Selenium‐dependent Resolution of Inflammation in Macrophages is mediated through Δ12PGJ2‐CRTH2 Signaling Axis

Abstract

Selenium in the form of selenoproteins is known to mitigate inflammation by differential regulation of cyclooxygenase (COX)‐derived prostaglandin (PG) synthesis in endotoxin lipopolysaccharide (LPS)‐treated macrophages as well as in other models of inflammation. During late phase of inflammation, MΦs supplemented with selenium produce elevated levels of pro‐resolution cyclopentenone prostaglandins (CyPGs), such as Δ12‐PGJ2 that downregulate inflammatory signalling pathways. MΦs express the chemoattractant receptor‐homologous molecule, a cell surface receptor, expressed on Th2 cells (CRTH2/DP2) that exhibits high affinity for Δ12‐PGJ2. In this study, we investigated the role of CRTH2 signalling during LPS‐induced inflammation in murine macrophages cultured in the presence or absence of selenium. Deletion of Crth2 in MΦs, using the CRISPR/ Cas9 system, resulted in significant increase in the expression of genes required for PG biosynthesis (COX‐2 and microsomal PGE2 synthase‐1) and pro‐inflammatory mediator such as iNOS, mimicking the effects seen in selenium deficiency. Furthermore, use of specific pharmacological antagonists of CRTH2, inhibition of heterotrimeric G protein downstream of receptor using pertussis toxin, or use of specific inhibitors of enzymes leading to the biosynthesis of Δ12‐PGJ2 all increased expression of proinflammatory genes, indicating a previously underappreciated feedback mechanism of autocrine/paracrine role of Δ12‐PGJ2‐mediated CRTH2 signalling in selenium‐dependent resolution of inflammation.Support or Funding InformationFunded by NIH R01 DK077152 to KSP