title: G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation.
abstract: Molecular danger signals attract neutrophilic granulocytes (polymorphonuclear leukocytes (PMNs)) to sites of infection. The G protein-coupled receptor (GPR) 43 recognizes propionate and butyrate and is abundantly expressed on PMNs. The functional role of GPR43 activation for in vivo orchestration of immune response is unclear. We examined dextrane sodium sulfate (DSS)-induced acute and chronic intestinal inflammatory response in wild-type and Gpr43-deficient mice. The severity of colonic inflammation was assessed by clinical signs, histological scoring, and cytokine production. Chemotaxis of wild-type and Gpr43-deficient PMNs was assessed through transwell cell chemotactic assay. A reduced invasion of PMNs and increased mortality due to septic complications were observed in acute DSS colitis. In chronic DSS colitis, Gpr43(-/-) animals showed diminished PMN intestinal migration, but protection against inflammatory tissue destruction. No significant difference in PMN migration and cytokine secretion was detected in a sterile inflammatory model. Ex vivo experiments show that GPR43-induced migration is dependent on activation of the protein kinase p38alpha, and that this signal acts in cooperation with the chemotactic cytokine keratinocyte chemoattractant. Interestingly, shedding of L-selectin in response to propionate and butyrate was compromised in Gpr43(-/-) mice. These results indicate a critical role for GPR43-mediated recruitment of PMNs in containing intestinal bacterial translocation, yet also emphasize the bipotential role of PMNs in mediating tissue destruction in chronic intestinal inflammation.
authors.affiliation: Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Sina
authors.forename: Olga
authors.initials: O
authors.lastname: Gavrilova
authors.forename: Matti
authors.initials: M
authors.lastname: Förster
authors.forename: Andreas
authors.initials: A
authors.lastname: Till
authors.forename: Stefanie
authors.initials: S
authors.lastname: Derer
authors.forename: Friederike
authors.initials: F
authors.lastname: Hildebrand
authors.forename: Björn
authors.initials: B
authors.lastname: Raabe
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.forename: Jürgen
authors.initials: J
authors.lastname: Scheller
authors.forename: Ateequr
authors.initials: A
authors.lastname: Rehmann
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.forename: Stephan
authors.initials: S
authors.lastname: Ott
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.forename: Susanna
authors.initials: S
authors.lastname: Nikolaus
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Fölsch
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.forename: Hui-Ping
authors.initials: HP
authors.lastname: Jiang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000276:immunology / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C506481:Ffar2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D016264:Dextran Sulfate; D048308:Mitogen-Activated Protein Kinase 14