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    G2A Signaling Dampens Colitic Inflammation via Production of IFN-γ


    Frasch, S. Courtney and McNamee, Eóin N. and Kominsky, Douglas J. 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, S.P. and Bratton, Donna L. (2016) G2A Signaling Dampens Colitic Inflammation via Production of IFN-γ. Journal of Immunology, 197. pp. 1425-1434. ISSN 0022-1767

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    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, G2A2/2 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 G2A2/2 colons showed significantly more TNF-a+ and Ly6ChiMHCII2 proinflammatory monocytes and eosinophils than in wild-type colons. Both monocytes and eosinophils were pathogenic as their depletion abolished the excess inflammation in G2A2/2 mice. G2A2/2 mice also had less IFN-g in inflamed colon tissues than wild-type mice. Fewer CD4+ lymphocytes were recruited to inflamed G2A2/2 colons, and fewer colonic lymphocytes produced IFN-g upon ex vivo stimulation. Administration of IFN-g to G2A2/2 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-g reduced the numbers of TNF-a+ monocyte and enhanced their maturation from Ly6ChiMHCII2 to Ly6CintMHCII+ . Taken together, the data suggest that G2A signaling serves to dampen intestinal inflammation via the production of IFN-g, which, in turn, enhances monocyte maturation to a less inflammatory program and ultimately reduces eosinophil-induced injury of colonic tissues.

    Item Type: Article
    Keywords: G2A Signaling; Dampens; Colitic Inflammation; IFN-γ;
    Academic Unit: Faculty of Science and Engineering > Biology
    Item ID: 12570
    Identification Number: https://doi.org/10.4049/jimmunol.1600264
    Depositing User: Eoin McNamee
    Date Deposited: 19 Mar 2020 17:38
    Journal or Publication Title: Journal of Immunology
    Publisher: American Association of Immunologists
    Refereed: Yes
    URI:

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