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

Abstract

The prime function of classically activated macrophages (activated by Th1-type signals, such as IFN-γ) 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 (NeMφ), that display IL-4-dependent features such as the expression of arginase 1, RELM-α (resistin-like molecule α), and Ym1. Since increasing evidence suggests that macrophages show functional adaptivity, the response of NeMφ 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 NeMφ were not terminally differentiated but could develop a more classically activated phenotype in response to LPS and IFN-γ. 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-α and Ym1. Furthermore, this enabled NeMφ to become antimicrobial, as LPS/IFN-γ-treated NeMφ 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.

Sequential expression of macrophage anti-microbial/inflammatory and wound healing markers following innate, alternative and classical activation

“…In these systems, the Th2-driven, chronic stage of infection is characterized by the presence of alternatively activated macrophages indicated by the IL-4-dependent expression of fizz1 and ym1 [7,9,27,29,46]. Recently, Mylonas et al [47] have used these in vivo models of parasite infection to demonstrate further the plasticity of macrophage activation. This study has shown that even after long-term exposure to Th2 cytokines, macrophages could still respond to LPS and IFN-g stimulation to become antimicrobial in function.…”

Alternative activation of macrophages by IL-4 impairs phagocytosis of pathogens but potentiates microbial-induced signalling and cytokine secretion

“…Our findings confirm and extend earlier studies on LPS 7-10,33,34 and staphylococcal enhancement of proinflammatory cytokine release by IL-4-pretreated M⌽s, with altered gene expression and signal transduction. 7 Interestingly, Mylonas et al 35 showed that nematodeelicited peritoneal M⌽s, which display IL-4-dependent features, secrete more proinflammatory cytokines in response to LPS/IFN-␥ challenge. The investigators also demonstrated that IL-4 priming of uninfected ThioM⌽s did not modify cytokine secretion after LPS/IFN-␥ stimulation in vitro.…”

“…These findings are consistent with recent evidence that, despite long-term exposure to Th2 cytokines in vivo, M⌽s could respond to Th1 stimuli and display a classically activated phenotype. 35 Moreover, Hagemann et al 50 demonstrated that tumor-promoting alternatively activated M⌽s can be reprogrammed to promote tumor killing. Our data confirm that highly polarized M⌽s maintain remarkable plasticity in their microenvironment.…”

Resistin-Like Molecule–α Regulates IL-13–Induced Chemokine Production but Not Allergen-Induced Airway Responses

“…Relm-a is a hallmark signature gene of murine alternatively activated macrophages (22)(23)(24)(25). However, we (and others) recently showed that intestinal epithelial cells and eosinophils can also express Relm-a (19,23,26).…”