Protective and pathogenic functions of macrophage subsets

Abstract

Macrophages are highly heterogenous cells that can rapidly change their function in response to local microenvironmental signals. Although distinct macrophage subsets with unique functional abilities have been described, it is generally believed that macrophages represent a spectrum of activated phenotypes rather than discrete stable subpopulations. They adopt context-dependent phenotypes that either promote or inhibit host antimicrobial defence, antitumour immune responses and inflammatory responses. Macrophages ingest and kill pathogens and maintain healthy tissue by removing dead cells and debris. Because macrophages must be selective of the cells and materials they phagocytose, they use pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), C-type lectin receptors, scavenger receptors, retinoic acid-inducible gene 1 (RIG1)-like helicase receptors (RLRs) and NOD-like receptors, to recognize signals associated with invading pathogens, foreign substances (for example, silica or asbestos), and dead or dying cells. Various macrophage subsets with distinct immune functions have been described. Classically activated macrophages (M1 macrophages) mediate defence of the host from various bacteria, protozoa and viruses, and also mediate antitumour immune responses. Alternatively activated macrophages (M2 macrophages) have an anti-inflammatory function and regulate wound healing. 'Regulatory' macrophages can secrete large amounts of interleukin-10 (IL-10) in response to Fc receptor-γ ligation. Other, less-well-defined macrophage subsets include tumour-associated macrophages, which suppress antitumour immunity, and myeloid-derived suppressor cells. Alternatively activated macrophages regulate tissue repair and suppress tissue-destructive M1 responses. They express immunoregulatory proteins such as IL-10, resistin-like molecule-α (RELMα), chitinase-like proteins and arginase 1 (ARG1), which have been shown to decrease the magnitude and duration of inflammatory responses and promote wound healing. Inflammatory (M1) and suppressive (M2) macrophages are crucially involved in the initiation and resolution of immune responses. Thus, macrophages exhibit both protective and pathogenic roles in a wide range of autoimmune and inflammatory diseases. Although murine M1- and M2-polarized macrophage subsets are relatively easy to distinguish on the basis of combinatorial gene expression profiles, the identification of equivalent subsets in humans has been less clear. The regulation of macrophages in the tissues remains unclear. We also do not understand how homeostasis is restored after infection, how the response to damaged tissues is resolved and what mechanisms are involved in the layered hierarchy of macrophage activation in situ. Research is needed on mechanisms that regulate the plasticity and stability of macrophage populations in vivo. Identifying the transcription factors and epigenetic changes that control macrophage plasticity will advance the field.