![]() 3-5 The immunological importance of these lysophospholipid receptors is illustrated by the profound immunodeficiency observed in mice lacking expression of the S1P 1 receptor in hematopoietic cells. 2 The mechanism of lysophospholipid-mediated cell migration recently has been shown to require the expression of specific GPCRs, such as the receptors for sphingosine 1-phosphate (S1P), lysophosphatidic acid (LPA), and LPC. The network of chemokines and their receptors has been well studied 1 however, recent developments have raised interest in nonpolypeptide regulators of immune cell trafficking belonging to a group of related molecules with a lysophospholipid-like structure. Many types of molecular controls regulate this process, but G-protein–coupled receptors are especially important. Precise control of immune cell trafficking is complex and essential to the development and function of the immune system. Defects in this signaling pathway may be related to the pathogenesis of systemic autoimmune disease. Collectively, these data establish that pertussis toxin–insensitive G2A signaling regulates macrophage chemotaxis to LPC. Unlike most GPCRs, including the chemokine receptors, coupling to G i is not required for LPC/G2A-mediated chemotaxis, but coupling to G q/11 and G 12/13 is necessary as judged by inhibition with dominant negative forms of these alpha subunits or with regulators of G-protein signaling (RGS) constructs. Mutation of the conserved DRY motif of G2A resulted in loss of chemotaxis to LPC, suggesting a requirement for G-protein signaling. RNAi-mediated knockdown of G2A in J774A.1 macrophages abolished LPC-induced chemotaxis, whereas overexpression of G2A significantly enhanced this process. Wild-type but not G2A-deficient mouse peritoneal macrophages migrated toward LPC. ![]() Here we demonstrate that macrophage chemotaxis to LPC is dependent on G2A function. Production of LPC during cell apoptosis serves as a chemotactic signal for macrophage recruitment. Previous studies have shown that lysophosphatidylcholine (LPC), a bioactive lipid associated with atherosclerosis and autoimmunity, acts through G2A to induce diverse biologic effects. G2A is a G-protein–coupled receptor (GPCR) involved in immune regulation. ![]()
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