Gi-independent macrophage chemotaxis to lysophosphatidylcholine via the immunoregulatory GPCR G2A.

Abstract

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 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. 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.

• Authors: Li V Yang, Caius G Radu, Li Wang, Mireille Riedinger, Owen N Witte
• Journal: Blood (Blood) Vol. 105 Issue 3 Pg. 1127-34 (Feb 01 2005) ISSN: 0006-4971 [Print] United States
• PMID: 15383458 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• DNA Primers
• G2A receptor
• Lysophosphatidylcholines
• RNA, Small Interfering
• Receptors, G-Protein-Coupled

Topics

• Animals
• Base Sequence
• Cell Cycle Proteins (drug effects, genetics, physiology)
• Cell Line
• Chemotaxis (drug effects, physiology)
• DNA Primers
• Gene Expression Regulation
• Lysophosphatidylcholines (pharmacology)
• Macrophages (drug effects, physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• RNA, Small Interfering (genetics)
• Receptors, G-Protein-Coupled (deficiency, drug effects, genetics, physiology)
• Reverse Transcriptase Polymerase Chain Reaction