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Updated: Jun 25, 2026
Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
Alternatively activated macrophages elicited by helminth infection can be reprogrammed to enable microbial killing
Katie J Mylonas1, Meera G Nair, Lidia Prieto-Lafuente
1Institute of Immunology and Infection Research, The University of Edinburgh, Edinburgh, United Kingdom.
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.
Insights
Nematode-elicited macrophages (NeMphi) in filarial infection can switch from alternative to classical activation. This functional adaptivity enables antimicrobial activity upon exposure to inflammatory signals like LPS and IFN-gamma.
Area of Science:
- Immunology
- Cell Biology
- Parasitology
Background:
- Macrophages exhibit distinct activation states, including classically activated (Th1-mediated, antimicrobial) and alternatively activated (Th2-mediated, allergy/helminth response).
- Alternatively activated macrophages, like nematode-elicited macrophages (NeMphi) in filarial infection models, express IL-4-dependent markers (arginase 1, RELM-alpha, Ym1).
- Functional adaptivity suggests macrophages may alter their activation state in response to environmental cues.
Purpose of the Study:
- To investigate the potential for functional plasticity in in vivo-derived alternatively activated macrophages.
- To determine if nematode-elicited macrophages (NeMphi) can switch to a classically activated phenotype when exposed to Th1-activating signals.
- To assess the functional consequences of such a potential phenotype switch on antimicrobial capabilities.
Main Methods:
- Utilized a murine model of filarial infection with surgically implanted nematodes to generate in vivo alternatively activated macrophages (NeMphi).
- Exposed NeMphi to lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) to mimic proinflammatory Th1-type signals.
- Assessed changes in macrophage phenotype, including arginine metabolism (arginase vs. inducible NO synthase), expression of RELM-alpha and Ym1, nitric oxide (NO) production, and antimicrobial activity against Leishmania mexicana.
Main Results:
- NeMphi, despite long-term in vivo Th2 cytokine exposure, were not terminally differentiated and could adopt a classically activated phenotype.
- Exposure to LPS and IFN-gamma induced a switch from arginase to inducible NO synthase, reduced RELM-alpha and Ym1 expression, and enabled NO-mediated killing of Leishmania mexicana.
- Key regulatory pathways, such as IL-12 production, remained unaltered, indicating incomplete adaptation.
Conclusions:
- In vivo-derived alternatively activated macrophages (NeMphi) possess functional plasticity, allowing a switch towards a classical activation phenotype.
- This adaptive response confers antimicrobial capabilities, demonstrating macrophage adaptability in an inflammatory context.
- The plasticity is specific, as certain regulatory pathways like IL-12 production remain unchanged.
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