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Institute of Immunology and Infection Research, The University of Edinburgh, Edinburgh, United Kingdom
The prime function of classically activated macrophages (activated by Th1-type signals, such as IFN-
) 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 (NeM
), that display IL-4-dependent features such as the expression of arginase 1, RELM-
(resistin-like molecule ), and Ym1. Since increasing evidence suggests that macrophages show functional adaptivity, the response of NeM 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 NeM were not terminally differentiated but could develop a more classically activated phenotype in response to LPS and IFN-. 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- and Ym1. Furthermore, this enabled NeM to become antimicrobial, as LPS/IFN--treated NeM 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Wellcome Trust and the Medical Research Council, United Kingdom.
2 K.J.M. and M.G.N. contributed equally to this work.
3 Current address: Department of Pathobiology, University of Pennsylvania, Philadelphia, PA 19104.
4 Address correspondence and reprint requests to Dr. Judith E. Allen, Institute of Immunology and Infection Research, The University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, United Kingdom. E-mail address: j.allen{at}ed.ac.uk
5 Abbreviations used in this paper: M, macrophage; CAM, classically activated macrophage; iNOS, inducible NO synthase; AAM, alternatively activated macrophage; NeM, nematode-elicited macrophage; PEC, peritoneal exudate cell; RELM-, resistin-like molecule ; WT, wild type; BMM, bone marrow-derived macrophage; PD-L, programmed death ligand; L-NMMA, NG-monomethyl-L-arginine; nor-NOHA, N
-hydroxy-nor-L-arginine; CBA, cytokine bead array; ThioM, thioglycollate-elicited macrophage; MFI, mean fluorescence intensity.
This article has been cited by other articles:
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  R. M. Maizels, E. J. Pearce, D. Artis, M. Yazdanbakhsh, and T. A. Wynn Regulation of pathogenesis and immunity in helminth infections J. Exp. Med., September 28, 2009; 206(10): 2059 - 2066. [Abstract] [Full Text] [PDF]
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