Regulating the Polarization of Macrophages: A Promising Approach to Vascular Dermatosis

Figure 2

Possible mechanisms of different macrophage polarizations in vascular disorders. Upon the different stimuli, monocytes tend to differentiate into M1 or M2 macrophages via different signaling pathways. In most vascular inflammatory diseases, M1 activation is dominant, whereas M2 activation is relatively inhibited. Through activation of the pathways (JAK/STAT1, IRF/STAT1, and MyD88/NF-κB), activated M1 macrophages release various inflammatory mediators, such as MHC-II, chemokines (CXCL10 and CXCL11), and inflammatory cytokines (TNF-α, IL-12, IL-23, and IL-27), to encourage the activation of Th1/Th17 cells and trigger Th1/Th17 response. Apart from that, M1 macrophages produce substantial ROS and NO. As the key factors that regulate the differentiation and chemotaxis of Th2/Treg cells, however, M2-secreted chemokines (CCL17, CCL18, CCL22, and CCL24) and anti-inflammatory cytokines (TGF-β, IL-10) markedly decrease along with the inhibition of activated M2. As a result, these events may contribute to the appearance of T cell dysregulation, OS damage, and increased inflammatory mediators in the pathological process of vascular inflammatory disorders or dermatoses, e.g., psoriasis, SLE, and BD. On the other hand, activated M2 macrophages secrete abundant angiogenic factors (e.g., VEGF-A/C, FGF-2, EGF, and PDGF) via stimulating the JAK/STAT6 and IL-10/STAT3 pathways, which not only facilitate normal angiogenesis in wound repair but also promote abnormal angiogenesis in angiogenesis-related diseases including IH by activating the PDGF and FGF signal pathways. Notes: the red and blue solid arrows indicate normal activation, while the red dotted arrow indicates relative inactivation; ⊕indicates “activation,” ↑ indicates “upregulation,” and ↓ indicates “downregulation.” Abbreviations: LPS: lipopolysaccharide; IFN-γ: interferon gamma; IL-4/10/13: interleukin 4/10/13; M1: classically activated macrophage; M2: alternatively activated macrophage; ROS: reactive oxygen species; NO: nitric oxide; MHC-II: major histocompatibility complex-II; CXCL9/10/11: chemokine (c-x-c motif) ligand 9/10/11; IL-10/12/23/27: interleukin 10/12/23/27; TNF-α: tumor necrosis factor alpha; CCL17/18/22/24: chemokine (c-c motif) ligand 17/18/22/24; VEGF-A/C: vascular endothelial growth factor A/C; EGF: epidermal growth factor; FGF-2: fibroblast growth factor 2; PDGF: platelet-derived growth factor; Th: T helper; Treg: regulatory T cells; OS: oxidative stress; SLE: systemic lupus erythematosus; BD: Behcet’s disease; IH: infantile hemangioma