Leukotriene BLT1
BLT1 has also been shown to be a receptor for RvE1 although its clone, high-affinity leukotriene B4 (LTB4) is a potent lipid inflammatory chemoattractant, inducing T helper cell chemotaxis and early effector T cell recruitment through BLT1 (Yokomizo et al. 1997; Arita et al. 2007). BLT1 shares 21% sequence identity with chemerin1; while this value is relatively low, selective BLT1 antagonist U-75,302 has been demonstrated to replace the binding of [3H]-RvE1 to the human PMN membrane (Arita et al. 2007). Besides, although RvE1 is 100 times less potent than LTB4, it inhibited adenylate cyclase activity and induced intracellular calcium mobilization in HEK293 cells overexpressing BLT1. These data indicate the role of RvE1 in reducing BLT1-induced inflammation by RvE1 acting as a partial agonist that competes with LTB4-mediated NF-κB activation and calcium mobilization (Arita et al. 2007).
Activation of BLT1 by RvE1 also serves as a feedback mechanism for other SPMs, including increased production of LXA4 in the FPR2/ALX-mediated resolution of allergic pulmonary inflammation (Haworth et al. 2008).
RvE2 was identified as an additional BLT1 agonist, and the β-arrestin assay showed that RvE2 blocked LTB4-mediated β-arrestin signalling with similar efficacy to RvE1, indicating direct competition with LTB4 (Oh et al. 2012). Various pro-resolving roles of RvE2 have been proposed, including regulation of PMN infiltration and IL-10 production (Oh et al. 2012). However, while RvE1 promotes NADPH oxidase-mediated ROS production through the BLT1, RvE2 and RvE3 do not exhibit this effect (Unno et al. 2018).