IL-17 regulates LN stromal cell metabolism and function

摘要 Th17细胞在各种自身免疫条件下促进病理，针对Th17细胞或 事实证明，IL-17非常有效。在健康状态下，Th17细胞维持粘膜内微生物的动态平衡 是细胞外细菌和真菌病原体的重要调节者3.Th17细胞在 次级淋巴器官(SLO)，但其主要作用通常是在周围靶组织中评估 与临床疾病表现有关。在SLO中，特殊的基质细胞称为成纤维细胞网状细胞 (FRC)为淋巴细胞提供结构支持，包括建立有组织的功能细胞 通过产生趋化因子和支持生存的细胞因子来形成利基环境。财务汇报局的另一个不太受欢迎的角色是 调节适应性免疫反应。FRC是包括抗体在内的有效抗病毒反应所必需的 (AB)产生，但反过来限制Th1T细胞和CD8T细胞的增殖，以响应T细胞产生的干扰素γ。 然而，Th17：FRC的相互作用几乎完全没有被探索过。我们现在表明，IL-17在 在两种不同的模型环境中FRC在扩张和存活中的作用：实验性自身免疫 脑脊髓炎(EAE)和结肠炎。出乎意料的是，IL-17诱导活化的FRC代谢重编程 在体外，我们发现IκBζ是IL-17介导的代谢效应的关键转录共激活因子。我们的 数据进一步表明，FRC的IL-17激活增强了获得性免疫：条件删除IL-17 CCL19+FRC上的17R导致B细胞生发中心形成和抗体产生受损。这些数据 告诉我们的中心假设，在Th17炎症期间，IL-17信号驱动成功的代谢 重新编程和扩展FRC，允许猛烈激活适应性免疫反应。在……里面 在这个应用中，我们建议询问IL-17激活FRC反应和FRC的机制 从而对适应性免疫产生影响。更广泛地说，通过使用FRC作为模型系统来审问IL- 17-I-κBζ-代谢途径及其对适应性免疫的影响，我们将从机制上了解已知的BUT IL-17在自身免疫性炎症、屏障维持、感染抵抗中的作用尚不清楚 和伤口愈合。这一知识对于指导未来的治疗策略非常重要 在维持有益功能的同时，IL-17的有害影响。 好了！

ABSTRACT Th17 cells promote pathology in a variety of autoimmune conditions, and new therapies targeting Th17 cells or IL-17 are proving highly effective. In the healthy state, Th17 cells maintain microbial homeostasis in mucosal sites and are important regulators of extracellular bacterial and fungal pathogens 3. Th17 cells are generated in secondary lymphoid organs (SLO), but their primary effects are usually assessed in peripheral target tissues related to clinical disease manifestations. In SLO, specialized stromal cells called fibroblastic reticular cells (FRC) provide structural support to lymphocytes, including establishment of organized functional cellular niches through production of chemokines and pro-survival cytokines. A less well-appreciated role of FRC is to modulate the adaptive immune response. FRC are required for effective anti-viral responses including antibody (Ab) production, but in turn limit Th1 and CD8 T cell proliferation in response to IFNγ produced by T cells. However, Th17:FRC interactions remain almost entirely unexplored. We now show that IL-17 plays a critical role in expansion and survival of FRC in two distinct model settings: experimental autoimmune encephalomyelitis (EAE) and colitis. Unexpectedly, IL-17 induced metabolic reprogramming of activated FRC and we identified IκBζ as a critical transcriptional coactivator of IL-17-mediated metabolic effects in vitro. Our data furthermore show that IL-17 activation of FRC enhances adaptive immunity: Conditional deletion of IL- 17R on CCL19+FRC resulted in impaired B cell germinal center formation and antibody production. These data inform our central hypothesis that during Th17 inflammation, IL-17 signaling drives successful metabolic reprogramming and expansion of FRC which allows fulminant activation of the adaptive immune response. In this application we propose interrogating the mechanisms by which IL-17 activates the FRC response and the consequent impact on adaptive immunity. More broadly, by using FRC as a model system to interrogate the IL- 17-IκBζ-metabolism pathway and impact on adaptive immunity, we will gain mechanistic insights on known but still poorly-understood functions of IL-17 in autoimmune inflammation, barrier maintenance, infection resistance and wound healing. This knowledge is important to guide future therapeutic strategies based on reducing harmful effects of IL-17 while maintaining beneficial functions. !