美国加州大学Alexander Marson以及美国索尔克生物研究所Ye Zheng、Ronald M. Evans、Sagar P. Bapat研究组合作揭示，肥胖改变炎症性疾病的病理和治疗反应。相关论文于2022年3月30日发表在《自然》杂志上。
他们使用两种特应性皮炎模型，显示瘦小鼠和肥胖小鼠产生明显不同的免疫反应。肥胖将与特应性皮炎相关的经典 2 型 T 辅助细胞 (TH2) 为主的疾病转变为具有显著 TH17 炎症的更严重疾病。他们还观察到针对 TH2 细胞因子的生物疗法的不同反应，这些细胞因子有力地保护了瘦小鼠，但加剧了肥胖小鼠的疾病。单细胞 RNA 测序结合全基因组结合分析显示，与瘦小鼠相比，肥胖小鼠的 TH2 细胞中核受体过氧化物酶体增殖物激活受体-γ (PPARγ) 的活性降低。
T 细胞中 PPARγ 的条件敲除表明，PPARγ 需要将体内 TH 反应集中在 TH2 主导状态并防止异常的非 TH2 炎症。用小分子 PPARγ 激动剂治疗肥胖小鼠限制了 TH17 病理学的发展，并释放了对靶向抗 TH2 生物疗法的治疗反应。这些研究揭示了肥胖对免疫疾病的影响，并提出了一种针对肥胖引起的免疫失调的精准医学方法。
据介绍，数十年的工作已经阐明了控制 T 细胞分化的细胞因子信号传导和转录途径，并为靶向生物疗法开辟了道路，这些疗法对一系列自身免疫性疾病、过敏性疾病和炎症性疾病有效。最近的证据表明，肥胖和代谢疾病也会影响免疫系统，尽管对免疫治疗结果的机制和影响仍然很大程度上未知。
附：英文原文
Title: Obesity alters pathology and treatment response in inflammatory disease
Author: Bapat, Sagar P., Whitty, Caroline, Mowery, Cody T., Liang, Yuqiong, Yoo, Arum, Jiang, Zewen, Peters, Michael C., Zhang, Ling-juan, Vogel, Ian, Zhou, Carmen, Nguyen, Vinh Q., Li, Zhongmei, Chang, Christina, Zhu, Wandi S., Hastie, Annette T., He, Helen, Ren, Xin, Qiu, Wenli, Gayer, Sarah G., Liu, Chang, Choi, Eun Jung, Fassett, Marlys, Cohen, Jarish N., Sturgill, Jamie L., Crotty Alexander, Laura E., Suh, Jae Myoung, Liddle, Christopher, Atkins, Annette R., Yu, Ruth T., Downes, Michael, Liu, Sihao, Nikolajczyk, Barbara S., Lee, In-Kyu, Guttman-Yassky, Emma, Ansel, K. Mark, Woodruff, Prescott G., Fahy, John V., Sheppard, Dean, Gallo, Richard L., Ye, Chun Jimmie, Evans, Ronald M., Zheng, Ye, Marson, Alexander
Issue&Volume: 2022-03-30
Abstract: Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1,2,3,4,5,6,7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.
DOI: 10.1038/s41586-022-04536-0
Source: https://www.nature.com/articles/s41586-022-04536-0
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
