G2A signaling dampens colitic inflammation via production of IFN-γ

S. Courtney Frasch, Eóin N. McNamee, Douglas Kominsky, Paul Jedlicka, Claudia Jakubzick, Karin Zemski Berry, Matthias Mack, Glenn T. Furuta, James J. Lee, Peter M. Henson, Sean P. Colgan, Donna L. Bratton

Research output: Contribution to journalArticle

6 Scopus citations

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 G-/- colons showed significantly more TNF-α+ 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 G-/- mice. G-/- mice also had less IFN-γ in inflamed colon tissues than wild-type mice. Fewer CD4+ lymphocytes were recruited to inflamed G-/- colons, and fewer colonic lymphocytes produced IFN-γ upon ex vivo stimulation. Administration of IFN-γ to G-/- 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-γ reduced the numbers of TNF-α+ 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-γ, which, in turn, enhances monocyte maturation to a less inflammatory program and ultimately reduces eosinophil-induced injury of colonic tissues.

Original languageEnglish (US)
Pages (from-to)1425-1434
Number of pages10
JournalJournal of Immunology
Volume197
Issue number4
DOIs
StatePublished - Aug 15 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Frasch, S. C., McNamee, E. N., Kominsky, D., Jedlicka, P., Jakubzick, C., Berry, K. Z., Mack, M., Furuta, G. T., Lee, J. J., Henson, P. M., Colgan, S. P., & Bratton, D. L. (2016). G2A signaling dampens colitic inflammation via production of IFN-γ. Journal of Immunology, 197(4), 1425-1434. https://doi.org/10.4049/jimmunol.1600264