Mucosal Macrophages and Post-Infectious IBD

粘膜巨噬细胞和感染后 IBD

• 批准号: 9768435
• 负责人: Milena Bogunovic
• 金额: $ 37.69万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-16 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768435
• 关键词: Anti-inflammatory; Antigen Presentation; Antigen-Presenting Cells; Antigens; Bacteria; Cell Count; Cell Size; Cells; Colitis; Cre-LoxP; Crohn' s disease; Data; Dendritic Cells; Development; Epithelial; Equilibrium; Eragrostis; Event; Genes; Goals; Immune; Immune Tolerance; Immune response; Immunity; Infection; Infection prevention; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Intestines; Left; Link; Mesentery; Microbe; Mucositis; Mucous Membrane; Mus; Oral; Phagocytes; Phenotype; Play; Process; Production; Property; Receptor Signaling; Regulatory T-Lymphocyte; Relapse; Role; Salmonella; Salmonella infections; Signal Transduction; Submucosa; T-Lymphocyte; TNF gene; Testing; Therapeutic; Toll-like receptors; Transforming Growth Factor beta; Transgenic Mice; Ulcerative Colitis; adaptive immune response; antimicrobial; bactericide; base; cell type; commensal bacteria; commensal microbes; cytokine; driving force; effector T cell; enteric infection; enteric pathogen; gastrointestinal; gastrointestinal infection; gut microbiota; innate immune function; insight; intestinal homeostasis; lymph nodes; macrophage; microbiota; migration; monocyte; mouse model; novel therapeutic intervention; pathogen; pathogenic bacteria; prevent; repaired; resident commensals; response; trafficking

PROJECT SUMMARY Inflammatory bowel disease (IBD) is the result of exacerbated immune response against commensal or “good” bacteria, whereas various gastrointestinal (GI) infections caused by “bad” bacteria such as Salmonella can initiate the onset and relapse of IBD. How the protective immune response against “bad” microbes is linked to the abnormal exacerbated immune response against “good” microbes is unclear. Primary immune responses to GI infections occur in the context of broader secondary responses against commensals that breach damaged mucosa. Intestinal antigen-presenting cells (APCs) are heterogeneous immune cells that capture “good” and “bad” intestinal microbes and present them to T cells. T cells, after being educated by APCs, help to eradicate “bad” microbes but become tolerant to “good” microbes. Signals provided by APCs that include pro- and anti-inflammatory cytokines will determine whether T cells will recognize microbes as “good” or as “bad”. APC subsets responsible for presenting pathogenic and commensal bacteria to T cells are unknown. Macrophages (Mφs) are the most numerous mucosal APCs but their role in adaptive immune responses against enteric pathogens has not been established. Our preliminary data show that mucosal Mφs are heterogeneous; they induce protective immunity against Salmonella through coordinated efforts of three functionally distinct subsets by providing the innate immune control, initiating mucosal inflammation and activating T cells in the mesenteric lymph nodes (MLNs) where some Mφs migrate upon infection. In this proposal, we will test the hypothesis that mucosal Mφs, a driving force of protective immunity against Salmonella, play a central role in maintaining intestinal homeostasis after infection is cleared. We anticipate that post-infection, mucosal Mφs re-establish the immunological tolerance to commensals through the balance between mucosa-resident and MLN-migratory Mφ subsets: 1) by switching their cytokine profile from pro- inflammatory to anti-inflammatory, and 2) by downregulating their migration to the MLNs to reduce interactions with T cells. Both processes are driven by sustained production of anti-inflammatory cytokines IL-10 and TGFβ, and by reduced pro-inflammatory (TNFα) and Toll-like receptor (TLR) signaling in mucosal Mφs following pathogen clearance, repair of the epithelial barrier and diminished translocation of commensal bacteria into the mucosa. Our hypothesis will be tested in mouse models of transient infectious and non-infectious colitis using mice depleted of mucosal Mφs or Il10, Tgfb1, Ccr7, Tnf and Myd88 genes in Mφs based on a Cre/loxP transgenic mouse approach. We anticipate that answering the questions raised in this proposal will provide new therapeutic strategies to reduce established inflammation and to prevent infection-driven IBD by promoting anti-inflammatory properties of mucosal Mφs without compromising anti-microbial immunity.

项目摘要 炎症性肠病（IBD）是针对共生或“良好”的免疫响应加剧的结果 细菌，而由沙门氏菌等“不良”细菌引起的各种胃肠道（GI）感染 发起IBD的发作和缓解。对“不良”微生物的保护免疫反应如何与 针对“良好”微生物的异常恶化的免疫反应尚不清楚。 对胃肠道感染的主要免疫反应发生在针对更广泛的次要反应的背景下 违反粘膜损坏的份子。肠道抗原细胞（APC）是异质的 捕获“好”和“坏”肠道微生物并将其呈现给T细胞的免疫细胞。 T细胞，在 受APC的教育，有助于放射性“不良”微生物，但对“好”微生物的宽容。信号 由APC提供的包括促疾病和抗炎细胞因子的APC将确定T细胞是否会 将微生物识别为“好”或“坏”。 APC子集负责呈现致病性和共生 T细胞的细菌未知。 巨噬细胞（MφS）是最多的粘膜APC，但它们在适应性免疫调查中的作用 尚未建立针对肠道病原体。我们的初步数据表明粘膜Mφ是 异质;他们通过三个协调的努力诱导免疫免疫力免疫。 通过提供先天免疫控制，启动粘膜注射和 激活肠系膜淋巴结（MLN）中的T细胞，其中一些Mφ在感染后迁移。 在此提案中，我们将检验以下假设：粘膜mφs是一种保护性免疫的动力 沙门氏菌，在清除感染后保持肠内稳态方面起着核心作用。我们期待 感染后，粘膜mφs通过平衡重新建立对共生的免疫耐受性 在粘膜居民和MLN迁移Mφ子集之间：1）通过将其细胞因子谱从pro切换 抗炎性炎症性，以及2）通过下调其迁移到MLN以减少相互作用 与T细胞。这两个过程均由抗炎细胞因子IL-10和 TGFβ，以及粘膜MφS中的促炎（TNFα）和类似受体（TLR）信号的降低 病原体清除率后，修复上皮屏障和共生的易位减少 细菌进入粘膜。 我们的假设将在使用小鼠的瞬态感染和非感染性结肠炎的小鼠模型中进行检验 基于CRE/LOXP转基因的MφS中粘膜MφS或IL10，TGFB1，CCR7，TNF和MYD88基因的耗尽 鼠标方法。我们预计回答本提案中提出的问题将提供新的 减少既定创新并通过促进感染驱动的IBD的治疗策略 粘膜mφs的抗炎特性，而不会损害抗微生物免疫。