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: 10159257
• 负责人: Ronen Sumagin
• 金额: $ 34.85万
• 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/10159257
• 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/antagonist; 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/文摘