The Evolving Roles of Macrophages in Organ Transplantation

Figure 1

Mechanisms underlying macrophage polarization. The major signaling pathways contributing to the generation of M1 and M2 subsets are outlined. M1 macrophages are polarized following stimulation with IFN-γ, LPS, TNF-α, and GM-CSF and engagement of TLR4. A predominance of NF-κB, IRF5, STAT1, and STAT5 activation promotes M1 macrophage polarization. In contrast, M2 macrophages are generated following stimulation with IL-4/IL-13. A predominance of STAT6 activation results in enhanced M2 macrophage polarization. PPARδ controls distinct aspects of M2 macrophage activation, and mTORC2 is involved in M2 polarization by regulating glucose metabolism. IL-4–induced c-Myc activation participates in promoting the expression of a subset of M2-associated genes. IL-4 also induces the expression of the M2-polarizing factor IRF4 to inhibit IRF5-mediated M1 polarization. M-CSF promotes M2 polarization through mTORC2 activation, while GM-CSF induces M1 polarization. IFN-γ: interferon-γ; LPS: lipopolysaccharide; TNF-α: tumor necrosis factor-α; GM-CSF: granulocyte-macrophage colony-stimulating factor; TLR4: Toll-like receptor 4; NF-κB: nuclear factor-kappa B; IRF5: interferon regulatory factor 5; STAT1: signal transducer and activator of transcription 1; STAT5: signal transducer and activator of transcription 5; IL-4: interleukin 4; IL-13: interleukin 13; STAT6: signal transducer and activator of transcription 6; PPARδ: peroxisome proliferator-activated receptor δ; mTORC2: mammalian target of rapamycin complex 2; M-CSF: macrophage colony-stimulating factor.