Bltr Mediates Leukotriene B4–Induced Chemotaxis and Adhesion and Plays a Dominant Role in Eosinophil Accumulation in a Murine Model of Peritonitis

Abstract

Leukotriene B4 (LTB4) 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 (LTB4 receptor), has recently been identified as an LTB4 receptor. To determine if BLTR is the sole receptor mediating LTB4-induced leukocyte activation and to determine the role of LTB4 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 LTB4-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, LTB4 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 LTB4-induced leukocyte activation and establishes a model to decipher the functional roles of BLTR and LTB4 in vivo.