M2型巨噬细胞在急性胰腺炎损伤修复中作用及机制研究

Acute pancreatitis (AP) is a common gastrointestinal disorder. AP is caused by inflammatory injury to exocrine pancreas and recovers via repair and regeneration of existed acinar cells. Imbalance in repair mechanisms after AP contributes to exocrine and endocrine function insufficiency, and chronic pancreatitis, characterized by persistent inflammation and fibrosis. Unraveling the cellular and molecular bases of pancreas repair may identify new therapeutic targets for treatment and prevention of related diseases. Macrophage plays a critical in pancreatitis progression, however, its role and mechanism during AP recovery remain unclear. Based on our pilot study, we found that macrophage amount and phenotype have a dynamic change during pancreas repair after AP, and depletion of macrophage after AP injury through clodronate liposomes halts pancreas repair and regeneration. Therefore, we will continue to reveal M2 polarized mechanism, and the role of M2 macrophage during pancreas repair after AP. Overall our finding may offer a better understanding for pancreas repair and regeneration after AP from immunological aspect, also may offer a potential target to related pancreatic diseases.

急性胰腺炎（AP）损伤修复失衡（不足或过度）会导致胰腺内外分泌功能不足，或出现腺泡萎缩、间质纤维化等病理变化并最终进展成为慢性胰腺炎。因此针对AP损伤修复的研究具有重要意义。申请人前期研究成果报道，巨噬细胞在急、慢性胰腺炎病理发展中起关键作用，但其在AP损伤修复中的作用未见报道。我们前期实验发现，1）巨噬细胞的数目和表型在AP损伤修复中呈动态变化，2）氯磷酸二钠脂质体清除AP损伤后胰腺中的巨噬细胞，会显著阻滞/延缓胰腺的损伤修复。本研究拟在现有研究基础上深入解析在急性胰腺炎损伤修复过程中巨噬细胞M2型极化的分子机制，以及M2型巨噬细胞在胰腺损伤修复中的作用及机制。这一研究将从独特的免疫学角度揭示急性胰腺炎损伤修复的分子机制，为与损伤修复失衡相关的胰腺疾病预防和治疗提供新的思路和理论基础。

胰腺损伤后再生过程受损或过度活跃会导致外分泌功能不全或复发/慢性胰腺炎，甚至具有潜在的癌变风险。巨噬细胞是胰腺再生过程中最丰富的免疫细胞，但它们在胰腺再生过程中的动态表型和功能仍然不明确。首先建立雨蛙素诱导的急性胰腺炎损伤修复模型，通过流式细胞术和转录组RNA-seq分析动态解析了胰腺组织内单核/巨噬细胞从急性炎症期到再生阶段的动态表型变化。进一步通过脂质体清除巨噬细胞以及Il4ra敲除的转基因小鼠来阐明巨噬细胞在胰腺再生过程中的作用和调节机制。我们发现M1巨噬细胞在AP的促炎阶段占主导地位，而M2样巨噬细胞在胰腺修复/再生期间占主导地位。在早期或晚期再生阶段巨噬细胞的消耗分别显着阻止了腺泡导管化生或延迟的炎症消退。此外，机制解析阐明了巨噬细胞的M2型极化依赖于IL-4RA信号传导，胰腺组织内巨噬细胞中的ECM/AKT激活促进了组织再生过程中的炎症消退。我们的研究结果说明了胰腺损伤修复/再生过程中巨噬细胞的动态表型和功能，帮助我们更好地了解胰腺再生的机制，并为新的治疗策略提供线索。