Scavenger receptor A mediates H2O2 production and suppression of IL-12 release in murine macrophages.
Although class A type I/II scavenger receptor (SR-A) is involved in numerous macrophage functions, its signaling ability remains uncertain. We used monoclonal antibodies (mAb) to specifically stimulate receptors on mouse alveolar (AMs) and peritoneal macrophages (PMs). Immobilized anti-SR-A (2F8) and anti-FcgammaR II/III (2.4G2) mAb stimulated hydrogen peroxide (H2O2) production in normal C3H/HeJ AMs (by 55% and 98%, respectively) and resident PMs (66% and 128%). The 2F8 mAb-stimulated H2O2 production resulted from specific stimulation of SR-A, since this response was absent in AMs from SR-A-deficient or C57BL/6 mice--the latter strain expressing an allelic form of SR-A, unrecognizable by 2F8 mAb. H2O2 production stimulated by anti-SR-A but not by anti-FcgammaRII/III mAb was preserved in FcgammaRI/III-deficient mice, ruling out involvement of FcgammaRs in the 2F8 mAb effect. In comparison with the FcgammaR-stimulated respiratory burst, the response to anti-SR-A mAb was delayed and, unlike the former, inhibited by pertussis toxin. Ligation of SR-A also inhibited lipopolysaccharide plus interferon-gamma-stimulated interleukin-12 (IL-12) release, by 25% in AMs and by 68% in thioglycollate-elicited PMs, consistent with different levels of SR-A expression. Neither nitrite nor IL-6 accumulation was affected by anti-SR-A mAb. SR-A-stimulated H2O2 does not seem to mediate the inhibition of IL-12 release, since the inhibition was neither reversed by scavenging of H2O2 nor mimicked by exogenous H2O2. Our results indicate that SR-A not only mediates endocytosis but can also generate signals such as H2O2, which may affect microbicidal or proinflammatory functions.
Józefowski
Szczepan
S
Physiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts, USA. sjozefow@hsph.harvard.edu
Kobzik
Lester
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D018955:CD36 Antigens / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D037342:Pertussis Toxin / Q000494:pharmacology; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051117:Scavenger Receptors, Class A; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D018955:CD36 Antigens; C485701:Fcgr1 protein, mouse; D016166:Free Radical Scavengers; D008070:Lipopolysaccharides; C495140:Msr1 protein, mouse; D017452:Receptors, IgG; D051117:Scavenger Receptors, Class A; D018664:Interleukin-12; D007371:Interferon-gamma; D006861:Hydrogen Peroxide; D037342:Pertussis Toxin