Neutrophils instruct macrophage responses to promote mucosal healing

中性粒细胞指导巨噬细胞反应以促进粘膜愈合

• 批准号: 10396573
• 负责人: Ronen Sumagin
• 金额: $ 34.99万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-05 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396573
• 关键词: Acute; Adhesions; Anti-Inflammatory Agents; Apoptotic; Binding; Biochemical; Cell Communication; Cells; Clinical; Colon Injury; Cues; Debridement; Disease; Education; Epithelial Cells; Gastrointestinal Diseases; Goals; Heterogeneity; Homeostasis; Imaging Techniques; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Intercellular adhesion molecule 1; Intestinal Mucosa; Intestines; Knockout Mice; Ligands; Ligation; Mediating; MicroRNAs; Modeling; Molecular; Mucositis; Mucous Membrane; Mus; Necrosis; Neutrophil Infiltration; Phagocytes; Phenotype; Production; Reporter; Resolution; Role; Severity of illness; Signal Transduction; Site; Surface; Testing; Tissues; Work; adhesion receptor; clinical remission; cytokine; design; epithelial injury; experimental study; extracellular vesicles; healing; improved; in vivo; inhibitor; injured; innovation; interest; intestinal injury; intravital microscopy; macrophage; mouse model; neutrophil; novel; receptor; repaired; response; small molecule inhibitor; therapy development; tissue repair; two-photon; wound; wound healing

Project Summary/Abstract Mucosal healing is considered an important clinical end-point of gastrointestinal disorders, including inflammatory bowel diseases (IBD). As such, it is an attractive target for developing therapies aimed at achieving sustained clinical remission. PMN presence in the intestinal mucosa is often associated with disease severity and tissue damage, however, PMN contributions to resolution of inflammation are increasingly recognized. Thus, while our view of PMNs as terminally differentiated phagocytes that promote tissue damage is changing, mechanisms underlying beneficial roles of PMNs remain poorly understood. Likewise, although macrophage (Mϕ) contributions to mounting immune responses in the gut and to resolution of inflammation are well recognized, molecular cues that instruct their effector functions remain to be defined. Our ongoing studies indicate a novel and beneficial contribution of tissue PMNs to the resolution of inflammation and mucosal injury. We have identified several novel mechanisms and new molecular players by which PMNs instruct the activity of inflammatory gut Mϕs to promote mucosal healing. We found that PMN extracellular vesicles (EVs) mediate localized transfer of regulatory micro-RNAs (miRNAs) and pro-repair factors (e.g. TGF- β1), which respectively, through parallel activity suppress inflammatory and promote pro-repair cytokine expression in gut Mϕs. We also identified a new regulatory role for a well-characterized PMN adhesion ligand, ICAM-1, in regulating Mϕ efferocytotic activity. ICAM-1 is highly upregulated during Mϕ activation (its expression is restricted to inflammatory Mϕs) and when ligated by PMN binding, critically regulates clearance of apoptotic/necrotic epithelial cells in injured tissue. Therefore, the overall goal of this proposal is to test a novel concept whereby tissue infiltrating PMNs facilitate reprogramming of gut Mϕs to promote inflammatory resolution of the injured intestinal mucosa. Proposed experiments will use state of the art imaging techniques, powerful in vivo injury models combined with innovative molecular and biochemical approaches to: 1. Determine how PMN-Mϕ interactions facilitate injury resolution in the intestinal mucosa. 2. Determine how PMN-EVs enhance the pro-repair activity of inflammatory wound Mϕs and 3. Determine how PMN binding and ICAM-1 signaling in wound Mϕs regulate efferocytosis and facilitate wound debridement. Our studies will define new mechanisms governing innate immune cell interactions in wounded mucosa and their function in injury resolution.

项目概要/摘要 粘膜愈合被认为是胃肠道疾病的重要临床终点，包括 炎症性肠病（IBD）。因此，它是开发旨在实现目标的疗法的一个有吸引力的目标 持续的临床缓解。肠粘膜中 PMN 的存在通常与疾病的严重程度相关 然而，中性粒细胞 (PMN) 对炎症消退的贡献越来越受到人们的认可。因此， 虽然我们对中性粒细胞作为促进组织损伤的终末分化吞噬细胞的看法正在改变， PMN 的有益作用背后的机制仍知之甚少。同样，虽然巨噬细胞 (Mψ) 对增强肠道免疫反应和解决炎症的贡献很大 公认的指导其效应器功能的分子线索仍有待定义。 我们正在进行的研究表明组织中性粒细胞对炎症的解决具有新颖且有益的贡献 和粘膜损伤。我们已经确定了 PMN 的几种新机制和新分子参与者 指导炎症性肠道 Mphis 的活性以促进粘膜愈合。我们发现PMN细胞外 囊泡 (EV) 介导调节性 micro-RNA (miRNA) 和促修复因子（例如 TGF- β1)，分别通过并行活性抑制炎症和促进促修复细胞因子 肠道 Mphis 中的表达。我们还确定了一种具有良好特征的 PMN 粘附配体的新调节作用， ICAM-1，调节 Mphi 细胞活性。 ICAM-1 在 Mphi 激活期间高度上调（其表达 仅限于炎症 Mphis)，并且当通过 PMN 结合连接时，严格调节 损伤组织中的凋亡/坏死的上皮细胞。 因此，该提案的总体目标是测试一种新颖的概念，即组织浸润中性粒细胞促进 肠道 Mphis 重新编程以促进受损肠粘膜的炎症消退。 拟议的实验将使用最先进的成像技术、强大的体内损伤模型以及 创新的分子和生化方法： 1. 确定 PMN-Mphi 相互作用如何促进损伤 肠粘膜的溶解。 2.确定PMN-EVs如何增强炎症的促修复活性 3. 确定伤口 Mphis 中的 PMN 结合和 ICAM-1 信号如何调节胞吞作用和 便于伤口清创。 我们的研究将定义控制受伤粘膜及其自身免疫细胞相互作用的新机制 在伤害解决中发挥作用。