Molecular mechanisms that influence the macrophage m1-m2 polarization balance

Abstract

As an essential component of innate immunity, macrophages have multiple functions in both inhibiting or promoting cell proliferation and tissue repair. Diversity and plasticity are hallmarks of macrophages. Classical M1 and alternative M2 activation of macrophages, mirroring the Th1-Th2 polarization of T cells, represent two extremes of a dynamic changing state of macrophage activation. M1-type macrophages release cytokines that inhibit the proliferation of surrounding cells and damage contiguous tissue, and M2-type macrophages release cytokines that promote the proliferation of contiguous cells and tissue repair. M1-M2 polarization of macrophage is a tightly controlled process entailing a set of signaling pathways, transcriptional and posttranscriptional regulatory networks. An imbalance of macrophage M1-M2 polarization is often associated with various diseases or inflammatory conditions. Therefore, identification of the molecules associated with the dynamic changes of macrophage polarization and understanding their interactions is crucial for elucidating the molecular basis of disease progression and designing novel macrophage-mediated therapeutic strategies.

Keywords: NLR; SOCS; TLR; innate immune response; macrophage polarization; microRNA.

Figure 1

Mechanisms underlying the polarization of macrophages. The major regulatory pathways of macrophage M1–M2 polarization are outlined. The crosstalk between the M1 and M2 macrophage polarizing pathways, particularly the balance between activation of STAT1 and STAT3/STAT6, tightly regulates macrophage polarization and activity. A predominance of NF-κB and STAT1 activation promotes M1 macrophage polarization, resulting in cytotoxic and tissue-damage proinflammatory functions. In contrast, a predominance of STAT3 and STAT6 activation by IL-4/13 and IL-10 increases M2 macrophage polarization, associated with immune tolerance and tissue repairing. PPARδ (and PPARγ) control distinct aspects of M2 macrophage activation and oxidative metabolism. KLF-4, a downstream of STAT6, participates in the promotion of M2 macrophage functions by suppressing the NF-κB/HIF-1α-dependent transcription. IL-4 induces not only c-Myc, which controls the expression of a subset of M2-associated genes but also the M2-polarizing IRF-4 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. MicroRNAs such as miR-155, miR-223, etc. are involved in modulating macrophage polarization via targeting SOCS1, CEBP, and Pknox1, respectively.