Elsevier

Immunobiology

Volume 214, Issue 7, July 2009, Pages 630-641
Immunobiology

REVIEW
Alternative activation of macrophages: Immune function and cellular biology

https://doi.org/10.1016/j.imbio.2008.11.009Get rights and content

Abstract

Macrophages are the first line of defense of the organism against pathogens and, in response to the microenvironment, become differentially activated. In the presence of IL-4 and IL-13, cytokines that are produced in a Th-2 type response, particularly during allergy and parasitic infections, macrophages become differentially activated. Alternative activated macrophages play an important role in the protection of the host by decreasing inflammation and promoting tissues repair. However, alternative activation of macrophages also downregulates host protection against selected pathogens. This defect is associated with an altered receptor expression pattern and extensive modulation of intracellular membrane trafficking. This review shows how alternative activation of macrophages induces extensive cellular remodelling of phagocytic, endocytic, signaling and secretory pathways which play an important, but unclear role in the pathogenesis of different disease.

Introduction

Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are major mediators of the inflammatory response. During infection, macrophage effector functions are critical for the elimination of pathogens, however uncontrolled inflammatory responses can induce injury of the tissue environment and must be repressed to allow the process of repair. Therefore the disease stage, tissue and cytokine microenvironment induce, in vivo, a heterogeneous macrophage population that displays an appropriate inflammatory phenotype (Gordon and Taylor, 2005). In vitro, two major macrophage populations are characterized. Classically activated or type I macrophages, induced in particular by IFNγ (Dalton et al., 1993), display a pro-inflammatory profile whereas alternatively activated or type II macrophages (AAMΦ), induced by Th-2 cytokines, express anti-inflammatory and tissue repair properties (Gordon, 2003).

In this review, we summarize the effects of IL-4-induced alternative activation on macrophages with special reference to altered immune functions and cellular biology.

Section snippets

IL-4-induced signal transduction

Alternative activation of macrophages is induced by IL-4 and IL-13, cytokines that are produced in a Th-2 type response, particularly during allergic, cellular and humoral responses to parasitic and selected pathogen infections. IL-4 is a pleiotropic type I cytokine produced by a subpopulation of CD4+ T cells, designated Th-2 cells, and by basophils and mast cells. IL-4 modulates other lymphoid cell activities such as regulation of the differentiation of antigen-stimulated T lymphocytes (Hsieh

Anti-inflammatory effects of IL-4

One of the main characteristics of AAMΦ is their anti-inflammatory properties (Fig. 2, Table 1, Table 2). Accordingly, IL-4 stimulates the production of anti-inflammatory cytokines such as IL-10 and IL-1R antagonist (Fenton et al., 1992; Schebesch et al., 1997) and inhibits expression of the pro-inflammatory cytokines IL-1, TNFα, IL-6, IL-12 and MIP-1α, thus reducing inflammation (Bonder et al., 1998; Cheung et al., 1990). Moreover, AAMΦ selectively increase production of macrophage-derived

Role of IL-4 in host defense to infection

In addition to their role in reducing inflammation and host injury, many studies have shown that AAMΦ down-regulate host protection against different pathogens. AAMΦ do not display enhanced killing towards most microbes. Indeed, the production of microbicidal NO is counteracted by increased expression of arginase 1 (Fig. 3) (Munder et al., 1998). Arginase 1 hydrolyzes l-arginine to urea and l-ornithine, but l-arginine also serves as the nitrogen source for the NOS (NO synthase) in the

Effect of alternative activation on macrophage membrane functions

Alternative activation of macrophages also leads to altered receptor expression pattern associated with modification of phagocytosis and membrane trafficking (Table 3). One characteristic of AAMΦ is the increase in mannose receptor (MR) expression (Doyle et al., 1994; Stein et al., 1992). The MR is an important route for uptake of a broad range of mannosylated glycoproteins and particulates (Stahl et al., 1980). Besides the MR, AAMΦ preferentially express other pattern recognition receptors of

Conclusion

AAMΦ seem to be major players in the immune system by preventing excessive inflammation while down-regulating host protection against different pathogens. These effects are linked to the modulation of expression of receptors at the cell surface and by modification of the endocytic and phagocytic pathway. A possible link to altered secretory activity and extracellular functions remains to be established. Moreover, AAMΦ are characterized by increase of scavenging and membrane trafficking

Acknowledgments

Audrey Varin is supported by a fellowship from Fondation pour la Recherche Médicale. Work in the laboratory of Siamon Gordon is supported by grants from the Medical Research Council, UK. We thank Laura Helming and Fernando Martinez for the critical reading of this manuscript.

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