BLTR mediates leukotriene B(4)-induced chemotaxis and adhesion and plays a dominant role in eosinophil accumulation in a murine model of peritonitis.
Leukotriene B(4) (LTB(4)) is a potent chemoattractant active on multiple leukocytes, including neutrophils, macrophages, and eosinophils, and is implicated in the pathogenesis of a variety of inflammatory processes. A seven transmembrane-spanning, G protein-coupled receptor, called BLTR (LTB(4) receptor), has recently been identified as an LTB(4) receptor. To determine if BLTR is the sole receptor mediating LTB(4)-induced leukocyte activation and to determine the role of LTB(4) and BLTR in regulating leukocyte function in inflammation in vivo, we generated a BLTR-deficient mouse by targeted gene disruption. This mouse reveals that BLTR alone is responsible for LTB(4)-mediated leukocyte calcium flux, chemotaxis, and firm adhesion to endothelium in vivo. Furthermore, despite the apparent functional redundancy with other chemoattractant-receptor pairs in vitro, LTB(4) and BLTR play an important role in the recruitment and/or retention of leukocytes, particularly eosinophils, to the inflamed peritoneum in vivo. These studies demonstrate that BLTR is the key receptor that mediates LTB(4)-induced leukocyte activation and establishes a model to decipher the functional roles of BLTR and LTB(4) in vivo.
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
A M
AM
Tager
J H
JH
Dufour
K
K
Goodarzi
S D
SD
Bercury
U H
UH
von Andrian
A D
AD
Luster
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002630:Chemotactic Factors / Q000276:immunology*; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology* / Q000502:physiology; D018390:Gene Targeting; D007975:Leukotriene B4 / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009132:Muscles / Q000098:blood supply; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology*; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000276:immunology*; D013864:Thioglycolates / Q000276:immunology / Q000494:pharmacology; D014699:Venules
D002630:Chemotactic Factors; D018102:Receptors, Leukotriene B4; D013864:Thioglycolates; D007975:Leukotriene B4; D002118:Calcium