title: Activation of murine macrophages by Neisseria meningitidis and IFN-gamma in vitro: distinct roles of class A scavenger and Toll-like pattern recognition receptors in selective modulation of surface phenotype.
abstract: Innate and adaptive immune activation of macrophages (Mphi) by microorganisms and antigen-activated lymphoid cells, respectively, plays an important role in host defense and immunopathology. Antigen-presenting cells express a range of pattern recognition receptors including the class A types I and II scavenger receptors (SR-A) and Toll-like receptors (TLR). Recognition of microbial products by SR-A and TLR controls uptake, killing, altered gene expression, and the adaptive immune response; however, the contribution of each receptor and interplay with cytokine stimuli such as interferon-gamma (IFN-gamma) are not defined. We used Neisseria meningitidis (NM), a potent activator of innate immunity, and IFN-gamma, a prototypic T helper cell type 1 proinflammatory cytokine, to compare surface antigens, secretion of mediators, and receptor functions in elicited peritoneal Mphi from wild-type and genetically modified mouse strains. We show that these stimuli regulate major histocompatibility complex type II (MHC-II) and costimulatory molecules differentially, as well as expression of the mannose receptor and of Mphi receptor with collagenous structure (MARCO), a distinct SR-A, which provides a selective marker for innate activation. In combination, NM inhibited up-regulation of MHC-II by IFN-gamma while priming enhanced release of tumor necrosis factor alpha and nitric oxide. The SR-A contributes to phagocytosis of the organisms but not to their ability to induce CD80, CD86, and MARCO or to inhibit MHC-II. Conversely, studies with lipopolysaccharide (LPS)-deficient organisms and/or TLR-4 mutant mice showed that LPS and TLR-4 are at least partially required to induce CD80, CD86, and MARCO, but LPS is not required to inhibit MHC-II. These studies provide an experimental model and identify surface markers for analysis of innate and acquired immune activation of Mphi.
authors.affiliation: Sir William Dunn School of Pathology, South Parks Road, Oxford, OX1 3RE, UK.
authors.forename: Subhankar
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Leanne
authors.initials: L
authors.lastname: Peiser
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000187:drug effects / Q000276:immunology; D018122:B7-1 Antigen / Q000187:drug effects / Q000276:immunology; D051940:B7-2 Antigen; D018955:CD36 Antigens / Q000276:immunology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000276:immunology*; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D037181:Lectins, C-Type / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000276:immunology; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009345:Neisseria meningitidis / Q000276:immunology; D010641:Phenotype; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology; D051117:Scavenger Receptors, Class A; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018955:CD36 Antigens; C497965:Cd86 protein, mouse; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; C092228:Marco protein, mouse; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051117:Scavenger Receptors, Class A; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma