Elsevier

Journal of Autoimmunity

Volume 33, Issues 3–4, November–December 2009, Pages 222-230
Journal of Autoimmunity

Alternatively activated macrophages in infection and autoimmunity

https://doi.org/10.1016/j.jaut.2009.09.012Get rights and content

Abstract

Macrophages are innate immune cells that play an important role in activation of the immune response and wound healing. Pathogens that require T helper-type 2 (Th2) responses for effective clearance, such as parasitic worms, are strong inducers of alternatively activated or M2 macrophages. However, infections such as bacteria and viruses that require Th1-type responses may induce M2 as a strategy to evade the immune system. M2 are particularly efficient at scavenging self tissues following injury through receptors like the mannose receptor and scavenger receptor-A. Thus, M2 may increase autoimmune disease by presenting self tissue to T cells. M2 may also exacerbate immune complex (IC)-mediated pathology and fibrosis, a hallmark of autoimmune disease in women, due to the release of profibrotic factors such as interleukin-1β, transforming growth factor-β, fibronectin and matrix metalloproteinases. We have found that M2 comprise anywhere from 30% to 70% of the infiltrate during acute viral or experimental autoimmune myocarditis, and shifts in M2 populations correlate with increased IC deposition, fibrosis and chronic autoimmune pathology. Thus, women may be at an increased risk of M2-mediated autoimmunity due to estrogen's ability to increase Th2 responses.

Introduction

A number of excellent reviews have been written in the past few years describing macrophage activation and polarization (see [1], [2], [3], [4]). The aim of this review is to highlight the role of infection and tissue damage in directing macrophage phenotype and the impact polarized macrophage populations have on the initiation and propagation of autoimmune diseases. The influence of sex hormones on macrophage polarization and function will also be examined. Most of the discussion of alternatively activated macrophages in this review will focus on research conducted in animal models.

Section snippets

Classification of macrophages

Macrophages are innate immune cells that play a key role in normal tissue homeostasis, presentation of foreign and self antigens following infection or injury, pathogen clearance, resolution of inflammation and wound healing [1], [2], [5], [6], [7]. Following antigen stimulation immature monocytes emigrate from blood vessels into peripheral tissues where they differentiate into mature macrophages and dendritic cells (DCs) comprising as much as 15% of total cells [1], [7]. Macrophages are

Infection and injury in AD

For some time infections have been postulated to play a role in the initiation and/or promotion of autoimmune diseases (ADs). The role of infection has been difficult to substantiate for a number of reasons. Many of the infections suspected to cause ADs are widespread in the population, such as coxsackievirus or cytomegalovirus, and often an active infection can no longer be detected by the time the signs and symptoms of AD appear [29]. Several theories have been proposed to explain

M2 and autoimmune diseases

Although the hallmark of AD is the generation of autoantigen-specific T and B cell responses, macrophages and neutrophils comprise the majority of the infiltrate during the peak of acute inflammation [42], [72]. Other factors critical in determining the development of AD include genetic background and sex [31], [42], [45], [53], [73]. For example, BALB/c mice develop predominant Th2 and M2 responses following infection or adjuvant inoculation compared to C57BL/6 mice due to their high numbers

Concluding remarks

Alternatively activated macrophages are induced by the Th2-type cytokines IL-4 and IL-13 and are well known for their ability to inhibit proinflammatory responses by the release of IL-10 and TGF-β. M2 and MDSCs are also induced in response to viral and bacterial infections usually associated with Th1 or Th17-type responses, such as CVB3, M. tuberculosis and CFA supplemented with M. tuberculosis and pertussis toxin that is used to induce AD in animal models (Table 1). Recent findings in animal

Acknowledgements

Work discussed in this review was supported by NIH R01 grants HL087033 (D.F.) and HL67290, HL70729 and a Fellowship Grant from the Myocarditis Foundation (D.C.).

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