IL-17 regulates LN stromal cell metabolism and function

IL-17 调节 LN 基质细胞代谢和功能

• 批准号: 10318971
• 负责人: Mandy J McGeachy
• 金额: $ 20.25万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318971
• 关键词: Antibodies; Antibody Formation; Antibody Response; Antigens; Antiviral Response; Autoantibodies; Autoimmune; Autoimmune Diseases; B-Cell Activation; B-Lymphocytes; Biological Assay; Biological Models; CCL19 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Communication; Cell physiology; Cells; Cellular Metabolic Process; Cessation of life; Citrobacter rodentium; Clinical; Colitis; Colonic inflammation; Complement; Data; Development; Disease; Disease susceptibility; Escherichia coli; Experimental Autoimmune Encephalomyelitis; Future; Gene Targeting; Genus Hippocampus; Homeostasis; Human; Impairment; In Vitro; Infection; Inflammation; Interferon Type II; Interleukin-17; Knockout Mice; Knowledge; Long-Term Effects; Lymphocyte; Maintenance; Mediating; Memory B-Lymphocyte; Metabolic; Metabolism; Modeling; Molecular; Mucous Membrane; Mus; Nutrient; Pathology; Pathway interactions; Peripheral; Play; Production; Relapse; Resistance to infection; Reticular Cell; Role; Signal Transduction; Stress; Stromal Cells; Structure; Structure of germinal center of lymph node; Supporting Cell; T cell regulation; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Tissues; Tonsil; Transcription Coactivator; Vaccination; adaptive immune response; adaptive immunity; autoimmune inflammation; base; chemokine; chronic autoimmune disease; cytokine; experimental study; extracellular; functional outcomes; glucose uptake; gut inflammation; in vitro Assay; in vivo; insight; lymph nodes; metabolic fitness; microbial; mucosal site; mucosal vaccination; new therapeutic target; pathogenic bacteria; pathogenic fungus; response; secondary lymphoid organ; side effect; small hairpin RNA; targeted treatment; wound healing

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. !

摘要 Th 17细胞在多种自身免疫性病症中促进病理学，靶向Th 17细胞或 IL-17是非常有效的。在健康状态下，Th 17细胞维持粘膜中的微生物稳态， 位点，是细胞外细菌和真菌病原体的重要调节因子3。Th 17细胞产生于 次级淋巴器官（SLO），但其主要效应通常在外周靶组织中评估 与临床疾病表现有关。在SLO中，专门的基质细胞称为成纤维网状细胞 (FRC)为淋巴细胞提供结构支持，包括建立有组织的功能性细胞 通过产生趋化因子和促生存细胞因子来调节小生境。财务汇报局另一个不太受重视的角色是 调节适应性免疫反应。有效的抗病毒应答需要FRC，包括抗体 (Ab)产生，但反过来限制了Th 1和CD 8 T细胞对T细胞产生的IFNγ的应答增殖。 然而，Th 17：FRC相互作用仍然几乎完全未被探索。我们现在表明IL-17在细胞内起着关键的作用。 在两种不同的模型设置中FRC的扩展和存活中的作用：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的代谢重编程， 我们在体外鉴定了IκB作为IL-17介导的代谢效应的关键转录辅激活因子。我们 数据进一步显示FRC的IL-17活化增强了获得性免疫：IL-17的条件性缺失 CCL 19 +FRC上的17 R导致B细胞生殖中心形成和抗体产生受损。这些数据 告知我们的中心假设，在Th 17炎症期间，IL-17信号传导驱动成功的代谢， FRC的重编程和扩增允许适应性免疫应答的爆发性激活。在 在本申请中，我们提出询问IL-17激活FRC反应的机制， 对获得性免疫的影响。更广泛地说，通过使用FRC作为模型系统来询问IL-1， 17-IκB β代谢途径及其对适应性免疫的影响，我们将获得关于已知但 IL-17在自身免疫性炎症、屏障维持、感染抵抗中的功能仍然知之甚少， 和伤口愈合。这一知识对于指导未来基于减少 IL-17的有害作用，同时保持有益的功能。 !