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.

项目总结/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，它是开发旨在实现以下目标的疗法的有吸引力的靶点： 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有关 和组织损伤，然而，越来越多的人认识到PMN对炎症消退的贡献。因此，在本发明中， 虽然我们认为中性粒细胞是促进组织损伤的终末分化吞噬细胞的观点正在改变， PMNs的有益作用的潜在机制仍然知之甚少。虽然巨噬细胞 （M）对肠道免疫反应和炎症消退的贡献是很好的。 虽然已经认识到，但指导其效应子功能的分子线索仍有待确定。 我们正在进行的研究表明，组织中性粒细胞对炎症的解决有一个新的和有益的贡献 和粘膜损伤。我们已经确定了一些新的机制和新的分子球员， 指导炎症性肠道M β的活性以促进粘膜愈合。我们发现细胞外的PMN 囊泡（EV）介导调节性微RNA（miRNA）和促修复因子（例如TGF-β 1）的局部转移。 β1），它们分别通过平行活性抑制炎症和促进促修复细胞因子 在肠巨噬细胞中的表达。我们还确定了一个新的调节作用，一个良好的特点PMN粘附配体， ICAM-1在调节M细胞增殖活性中的作用。ICAM-1在M β活化过程中高度上调（其表达 仅限于炎性M细胞），当通过PMN结合连接时， 损伤组织中的凋亡/坏死上皮细胞。 因此，本提案的总体目标是测试一种新的概念，即组织浸润性中性粒细胞促进 肠巨噬细胞的重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， 创新的分子和生物化学方法：1。确定PMN-M β相互作用如何促进损伤 在肠粘膜中消退。2.确定PMN-EV如何增强炎症介质的促修复活性 创伤性多发性硬化症和3.确定伤口M细胞中PMN结合和ICAM-1信号传导如何调节红细胞增多， 便于伤口清创。 我们的研究将确定新的机制，管理先天免疫细胞的相互作用，在受伤的粘膜和他们的免疫反应。 在解决伤害方面发挥作用。