title: Alternative activation of macrophages by IL-4 impairs phagocytosis of pathogens but potentiates microbial-induced signalling and cytokine secretion.
abstract: Alternatively activated macrophages play an important role in host defense in the context of a T helper type 2 (Th2) microenvironment such as parasitic infection. However, the role of these macrophages during secondary challenge with Th1 pathogens is poorly defined. In this study, thioglycollate-elicited mouse peritoneal macrophages were treated with interleukin-4 (IL-4) or IL-13 in vitro and challenged with Neisseria meningitidis. After 8 to 12 hours of IL-4 pretreatment, the nonopsonic phagocytic uptake of N meningitidis was markedly reduced, depending on the common IL-4Ralpha chain, but independent of Scavenger receptor A and macrophage receptor with collagenous structure (MARCO), 2 known receptors for N meningitidis. Inhibition of phagocytosis extended to several other microbial particles, zymosan, and other bacteria. Concomitantly, IL-4 potentiated the secretion of proinflammatory cytokines, after additional bacterial stimulation, which depended on the MyD88 signaling pathway. Similar results were obtained after intraperitoneal stimulation of IL-4 and N meningitidis in vivo. Further in vitro studies showed a striking correlation with inhibition of Akt phosphorylation and stimulation of the mitogen-activated protein kinase pathway; inhibition of phagocytosis was associated with inhibition of phagosome formation. These findings are relevant to host defense in mixed infections within a Th2 microenvironment and shed light on immunologic functions associated with alternative priming and full activation of macrophages.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Audrey
authors.initials: A
authors.lastname: Varin
authors.forename: Subhankar
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Georges
authors.initials: G
authors.lastname: Herbein
authors.forename: Siamon
authors.initials: S
authors.lastname: Gordon
mesh_terms: D000818:Animals; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D038541:Neisseria meningitidis, Serogroup B; D010587:Phagocytosis; D010766:Phosphorylation / Q000187:drug effects / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D053662:Interleukin-4 Receptor alpha Subunit
chemical_list: D018793:Interleukin-13; D015847:Interleukin-4; D053594:Myeloid Differentiation Factor 88; D051057:Proto-Oncogene Proteins c-akt; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C092228:Marco protein, mouse; C507780:Myd88 protein, mouse