G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation.
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.
Sina
Christian
C
Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Kiel, Germany.
Gavrilova
Olga
O
Förster
Matti
M
Till
Andreas
A
Derer
Stefanie
S
Hildebrand
Friederike
F
Raabe
Björn
B
Chalaris
Athena
A
Scheller
Jürgen
J
Rehmann
Ateequr
A
Franke
Andre
A
Ott
Stephan
S
Häsler
Robert
R
Nikolaus
Susanna
S
Fölsch
Ulrich R
UR
Rose-John
Stefan
S
Jiang
Hui-Ping
HP
Li
Jun
J
Schreiber
Stefan
S
Rosenstiel
Philip
P
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
C506481:Ffar2 protein, mouse; D043562:Receptors, G-Protein-Coupled; D016264:Dextran Sulfate; D048308:Mitogen-Activated Protein Kinase 14