Abstract
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.
Original language | English |
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Pages (from-to) | 3084-3094 |
Number of pages | 11 |
Journal | The Journal of Immunology |
Volume | 182 |
Issue number | 5 |
DOIs | |
Publication status | Published - Mar 2009 |
Keywords / Materials (for Non-textual outputs)
- Animals
- Brugia malayi
- Cells, Cultured
- Female
- Filariasis
- Inflammation Mediators
- Leishmania major
- Leishmaniasis, Cutaneous
- Macrophage Activation
- Macrophages, Peritoneal
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Signal Transduction
- Th1 Cells
- Th2 Cells