Alternatively Activated Macrophages Elicited by Helminth Infection Can Be Reprogrammed to Enable Microbial Killing

• Published in: The Journal of immunology (1950) 2009-03, Vol.182 (5), p.3084-3094
• Main Authors: Mylonas, Katie J, Nair, Meera G, Prieto-Lafuente, Lidia, Paape, Daniel, Allen, Judith E
• Format: Article
• Language: English
• Subjects: Animals; Brugia malayi - immunology; Cells, Cultured; Female; Filariasis - immunology; Filariasis - pathology; Filariasis - prevention & control; Inflammation Mediators - physiology; Leishmania major - growth & development; Leishmania major - immunology; Leishmaniasis, Cutaneous - immunology; Leishmaniasis, Cutaneous - pathology; Leishmaniasis, Cutaneous - prevention & control; Macrophage Activation - immunology; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - parasitology; Mice; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction - immunology; Th1 Cells - immunology; Th1 Cells - metabolism; Th1 Cells - pathology; Th2 Cells - immunology; Th2 Cells - metabolism; Th2 Cells - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0803463

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.