene encoding cholesterol 25-hydroxylase (Ch25h) was induced in CD4+ T cells by IL-27, enhanced by transforming growth factor–β (TGF-β), and antagonized by T-bet. Ch25h catalyzes cholesterol to generate 25-hydroxycholesterol (25OHC), which was subsequently released to the cellular milieu, functioning as a modulator of T cell response. Extracellular 25OHC suppressed cholesterol biosynthesis in T cells, inhibited cell growth, and induced nutrient deprivation cell death without releasing high-mobility group box 1 (HMGB1). This growth inhibitory effect was specific to actively proliferating cells with high cholesterol demand and was reversed when extracellular cholesterol was replenished. Ch25h-expressing CD4+ T cells that received IL-27 and TGF-β signals became refractory to 25OHC-mediated growth inhibition in vitro. Nonetheless, IL-27–treated T cells negatively affected viability of bystander cells in a paracrine manner, but only if the bystander cells were in the early phases of activation. In mouse models of skin inflammation due to autoreactive T cells or chemically induced hypersensitivity, genetic deletion of Ch25h or Il27ra led to worse outcomes. Thus, Ch25h is an immunoregulatory metabolic switch induced by IL-27 and dampens excess bystander T effector expansion in tissues through its metabolite derivative, 25OHC. This study reveals regulation of cholesterol metabolism as a modality for controlling tissue inflammation and thus represents a mechanism underlying T cell immunoregulatory functions.

10层细胞工厂
10层细胞工厂

白细胞介素 27 (IL-27) 是一种免疫调节细胞因子,其基本功能是限制免疫反应。我们发现编码胆固醇 25-羟化酶 (Ch25h) 的基因在 CD4 +IL-27 诱导 T 细胞,通过转化生长因子-β (TGF-β) 增强,并被 T-bet 拮抗。Ch25h 催化胆固醇生成 25-羟基胆固醇 (25OHC),随后释放到细胞环境中,作为 T 细胞反应的调节剂。细胞外 25OHC 抑制 T 细胞中胆固醇的生物合成,抑制细胞生长,并诱导营养缺乏细胞死亡,而不会释放高迁移率族框 1 (HMGB1)。这种生长抑制作用对高胆固醇需求的活跃增殖细胞具有特异性,并且在补充细胞外胆固醇时会逆转。Ch25h 表达 CD4 +接受 IL-27 和 TGF-β 信号的 T 细胞在体外对 25OHC 介导的生长抑制产生耐药性。尽管如此,IL-27 处理的 T 细胞以旁分泌方式对旁观者细胞的活力产生负面影响,但前提是旁观者细胞处于激活的早期阶段。在由自身反应性 T 细胞或化学诱导的超敏反应引起的皮肤炎症小鼠模型中,Ch25hIl27ra 的基因缺失导致了更糟糕的结果。因此,Ch25h 是由 IL-27 诱导的免疫调节代谢开关,并通过其代谢产物衍生物 25OHC 抑制组织中过量的旁观者 T 效应子扩张。这项研究揭示了胆固醇代谢的调节是控制组织炎症的一种方式,因此代表了 T 细胞免疫调节功能的潜在机制。



来源:science(https://www.science.org/doi/10.1126/sciimmunol.abb6444

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