Protease-activated receptor 1 activation is necessary for monocyte chemoattractant protein 1-dependent leukocyte recruitment in vivo.
Thrombin, acting through a family of protease-activated receptors (PARs), is known to amplify inflammatory responses, but the in vivo importance of PARs in inflammation is not fully appreciated. In a mouse heart-to-rat transplant model, where it is possible to distinguish graft (mouse) from systemic (rat) chemokines, we show that donor PAR-1 is required to generate the local monocyte chemoattractant protein (MCP)-1 needed to recruit rat natural killer cells and macrophages into the hearts. We have confirmed the importance of this mechanism in a second model of thioglycollate-induced peritonitis and also show that PAR-1 is important for the production of MCP-3 and MCP-5. Despite the presence of multiple other mediators capable of stimulating chemokine production in these models, these data provide the first evidence that thrombin and PAR activation are required in vivo to initiate inflammatory cell recruitment.
Chen
Daxin
D
Department of Immunology, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, England, UK.
Carpenter
Adam
A
Abrahams
Joel
J
Chambers
Rachel C
RC
Lechler
Robert I
RI
McVey
John H
JH
Dorling
Anthony
A
D000818:Animals; D002465:Cell Movement; D018932:Chemokine CCL2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology / Q000502:physiology; D007962:Leukocytes / Q000276:immunology / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018945:Monocyte Chemoattractant Proteins / Q000096:biosynthesis; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D044463:Receptor, PAR-1 / Q000378:metabolism*; D044462:Receptors, Proteinase-Activated / Q000378:metabolism; D013864:Thioglycolates / Q000633:toxicity; D014019:Tissue Donors
C103558:Ccl12 protein, rat; C491768:Ccl2 protein, mouse; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D018945:Monocyte Chemoattractant Proteins; D044463:Receptor, PAR-1; D044462:Receptors, Proteinase-Activated; D013864:Thioglycolates; C481942:protease-activated receptor 4, mouse