Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms

Abstract

The alternatively activated or M2 macrophages are immune cells with high phenotypic heterogeneity and are governing functions at the interface of immunity, tissue homeostasis, metabolism, and endocrine signaling. Today the M2 macrophages are identified based on the expression pattern of a set of M2 markers. These markers are transmembrane glycoproteins, scavenger receptors, enzymes, growth factors, hormones, cytokines, and cytokine receptors with diverse and often yet unexplored functions. This review discusses whether these M2 markers can be reliably used to identify M2 macrophages and define their functional subdivisions. Also, it provides an update on the novel signals of the tissue environment and the neuroendocrine system which shape the M2 activation. The possible evolutionary roots of the M2 macrophage functions are also discussed.

Figure 1

Overview of the macrophage activation states. Macrophage activation is widely considered as a polarization towards M1 or M2 states. However, the M2 activation state involves heterogeneous and functionally distinct macrophages. The diagram represents the most prevalent examples of the M2 activation and lists the markers associated with the distinct activation phenotypes. The upstream signals are labeled in dotted frames. Abbreviations are defined in the text.

Figure 2

Alternative model depicting sensor and effector functions of the M2 macrophages. The macrophage phenotype is principally determined by eliciting signals, derived from immune cells, pathogens, apoptotic or damaged cells, and a wide range of chemical mediators. They act through receptors and signal pathways which elicit a wide range of effector functions. Abbreviations are defined in the text.