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Selenium‐dependent Resolution of Inflammation in Macrophages is mediated through Δ12PGJ 2 ‐CRTH2 Signaling Axis
Author(s) -
BastihalliTukaramrao Diwakar,
Nettleford Shaneice,
Prabhu K. Sandeep
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.802.14
Subject(s) - inflammation , autocrine signalling , receptor , microbiology and biotechnology , paracrine signalling , chemistry , downregulation and upregulation , lipopolysaccharide , lipid signaling , proinflammatory cytokine , biology , biochemistry , immunology , gene
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‐PGJ 2 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‐PGJ 2 . 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 PGE 2 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‐PGJ 2 all increased expression of proinflammatory genes, indicating a previously underappreciated feedback mechanism of autocrine/paracrine role of Δ12‐PGJ 2 ‐mediated CRTH2 signalling in selenium‐dependent resolution of inflammation. Support or Funding Information Funded by NIH R01 DK077152 to KSP