Frasch, S. Courtney and McNamee, Eoin N. and Kominsky, Douglas and Jedlicka, Paul and Jakubzick, Claudia and Berry, Karin Zemski and Mack, Matthias and Furuta, Glenn T. and Lee, James J. and Henson, Peter M. and Colgan, Sean P. and Bratton, Donna L. (2016) G2A Signaling Dampens Colitic Inflammation via Production of IFN-gamma. JOURNAL OF IMMUNOLOGY, 197 (4). pp. 1425-1434. ISSN 0022-1767, 1550-6606
Full text not available from this repository. (Request a copy)Abstract
Proinflammatory consequences have been described for lysophosphatidylcholine, a lipid product of cellular injury, signaling via the G protein-coupled receptor G2A on myeloid and lymphoid inflammatory cells. This prompted the hypothesis that genetic deletion of G2A would limit intestinal inflammation in a mouse model of colitis induced by dextran sodium sulfate. Surprisingly, G2A(-/-) mice exhibited significantly worsened colitis compared with wild-type mice, as demonstrated by disease activity, colon shortening, histology, and elevated IL-6 and IL-5 in colon tissues. Investigation of inflammatory cells recruited to inflamed G2A(-/-) colons showed significantly more TNF-alpha(+) and Ly6C(hi)MHCII(-) proinflammatory monocytes and eosinophils than in wild-type colons. Both monocytes and eosinophils were pathogenic as their depletion abolished the excess inflammation in G2A(-/-) mice. G2A(-/-) mice also had less IFN-gamma in inflamed colon tissues than wild-type mice. Fewer CD4(+) lymphocytes were recruited to inflamed G2A(-/-) colons, and fewer colonic lymphocytes produced IFN-gamma upon ex vivo stimulation. Administration of IFN-gamma to G2A(-/-) mice during dextran sodium sulfate exposure abolished the excess colitic inflammation and reduced colonic IL-5 and eosinophil numbers to levels seen in wild-type mice. Furthermore, IFN-gamma reduced the numbers of TNF-alpha(+) monocyte and enhanced their maturation from Ly6C(hi)MHCII(-) to Ly6C(int)MHCII(+). Taken together, the data suggest that G2A signaling serves to dampen intestinal inflammation via the production of IFN-gamma, which, in turn, enhances monocyte maturation to a less inflammatory program and ultimately reduces eosinophil-induced injury of colonic tissues.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EXPERIMENTAL MURINE COLITIS; SULFATE-INDUCED COLITIS; ULCERATIVE-COLITIS; LY6C(HI) MONOCYTES; INTESTINAL MUCUS; INTERFERON-GAMMA; DENDRITIC CELLS; CROHNS-DISEASE; BOWEL-DISEASE; LYSOPHOSPHATIDYLCHOLINE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Abteilung für Nephrologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 03 Apr 2019 07:22 |
| Last Modified: | 03 Apr 2019 07:22 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3482 |
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