title: G2A Signaling Dampens Colitic Inflammation via Production of IFN-γ.
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-α(+) 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-γ in inflamed colon tissues than wild-type mice. Fewer CD4(+) lymphocytes were recruited to inflamed G2A(-/-) colons, and fewer colonic lymphocytes produced IFN-γ upon ex vivo stimulation. Administration of IFN-γ 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-γ reduced the numbers of TNF-α(+) 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-γ, which, in turn, enhances monocyte maturation to a less inflammatory program and ultimately reduces eosinophil-induced injury of colonic tissues.
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, CO 80206; fraschc@njhealth.org.
authors.forename: S Courtney
authors.initials: SC
authors.lastname: Frasch
authors.affiliation: Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Eóin N
authors.identifier: 0000-0002-3331-3148
authors.initials: EN
authors.lastname: McNamee
authors.affiliation: Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Douglas
authors.initials: D
authors.lastname: Kominsky
authors.affiliation: Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Paul
authors.initials: P
authors.lastname: Jedlicka
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, CO 80206; Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80206;
authors.forename: Claudia
authors.initials: C
authors.lastname: Jakubzick
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Karin
authors.initials: K
authors.lastname: Zemski Berry
authors.affiliation: Department of Internal Medicine, University of Regensburg, 93042 Regensburg, Germany;
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.affiliation: Digestive Health Institute, Children's Hospital Colorado, Aurora, CO 80045; Gastrointestinal Eosinophilic Diseases Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045; and.
authors.forename: Glenn T
authors.initials: GT
authors.lastname: Furuta
authors.affiliation: Division of Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic in Arizona, Scottsdale, AZ 85259.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, CO 80206;
authors.forename: Peter M
authors.identifier: 0000-0003-1934-8405
authors.initials: PM
authors.lastname: Henson
authors.affiliation: Mucosal Inflammation Program, Department of Anesthesiology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045;
authors.forename: Sean P
authors.identifier: 0000-0003-0431-8887
authors.initials: SP
authors.lastname: Colgan
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, CO 80206;
authors.forename: Donna L
authors.initials: DL
authors.lastname: Bratton
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003092:Colitis / Q000378:metabolism / Q000473:pathology*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; C115270:G2A receptor; D043562:Receptors, G-Protein-Coupled; D007371:Interferon-gamma; D016264:Dextran Sulfate