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Blood, 1 February 2005, Vol. 105, No. 3, pp. 1127-1134.
Prepublished online as a Blood First Edition Paper on September 21, 2004; DOI 10.1182/blood-2004-05-1916.
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IMMUNOBIOLOGY
Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A
Li V. Yang,
Caius G. Radu,
Li Wang,
Mireille Riedinger, and
Owen N. Witte
From the Howard Hughes Medical Institute, the Department of Microbiology, Immunology and Molecular Genetics; and the Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA.
G2A is a G-protein–coupled receptor (GPCR) involved in immune regulation. Previous studies have shown that lysophosphatidylcholine (LPC), a bioactive lipid associated with atherosclerosis and autoimmunity, acts through G2A to induce diverse biologic effects. Production of LPC during cell apoptosis serves as a chemotactic signal for macrophage recruitment. Here we demonstrate that macrophage chemotaxis to LPC is dependent on G2A function. Wild-type but not G2A-deficient mouse peritoneal macrophages migrated toward LPC. RNAi-mediated knockdown of G2A in J774A.1 macrophages abolished LPC-induced chemotaxis, whereas overexpression of G2A significantly enhanced this process. Mutation of the conserved DRY motif of G2A resulted in loss of chemotaxis to LPC, suggesting a requirement for G-protein signaling. Unlike most GPCRs, including the chemokine receptors, coupling to Gi is not required for LPC/G2A-mediated chemotaxis, but coupling to Gq/11 and G12/13 is necessary as judged by inhibition with dominant negative forms of these alpha subunits or with regulators of G-protein signaling (RGS) constructs. Collectively, these data establish that pertussis toxin–insensitive G2A signaling regulates macrophage chemotaxis to LPC. Defects in this signaling pathway may be related to the pathogenesis of systemic autoimmune disease.
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