title: Rac2-deficient murine macrophages have selective defects in superoxide production and phagocytosis of opsonized particles.
abstract: The Rho family GTPase Rac is a crucial participant in numerous cellular functions and acts as a molecular switch for signal transduction. Mice deficient in hemopoietic-specific Rac2 exhibited agonist-specific defects in neutrophil functions including chemoattractant-stimulated filamentous actin polymerization and chemotaxis, and superoxide production elicited by phorbol ester, fMLP, or IgG-coated particles, despite expression of the highly homologous Rac1 isoform. In this study, functional responses of Rac2-null murine macrophages were characterized to examine whether Rac2 also has nonredundant functions in this phagocytic lineage. In contrast to murine neutrophils, in which Rac1 and Rac2 are present in similar amounts, Rac1 was approximately 4-fold more abundant than Rac2 in both bone marrow-derived and peritoneal exudate macrophages, and macrophage Rac1 levels were unchanged by the absence of Rac2. Accumulation of exudate macrophages during peritoneal inflammation was reduced in rac2(-/-) mice. FcgammaR-mediated phagocytosis of IgG-coated SRBC was also significantly decreased in Rac2-null macrophages, as was NADPH oxidase activity in response to phorbol ester or FcgammaR stimulation. However, phagocytosis and oxidant production stimulated by serum-opsonized zymosan was normal in rac2(-/-) macrophages. Macrophage morphology was also similar in wild-type and Rac2-null cells, as was actin polymerization induced by FcgammaR-mediated phagocytosis or M-CSF. Hence, Rac2-null macrophages have selective defects paralleling many of the observed functional defects in Rac2-null neutrophils. These results provide genetic evidence that although Rac2 is a relatively minor isoform in murine macrophages, it plays a nonoverlapping role with Rac1 to regulate host defense functions in this phagocyte lineage.
authors.affiliation: Inha University College of Medicine, Incheon, Korea. mdinauer@iupui.edu
authors.forename: Akira
authors.initials: A
authors.lastname: Yamauchi
authors.forename: Chaekyun
authors.initials: C
authors.lastname: Kim
authors.forename: Shijun
authors.initials: S
authors.lastname: Li
authors.forename: Christophe C
authors.initials: CC
authors.lastname: Marchal
authors.forename: Jason
authors.initials: J
authors.lastname: Towe
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Atkinson
authors.forename: Mary C
authors.initials: MC
authors.lastname: Dinauer
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000954:Antigens, Surface / Q000096:biosynthesis; D001202:Ascitic Fluid / Q000166:cytology / Q000276:immunology; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D004912:Erythrocytes / Q000276:immunology; D005260:Female; D007074:Immunoglobulin G / Q000097:blood / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009895:Opsonin Proteins / Q000097:blood / Q000378:metabolism*; D016877:Oxidants / Q000096:biosynthesis; D010587:Phagocytosis / Q000235:genetics* / Q000276:immunology; D010703:Phorbol Esters / Q000494:pharmacology; D020033:Protein Isoforms / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D017452:Receptors, IgG / Q000502:physiology; D012756:Sheep; D013481:Superoxides / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D020830:rac1 GTP-Binding Protein / Q000096:biosynthesis / Q000502:physiology; D000097766:RAC2 GTP-Binding Protein
chemical_list: D000199:Actins; D000954:Antigens, Surface; D007074:Immunoglobulin G; D016173:Macrophage Colony-Stimulating Factor; D009895:Opsonin Proteins; D016877:Oxidants; D010703:Phorbol Esters; D020033:Protein Isoforms; D017452:Receptors, IgG; D013481:Superoxides; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein