Alternatively activated macrophages elicited by helminth infection can be reprogrammed to enable microbial killing.
The prime function of classically activated macrophages (activated by Th1-type signals, such as IFN-gamma) is microbial destruction. Alternatively activated macrophages (activated by Th2 cytokines, such as IL-4 and IL-13) play important roles in allergy and responses to helminth infection. We utilize a murine model of filarial infection, in which adult nematodes are surgically implanted into the peritoneal cavity of mice, as an in vivo source of alternatively activated macrophages. At 3 wk postinfection, the peritoneal exudate cell population is dominated by macrophages, termed nematode-elicited macrophages (NeMphi), that display IL-4-dependent features such as the expression of arginase 1, RELM-alpha (resistin-like molecule alpha), and Ym1. Since increasing evidence suggests that macrophages show functional adaptivity, the response of NeMphi to proinflammatory Th1-activating signals was investigated to determine whether a switch between alternative and classical activation could occur in macrophages differentiated in an in vivo infection setting. Despite the long-term exposure to Th2 cytokines and antiinflammatory signals in vivo, we found that NeMphi were not terminally differentiated but could develop a more classically activated phenotype in response to LPS and IFN-gamma. This was reflected by a switch in the enzymatic pathway for arginine metabolism from arginase to inducible NO synthase and the reduced expression of RELM-alpha and Ym1. Furthermore, this enabled NeMphi to become antimicrobial, as LPS/IFN-gamma-treated NeMphi produced NO that mediated killing of Leishmania mexicana. However, the adaptation to antimicrobial function did not extend to key regulatory pathways, such as IL-12 production, which remained unaltered.
Mylonas
Katie J
KJ
Institute of Immunology and Infection Research, The University of Edinburgh, Edinburgh, United Kingdom.
Nair
Meera G
MG
Prieto-Lafuente
Lidia
L
Paape
Daniel
D
Allen
Judith E
JE
D000818:Animals; D017178:Brugia malayi / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D005368:Filariasis / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000502:physiology; D018320:Leishmania major / Q000254:growth & development / Q000276:immunology; D016773:Leishmaniasis, Cutaneous / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008262:Macrophage Activation / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D018836:Inflammation Mediators