G Protein-Coupled Receptor 43 Is Essential for Neutrophil Recruitment during Intestinal Inflammation

被引:280
作者
Sina, Christian [1 ,3 ]
Gavrilova, Olga [1 ]
Foerster, Matti [1 ]
Till, Andreas [1 ]
Derer, Stefanie [1 ]
Hildebrand, Friederike [1 ]
Raabe, Bjoern [2 ]
Chalaris, Athena [2 ]
Scheller, Juergen [2 ]
Rehmann, Ateequr [1 ]
Franke, Andre [1 ]
Ott, Stephan [1 ,3 ]
Haesler, Robert [1 ]
Nikolaus, Susanna [1 ,3 ]
Foelsch, Ulrich R. [3 ]
Rose-John, Stefan [2 ]
Jiang, Hui-Ping [4 ]
Li, Jun [5 ]
Schreiber, Stefan [1 ,3 ]
Rosenstiel, Philip [1 ]
机构
[1] Univ Hosp Schleswig Holstein, Inst Clin Mol Biol, D-24105 Kiel, Germany
[2] Univ Kiel, Inst Biochem, Fac Med, D-2300 Kiel, Germany
[3] Univ Hosp Schleswig Holstein, Dept Gen Internal Med, D-24105 Kiel, Germany
[4] Boehringer Ingelheim Pharmaceut Inc, Dept Translat Sci, Ridgefield, CT 06877 USA
[5] Boehringer Ingelheim Pharmaceut Inc, Dept Immunol & Inflammat, Ridgefield, CT 06877 USA
关键词
CHAIN FATTY-ACIDS; ACTIVE CROHNS-DISEASE; GENOME-WIDE ASSOCIATION; CANCER CELL-LINE; PROJECT RDP-II; BOWEL-DISEASE; ANTI-INTERLEUKIN-12; ANTIBODY; EXPERIMENTAL COLITIS; L-SELECTIN; TNF-ALPHA;
D O I
10.4049/jimmunol.0900063
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 p38 alpha, 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. The Journal of Immunology, 2009, 183: 7514-7522.
引用
收藏
页码:7514 / 7522
页数:9
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