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）是由于免疫反应加剧， 细菌，而由“坏”细菌如沙门氏菌引起的各种胃肠道（GI）感染， 引发IBD的发作和复发。对抗“坏”微生物的保护性免疫反应如何与 针对“好”微生物的异常加剧的免疫反应尚不清楚。 对胃肠道感染的初级免疫应答发生在针对胃肠道感染的更广泛的次级免疫应答的背景下。 破坏受损粘膜的血管。肠道抗原呈递细胞（APC）是异质性的 免疫细胞捕获“好”和“坏”肠道微生物并将其呈递给T细胞。T细胞在被 经过APC的训练，有助于根除“坏”微生物，但对“好”微生物具有耐受性。信号 由APC提供的包括促炎细胞因子和抗炎细胞因子将决定T细胞是否 识别微生物是“好”还是“坏”。APC亚群负责呈现致病性和侵袭性 细菌对T细胞的作用是未知的。 巨噬细胞（Mφs）是数量最多的粘膜APC，但它们在适应性免疫应答中的作用 针对肠道病原体的疫苗尚未建立。我们的初步数据表明，粘膜Mφ是 它们通过三种免疫系统的协调努力诱导针对沙门氏菌的保护性免疫。 通过提供先天免疫控制，引发粘膜炎症， 激活肠系膜淋巴结（MLN）中的T细胞，其中一些Mφ在感染时迁移。 在这个提议中，我们将检验粘膜Mφs的假设，Mφs是保护性免疫的驱动力， 沙门氏菌在感染清除后维持肠道内环境稳定方面发挥着重要作用。我们预计 感染后，粘膜Mφ通过平衡免疫耐受性重建了对抗生素的免疫耐受， 粘膜驻留和MLN迁移Mφ亚群之间：1）通过将它们的细胞因子谱从亲- 炎症性到抗炎性，和2）通过下调它们向MLN的迁移以减少相互作用 T细胞。这两个过程都是由持续产生抗炎细胞因子IL-10和 TGFβ，并通过减少粘膜Mφ中的促炎性（TNFα）和Toll样受体（TLR）信号传导 病原体清除后，上皮屏障修复， 细菌进入粘膜。 我们的假设将在小鼠短暂感染性和非感染性结肠炎模型中进行测试， 基于Cre/loxP转基因的粘膜Mφ或Mφ中的Il 10、Tgfb 1、Ccr 7、Tnf和Myd 88基因的缺失 鼠标方法。我们预计，回答本提案中提出的问题将提供新的 治疗策略，以减少已建立的炎症和预防感染驱动的IBD， 粘膜Mφ的抗炎特性，而不损害抗微生物免疫。