Irisin drives macrophage anti-inflammatory differentiation via JAK2-STAT6-dependent activation of PPARγ and Nrf2 signaling

Irisin is an exercise-induced myokine that alleviates inflammation and obesity. The induction of anti-inflammatory (M2) macrophage is facilitated for treatment of sepsis and associated lung damage. However, whether irisin drives macrophage M2 polarization remains unclear. Here, we found that irisin induced-macrophage anti-inflammatory differentiation in vivo using an LPS-induced septic mice model and in vitro using RAW64.7 cells and bone marrow-derived macrophages (BMDMs). Irisin also promoted the expression, phosphorylation, and nuclear translocation of peroxisome proliferator-activated receptor gamma (PPAR-γ) and nuclear factor-erythroid 2-related factor 2 (Nrf2). Inhibition or knockdown of PPAR-γ and Nrf2 abolished irisin-induced accumulation of M2 macrophage markers, such as interleukin (IL)-10 and Arginase 1. Furthermore, dual-luciferase reporter and chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) assays confirmed that STAT6 boosts PPAR-γ and Nrf2 transcription by binding to their DNA promoters in irisin-stimulated macrophages. In contrast, STAT6 shRNA blocked the irisin-induced activation of Pparγ, Nrf2, and related downstream genes. Moreover, the interaction of irisin with its ligand integrin αVβ5 remarkably promoted Janus kinase 2 (JAK2) phosphorylation, while inhibition or knockdown of integrin αVβ5 and JAK2 attenuated the activation of STAT6, PPAR-γ, and Nrf2 signaling. Interestingly, co-immunoprecipitation (Co-IP) assay also revealed that the binding between JAK2 and integrin αVβ5 is critical for irisin-induced macrophage anti-inflammatory differentiation by enhancing the activation of the JAK2-STAT6 pathway. In conclusion, irisin boosted M2 macrophage differentiation by inducing JAK2-STAT6-dependent transcriptional activation of the PPAR-γ-related anti-inflammatory system and Nrf2-related antioxidant genes. The findings of this study suggest that the administration of irisin is a novel and promising therapeutic strategy for infectious and inflammatory diseases.