Mechanisms of immune homeostasis and regulation of intraocular inflammation

免疫稳态机制和眼内炎症调节

• 批准号: 10019987
• 负责人: Charles E Egwuagu
• 金额: $ 50.4万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10019987
• 关键词: Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Binding; CD8-Positive T-Lymphocytes; CISH gene; CNS autoimmune disease; Cell Death; Cell Proliferation; Cells; Communicable Diseases; Disease; Elements; Embryonic Development; Etiology; Goals; Homeostasis; Immune; Immune system; Inflammation; Inflammatory; Innate Immune System; Insecta; Instruction; Interferons; Interleukin-10; Lymphocyte; Mammals; Mediating; Multiple Sclerosis; Neurodegenerative Disorders; PTPN6 gene; Pathologic; Pathway interactions; Physarum polycephalum; Physiological; Physiological Processes; Platelet Factor 4; Play; Production; Proteins; Regulation; Regulatory T-Lymphocyte; Research; Role; STAT3 gene; Signal Pathway; Signal Transduction; Signal Transduction Pathway; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Transcription Factor AP-1; Uveitis; adaptive immune response; base; cell type; cytokine; effector T cell; in vivo; monocyte; recruit; transcription factor

Innate lymphocytes, monocytes, regulatory T cells (Tregs) and regulatory B cells (Bregs) suppress CNS autoimmune diseases such as Uveitis or Multiple Sclerosis by secreting IL-10 and IL-35. The activities of these immune suppressive cytokines are mediated through activation of JAK/STAT signaling pathway and are under stringent regulation. In this study, we sought to identify major cell types that produce both cytokines in-vivo and to characterize mechanisms that regulate their production. Compared to innate or Tregs we found that Bregs are the major producers of IL-35 and IL-10 in vivo during ocular inflammatory diseases. We also found that BATF, IFN regulatory factor (IRF)-4, and IRF-8 transcription factors are recruited and bind to AP1-IRF-composite elements (AICEs) of il12a, ebi3, and/or il10 loci, suggesting that these transcription factors regulate IL-10 and IL-35 expression by activated B cells. We also found that STAT3-dependent and independent pathways control ocular inflammation. These studies suggest that targeting STAT3 pathways and the BATF/IRF-4/IRF-8 axis can be exploited therapeutically to regulate physiological levels of IL-10/IL-35-Bregs and ocular inflammation.

天然淋巴细胞、单核细胞、调节性T细胞(Tregs)和调节性B细胞(Bregs)通过分泌IL-10和IL-35抑制葡萄膜炎或多发性硬化症等中枢神经系统自身免疫性疾病。这些免疫抑制细胞因子的活性是通过激活JAK/STAT信号通路介导的，并受到严格的调控。在这项研究中，我们试图确定体内产生细胞因子的主要细胞类型，并描述调节它们产生的机制。 与先天或Tregs相比，我们发现Bregs在眼部炎症性疾病中是体内产生IL-35和IL-10的主要来源。我们还发现，BATF、干扰素调节因子(IRF)-4和IRF-8转录因子被招募并与il12a、ebi3和/或il10基因座的AP1-IRF-复合元件(AICE)结合，表明这些转录因子通过激活B细胞来调节IL-10和IL-35的表达。我们还发现，STAT3依赖和独立的通路控制着眼部炎症。这些研究表明，靶向STAT3通路和BATF/IRF-4/IRF-8轴可以在治疗上调节IL-10/IL-35-Bregs的生理水平和眼部炎症。