Alternatively Activated Macrophages Revisited: New Insights into the Regulation of Immunity, Inflammation and Metabolic Function following Parasite Infection

Abstract

The role of macrophages in homeostatic conditions and the immune system range from clearing debris to recognizing and killing pathogens. While classically activated macrophages (CAMacs) are induced by T helper type 1 (Th1) cytokines and exhibit microbicidal properties, Th2 cytokines promote alternative activation of macrophages (AAMacs). AAMacs contribute to the killing of helminth parasites and mediate additional host-protective processes such as regulating inflammation and wound healing. Yet, other parasites susceptible to Th1 type responses can exploit alternative activation of macrophages to diminish Th1 immune responses and prolong infection. In this review, we will delineate the factors that mediate alternative activation (e.g. Th2 cytokines and chitin) and the resulting downstream signaling events (e.g. STAT6 signaling). Next, the specific AAMac-derived factors (e.g. Arginase1) that contribute to resistance or susceptibility to parasitic infections will be summarized. Finally, we will conclude with the discussion of additional AAMac functions beyond immunity to parasites, including the regulation of inflammation, wound healing and the regulation of metabolic disorders.

Can Parasitic Worms Cure the Modern World’s Ills?

“…Type 2 (Th2) immune responses are induced to clear parasitic helminth infections, but the worms have evolved a variety of mechanisms to elicit regulatory responses that promote their survival and counter the Th1/Th17-mediated pathology that would likely arise in the absence of such a modified Th2 response [8]. These regulatory responses notably involve regulatory B-and T-cells and macrophages (often termed M2 or alternatively-activated [AAM] macrophages) and the production of a range of cytokines, particularly IL-10, IL-35 and TGF-β, and AAM products like RELMα, Arginase and Ym1 [27]. Such regulatory responses have the serendipitous sideeffect of also alleviating aberrant inflammation irrespective of its phenotype, explaining the ability of helminths to target both Th2-driven allergic and Th1/Th17driven autoimmune inflammation [8].…”

Spatial regulation of IL-4 signalling in vivo

“…The targets of this IL-13 production are dendritic cells, epithelial cells and fibroblasts, all tissue-based cells. IL-4 is also active in the infected tissue, polarising dendritic cell function [50] and driving the alternative activation of macrophages [51,52], important for tissue repair [53,54]. In the lymph node, type 2 cytokines are essential to promote Th2 differentiation and to skew B cell class switching towards IgE [7][8][9].…”

TNF-a mediated inflammatory macrophage polarization contributes to the pathogenesis of steroid-induced osteonecrosis in mice

“…2 Macrophages are immune effector cells that orchestrate a diverse array of functions including inflammatory response, tissue repair, immune responses, and so on. [3][4][5] Their diverse but polarized functional phenotypes, driven by micro-environmental cues, allow them to adapt readily to changing conditions within tissues. 6 In response to diverse signals derived from damaged tissues, macrophages undergo reprogramming, which leads to two different polarization states, M1 macrophages (classically activated) and M2 macrophages (alternatively activated).…”