title: Deletion of the G2A receptor fails to attenuate experimental autoimmune encephalomyelitis.
abstract: Lysophosphatidylcholine (LPC) is a chemotactic lysolipid produced during inflammation by the hydrolytic action of phospholipase A(2) enzymes. LPC stimulates chemotaxis of T cells in vitro through activation of the G protein-coupled receptor, G2A. This has led to the proposition that G2A contributes to the recruitment of T cells to sites of inflammation and thus promotes chronic inflammatory autoimmune diseases associated with the generation and subsequent tissue infiltration of auto-antigen-specific effector T cells. However, one study suggests that G2A may negatively regulate T cell proliferative responses to antigen receptor engagement and thereby attenuates autoimmunity by reducing the generation of autoreactive T cells. To address the relative contribution of these G2A-mediated effects to the pathophysiology of T cell-mediated autoimmune disease, we examined the impact of G2A inactivation on the onset and severity of murine experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Wild type (G2A(+/+)) and G2A-deficient (G2A(-/-)) C57BL/6J mice exhibited a similar incidence and onset of disease following immunization with MOG(35-55) peptide. Disease severity was only moderately reduced in G2A(-/-) mice. Similar numbers of MOG(35-55) specific T cells were generated in secondary lymphoid organs of MOG(35-55)-immunized G2A(+/+) and G2A(-/-) mice. Comparable numbers of T cells were detected in spinal cords of G2A(+/+) and G2A(-/-) mice. We conclude that the proposed anti-proliferative and chemotactic functions of G2A are not manifested in vivo and therefore therapeutic targeting of G2A is unlikely to be beneficial in the treatment of MS.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Inga
authors.initials: I
authors.lastname: Osmers
authors.forename: Sherry S
authors.initials: SS
authors.lastname: Smith
authors.forename: Brian W
authors.initials: BW
authors.lastname: Parks
authors.forename: Shaohua
authors.initials: S
authors.lastname: Yu
authors.forename: Roshni
authors.initials: R
authors.lastname: Srivastava
authors.forename: Jillian E
authors.initials: JE
authors.lastname: Wohler
authors.forename: Scott R
authors.initials: SR
authors.lastname: Barnum
authors.forename: Janusz H S
authors.initials: JH
authors.lastname: Kabarowski
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology*; D005434:Flow Cytometry / Q000379:methods; D017353:Gene Deletion; D006023:Glycoproteins / Q000009:adverse effects; D007371:Interferon-gamma / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments / Q000009:adverse effects; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
chemical_list: D018797:Cell Cycle Proteins; C115270:G2A receptor; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D043562:Receptors, G-Protein-Coupled; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma