促红细胞生成素调控巨噬细胞吞噬功能在炎症消退中的作用和机制研究

The inflammatory response protects the body against infection and injury but dysregulated inflammation can cause deleterious consequences to the host. Therefore, the duration and intensity of the inflammation is under strict control in our body. The beginning of an inflammation will active a serial pathways to promote the resolution of inflammation. And it is now well established that inflammation resolution is an active rather than a passive process. Therefore, the treatment of inflammation-associated diseases based on endogenous agonists of inflammation resolution is a novel way for inflammation control. It is known that apoptotic cell clearance by macrophages is essential to promote inflammation resolution. Erythropoietin (EPO) is critical for the formation of red blood cell and widely applied in clinic. Our recent data showed that EPO and EPO receptor (EPOR) were induced following acute inflammation, EPO promoted the phagocytosis of apoptotic cells by macrophages and EPO played an important role in inflammation resolution. So EPO might be a new endogenous resolver. The project here aim to investigate the functions and mechanisms of EPO in inflammation resolution in zymosan A induced peritonitis by using conditional EPOR knockout mice and LXRα knockout mice. And we hope to elucidate following issues: 1. how inflammation induces EPO/EPOR and our investigation will focus on the PHD/HIF pathway; 2. how EPO promotes inflammation resolution and our study will focus on the apoptotic cell clearance, inflammatory cytokine inhibition, anti-inflammatory mediator induction, macrophage migration to lymph nodes and neutrophil apoptosis induction; 3. how EPO promotes apoptotic cell phagocytosis by macrophages and its contribution to EPO-induced inflammation resolution, and our study will focus on the LXRα/MER/Rac-1/actin pathway; 4. Therapeutic effects and mechanisms of EPO and its nonerythropoietic analogue in pathogenic inflammation resolution model. Through this project we hope to identified EPO as an endogenous resolver, reveal its underlying mechanisms in inflammation resolution and provide new therapeutic target for inflammation-associated diseases.

炎症消退(inflammation resolution, IR) 是炎症自身反馈调控机制，为多机制参与炎症生理阶段，起着终止炎症反应作用，其功能不足导致炎症慢性化，与多种慢性炎症性疾病密切相关；促IR分子抗炎机制不同于传统药物，为抗炎药物研制新方向，因此发现新促IR分子及其机理具重要意义。已知巨噬细胞（MΦ）吞噬凋亡细胞（AC）在促IR中起关键作用，我们首次发现促红细胞生成素（EPO）在促MΦ吞噬AC和促IR中起重要作用，为新内源性促IR分子，但其机制不清。本项目拟采用MΦ特异EPO受体敲除等小鼠，在zymosanA诱导腹膜炎和细胞模型中，从正反角度，阐明炎症诱导内源性EPO及其受体途径，分析EPO促IR作用和机制，研究EPO诱导LXRα/MER通路促MΦ吞噬AC作用、机制及在促IR中关键作用，检测EPO及其无促造血功能衍生物促病理性炎症消退作用。以发现促IR新机制、新分子和调控新靶点。

炎症消退(inflammation resolution, IR) 是多机制参与主动过程，炎症的起始进展可同时激活炎症消退通路，从而反馈调控炎症反应并恢复组织稳态作用，其功能不足导致炎症慢性化，与多种严重危害人类健康的慢性炎症性疾病密切相关；促IR分子抗炎机制不同于传统药物，为抗炎药物研制新方向，因此发现新促IR分子并阐明其机理具重要意义。已知巨噬细胞吞噬凋亡细胞（AC）在促IR中起着关键作用，巨噬细胞吞噬AC可促进炎症抑制分子和组织修复分子表达，从而抑制炎症进展，恢复组织稳态。通过本项目资助，我们研究首次发现：1、AC可通过其分泌的S1P分子诱导巨噬细胞促红细胞生成素（EPO）通路激活，EPO在促进巨噬细胞吞噬清除AC中起着重要作用，巨噬细胞EPO受体敲除小鼠会发生体内AC聚集和SLE样病变，外源性EPO治疗可改善小鼠SLE样病变，该部分研究揭示了巨噬细胞EPO通路在AC清除和免疫耐受维持中的重要作用；2、炎症的起始进展会促进中性粒细胞和巨噬细胞的浸润及氧呼吸爆发，该过程有利于机体杀伤外来物质但也会同时导致组织损伤，而我们发现该过程会导致局部低氧从而反馈激活巨噬细胞EPO通路，EPO通过促进巨噬细胞清除凋亡细胞、淋巴结迁移等机制，从而促进炎症消退，恢复组织稳态，该部分研究发现了炎症的自身反馈调控通路，揭示了EPO为机体内源性促炎症消退分子；3、发现在自身免疫性炎症过程中，RvD1分子通过促进巨噬细胞吞噬AC，从而诱导TGF-β表达，促进Treg数量，从而促进自身免疫性炎症消退和疾病康复，该研究揭示了RvD1的促自身免疫性炎症消退作用和机制。通过研究我们发现了AC吞噬清除新机制和调控通路，揭示了促炎症消退的新分子和调控新靶点，为相关疾病的防治提供了新靶点。