Macrophage Polarization in Inflammatory Diseases

Liu, Yan-Cun; Zou, Xian-Biao; Chai, Yan-Fen; Yao, Yong-Ming

In 1989, when the heterogeneity in the helper T-cell compartment was subsequently reported, Mosrnann and Coffman reviewed the different functions and lymphokines secretion between two types of cloned helper T cells (Th), and proposed the concept of Th1 and Th2 [5] . One year later, Abramson and his Ivyspring International Publisher colleagues recognized that interleukin (IL)-4, which was mainly produced by Th2 cells, could convert macrophages into a special activation state compared with IFN-γ induced activation in which respiratory burst was inhibited and major histocompatibility complex class II antigens (MHC-II) expression was increased [6] . With the discovery of up-regulation of macrophage mannose receptor (MRC1) as a specific marker of IL-4/IL-13-activated macrophages in 1992, which was coupled with the enhanced expression of MHC-II, the concept of alternatively activated macrophages (AAM, also known as M2) was first proposed [7] . In the following years, when the plasticity of macrophages in response to different environment was gradually studied, Mosser and Edwards reviewed the full spectrum of macrophage activation and pointed out that M1 and M2 were two terminals of the spectrum [8] . In addition to IL-4/IL-13, a great number of stimuli, such as antibody immune complexes together with lipopolysaccharide (LPS) or IL-1, transforming growth factor-β (TGF-β), glucocorticoids and IL-10, were found to have the ability of alternative activation of macrophages. As they shared properties with IL-4/IL-13-activated macrophages, a new functional state called M2-like phenotype [9] was proposed, and it held great promise for the research of macrophage activation in a dynamic microenvironment ( Figure 1 ). M1 phenotype macrophages express numerous pro-inflammatory mediators including tumor necrosis factor (TNF)-α, IL-1, IL-6, reactive nitrogen and oxygen intermediates, which have a strong microbicidal and tumoricidal activity; while M2 phenotype express molecules including resistin-like-α (also known as Fizz1), Arginase1 (Arg1), chitinase 3-like 3 (also known as Ym1), IL-10 and Mrc1 (also known as CD206), which are supposed to be involved in parasite infestation, tissue remodeling and tumor progression (immunoregulatory functions) [10] . M1 and M2 phenotype macrophages can be converted into each other in their specific microenvironment, and they are quite different with Th1 and Th2 [11] . Many key transcription factors are involved in macrophage polarization [12] , like signal transducer and activator of transcription (STATs)[13], interferon-regulatory factor (IRFs) [14, 15] , nuclear factor (NF)-κB [16] , activator protein (AP) 1 [17] , peroxisome proliferator-activated receptor (PPAR)-γ [18, 19] and cAMP-responsive element-binding protein (CREB) [20] , which interact with each other and regulate macrophages to certain phenotype in the various inflammatory diseases ( Figure 2 ). Here we briefly review the polarization of macrophages and their functions in some typical inflammatory diseases. Those include the activation of STAT1 mediated by IFN-γ receptor, increase in IRF5, NF-κB, as well as AP1 expression mediated by Toll-like receptor 4 (TLR4), enhanced AP1 expression mediated by cytokine receptor, activation of STAT6 and increased IRF4 mediated by IL-4 receptor, increased level of PPARγ mediated by fatty acid receptor, and enhanced expression in CREB by TLR4. The feedback regulation between M1 and M2 are implemented by STAT1-STAT6, IRF5-I