G2A Signaling Dampens Colitic Inflammation Via Production of Ifngamma Which Drives Anti-Inflammatory Monocyte Maturation
Sunday, March 6, 2016: 4:45 PM
Concourse Foyer (Convention Center)
S. Courtney Frasch, Ph.D., Eoin McNamee, Ph.D., Doug Kominsky, Ph.D., Claudia Jakubzick, Ph.D., Sean Colgan, Ph.D., Donna Bratton, MD

Signaling via the g-protein coupled receptor G2A (gpr132), expressed on nearly all leukocytes, enhances host inflammatory responses via recruitment of phagocytes and their production of ROS, and production of IFNγ from lymphocytes. We hypothesized that blockade of G2A signaling would be beneficial in colitis where exaggerated responses to intestinal microflora by the innate immune system drives disease. 


DSS colitis was characterized in G2A-/- and wild type (WT) mice using disease activity scores, colon shortening, flow cytometry, cytokine measurement and histology.  


Surprisingly, DSS colitis was significantly more severe in G2A-/- vs. WT mice by all measures. Inflammatory cell infiltrates into colons were similar, except that more Ly6CHIMHCII-TNFα+IL-6+ “inflammatory” monocytes (Mo) were present in G2A-/- mice than WT, while both had similar numbers of more mature Ly6CLOMHCII+ Mo known for IL-10 production. Mo were pathogenic in that their depletion abrogated the excess morbidity in the G2A-/- mice. G2A-/- mice also had reduced IFNγ in colonic tissues, as well as stimulated IFNγ production from colonic lymphocytes (but not splenic lymphocytes) compared to WT mice. Surprisingly, treatment of G2A-/- mice with IFNγ after induction of colitis inhibited exaggerated colitis and normalized the numbers of “inflammatory” Mo and the proportion of Ly6CLOMHCII+ Mo. 


Signaling via G2A restrains colitis via the production of IFNγ, which in turn, has a heretofore, unrecognized role in the maturation of Mo from an inflammatory to an anti-inflammatory program.