Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Department of Medical and Molecular Pharmacology, University of California, Los Angeles, Los Angeles, California.
Cell Mol Gastroenterol Hepatol. 2022;13(4):1095-1120. doi: 10.1016/j.jcmgh.2022.01.002. Epub 2022 Jan 10.
Phagocytosis (efferocytosis) of apoptotic neutrophils by macrophages anchors the resolution of intestinal inflammation. Efferocytosis prevents secondary necrosis and inhibits further inflammation, and also reprograms macrophages to facilitate tissue repair and promote resolution function. Macrophage efferocytosis and efferocytosis-dependent reprogramming are implicated in the pathogenesis of inflammatory bowel disease. We previously reported that absence of macrophage cyclooxygenase 2 (COX2) exacerbates inflammatory bowel disease-like intestinal inflammation. To elucidate the underlying pathogenic mechanism, we investigated here whether COX2 mediates macrophage efferocytosis and efferocytosis-dependent reprogramming, including intestinal epithelial repair capacity.
Using apoptotic neutrophils and synthetic apoptotic targets, we determined the effects of macrophage specific Cox2 knockout and pharmacological COX2 inhibition on the efferocytosis capacity of mouse primary macrophages. COX2-mediated efferocytosis-dependent eicosanoid lipidomics was determined by liquid chromatography tandem mass spectrometry. Small intestinal epithelial organoids were employed to assay the effects of COX2 on efferocytosis-dependent intestinal epithelial repair.
Loss of COX2 impaired efferocytosis in mouse primary macrophages, in part, by affecting the binding capacity of macrophages for apoptotic cells. This effect was comparable to that of high-dose lipopolysaccharide and was accompanied by both dysregulation of macrophage polarization and the inhibited expression of genes involved in apoptotic cell binding. COX2 modulated the production of efferocytosis-dependent lipid inflammatory mediators that include the eicosanoids prostaglandin I2, prostaglandin E2, lipoxin A4, and 15d-PGJ2; and further affected secondary efferocytosis. Finally, macrophage efferocytosis induced, in a macrophage COX2-dependent manner, a tissue restitution and repair phenotype in intestinal epithelial organoids.
Macrophage COX2 potentiates efferocytosis capacity and efferocytosis-dependent reprogramming, facilitating macrophage intestinal epithelial repair capacity.
巨噬细胞吞噬凋亡中性粒细胞（胞噬作用）可以锚定肠道炎症的消退。胞噬作用可防止二次坏死并抑制进一步的炎症，还可重塑巨噬细胞以促进组织修复和促进消退功能。巨噬细胞的胞噬作用和胞噬作用依赖性重编程与炎症性肠病的发病机制有关。我们之前的研究报告指出，巨噬细胞环氧化酶 2（COX2）缺失会加剧类似炎症性肠病的肠道炎症。为了阐明潜在的发病机制，我们在此研究了 COX2 是否介导了巨噬细胞的胞噬作用和胞噬作用依赖性重编程，包括肠道上皮修复能力。
使用凋亡中性粒细胞和合成的凋亡靶标，我们确定了巨噬细胞特异性 Cox2 敲除和药理 COX2 抑制对小鼠原代巨噬细胞的胞噬作用能力的影响。通过液相色谱串联质谱法确定 COX2 介导的胞噬作用依赖性类花生酸脂质组学。使用小肠上皮类器官来检测 COX2 对胞噬作用依赖性肠道上皮修复的影响。
COX2 的缺失会损害小鼠原代巨噬细胞的胞噬作用，部分原因是影响了巨噬细胞与凋亡细胞的结合能力。这种作用与高剂量脂多糖的作用相当，并且伴随着巨噬细胞极化的失调和参与凋亡细胞结合的基因表达的抑制。COX2 调节了胞噬作用依赖性脂质炎症介质的产生，包括前列腺素 I2、前列腺素 E2、脂氧素 A4 和 15d-PGJ2；并进一步影响了二次胞噬作用。最后，巨噬细胞的胞噬作用以巨噬细胞 COX2 依赖性的方式诱导了肠道上皮类器官中的组织修复和修复表型。
巨噬细胞 COX2 增强了胞噬作用能力和胞噬作用依赖性重编程，促进了巨噬细胞的肠道上皮修复能力。
