Advances in the role of STAT3 in macrophage polarization

Abstract

The physiological processes of cell growth, proliferation, differentiation, and apoptosis are closely related to STAT3, and it has been demonstrated that aberrant STAT3 expression has an impact on the onset and progression of a number of inflammatory immunological disorders, fibrotic diseases, and malignancies. In order to produce the necessary biological effects, macrophages (M0) can be polarized into pro-inflammatory (M1) and anti-inflammatory (M2) types in response to various microenvironmental stimuli. STAT3 signaling is involved in macrophage polarization, and the research of the effect of STAT3 on macrophage polarization has gained attention in recent years. In order to provide references for the treatment and investigation of disorders related to macrophage polarization, this review compiles the pertinent signaling pathways associated with STAT3 and macrophage polarization from many fundamental studies.

Keywords: M1 macrophage; M2 macrophage; STAT3; macrophage polarization; signaling pathway.

Figure 1

Phenotypes and functions of macrophage polarization. When exposed to different microenvironmental stimuli, M0 macrophages can be polarized into M1 macrophages and M2 macrophages. M2 macrophages can be subdivided into M2a, M2b, M2c and M2d. M1-type macrophages express the cell surface markers CD40, CD80, CD86, and MHC-IIR and release pro-inflammatory molecules such as TNF-α, IL-1β, IL-6, and iNOS. These cells possess strong anti-pathogen, anti-tumor, and pro-inflammatory effects. M2-type macrophages express the cell surface markers CD163, CD204 and CD206. M2a macrophages secrete like TGF-β, IGF, and fibronectin, and they can promote wound healing and fibrosis; M2b macrophages secrete IL-10, and they have strong immunomodulatory and anti-inflammatory effects;M2c macrophages secrete TGF-β and IL-10, and they exert phagocytosis, immunosuppression, angiogenesis, and development of tissue fibrosis;M2d macrophages secrete IL-10, TGF-β, and VEGF, and they promote angiogenesis and cancer metastasis.

Figure 2

Diagram of signaling pathways related to STAT3 and macrophage polarization. STAT3 influence macrophage polarization through different signaling pathways. The major pathway associated with STAT3 is JAK/STAT signaling pathway, and SOCS, PIAS and PTP can inhibit different targets of this signaling pathway, which ultimately affects the direction of macrophage polarization. The NF-κB signaling pathway, PI3K/AKT signaling pathway, Notch signaling pathway, Hedgehog signaling pathway, Wnt signaling pathway and MAPK signaling pathway crosstalk with JAK/STAT3 signaling pathway, which regulates gene transcription and have effects on macrophage polarization.