Macrophage plasticity and polarization: in vivo veritas

Abstract

Diversity and plasticity are hallmarks of cells of the monocyte-macrophage lineage. In response to IFNs, Toll-like receptor engagement, or IL-4/IL-13 signaling, macrophages undergo M1 (classical) or M2 (alternative) activation, which represent extremes of a continuum in a universe of activation states. Progress has now been made in defining the signaling pathways, transcriptional networks, and epigenetic mechanisms underlying M1-M2 or M2-like polarized activation. Functional skewing of mononuclear phagocytes occurs in vivo under physiological conditions (e.g., ontogenesis and pregnancy) and in pathology (allergic and chronic inflammation, tissue repair, infection, and cancer). However, in selected preclinical and clinical conditions, coexistence of cells in different activation states and unique or mixed phenotypes have been observed, a reflection of dynamic changes and complex tissue-derived signals. The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for macrophage-centered diagnostic and therapeutic strategies.

Figures

Figure 1. Mechanisms of macrophage polarization.

The major pathways of macrophage polarization are outlined. The crosstalk between the M1-M2 macrophage–polarizing pathways is also indicated. The balance between activation of STAT1 and STAT3/STAT6 finely regulates macrophage polarization and activity. A predominance of NF-κB and STAT1 activation promotes M1 macrophage polarization, resulting in cytotoxic and inflammatory functions. In contrast, a predominance of STAT3 and STAT6 activation results in M2 macrophage polarization, associated with immune suppression and tumor progression. PPARγ and PPARδ control distinct aspects of M2 macrophage activation and oxidative metabolism. KLF4 and KLF2 participate in the promotion of M2 macrophage functions by cooperating with STAT6 and suppressing the NF-κB/HIF-1α–dependent transcription, respectively. IL-4–induced c-Myc activity controls a subset of M2-associated genes. IL-4 also induces the M2-polarizing Jmjd3-IRF4 axis to inhibit IRF5-mediated M1 polarization. IL-10 promotes M2 polarization through the induction of p50 NF-κB homodimer, c-Maf, and STAT3 activities.

Figure 2. Schematic representation of macrophage plasticity and polarization in pathology.

Dynamic changes occur over time with evolution of pathology: for instance, a switch from M1 to M2 macrophage polarization characterizes the transition from early to chronic phases of infection. Moreover, mixed phenotypes or populations with different phenotypes can coexist. For pathologies not discussed in the text, see Supplemental References. Images adapted from refs. –.