Macrophage COX2 Mediates Efferocytosis, Resolution Reprogramming, and Intestinal Epithelial Repair
| Autor: | David Meriwether, Anthony E. Jones, Julianne W. Ashby, R. Sergio Solorzano-Vargas, Nasrin Dorreh, Shoreh Noori, Victor Grijalva, Andréa B. Ball, Margarita Semis, Ajit S. Divakaruni, Julia J. Mack, Harvey R. Herschman, Martin G. Martin, Alan M. Fogelman, Srinivasa T. Reddy |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Inflammation
Hepatology Macrophage Macrophages Inflammatory Bowel Disease Gastroenterology Inflammation Resolution Inflammatory Bowel Diseases Autoimmune Disease Oral and gastrointestinal Mice Phagocytosis Cyclooxygenase 2 Lipidomics Eicosanoids 2.1 Biological and endogenous factors Animals Aetiology Digestive Diseases |
| Zdroj: | Cellular and molecular gastroenterology and hepatology, vol 13, iss 4 |
| ISSN: | 2352-345X |
| Popis: | Background and aimsPhagocytosis (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.MethodsUsing 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.ResultsLoss 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.ConclusionsMacrophage COX2 potentiates efferocytosis capacity and efferocytosis-dependent reprogramming, facilitating macrophage intestinal epithelial repair capacity. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|