Irisin drives macrophage anti-inflammatory differentiation via JAK2-STAT6-dependent activation of PPARγ and Nrf2 signaling
Abstract
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.
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STAT6 regulates macrophage fate through downstream activation of nuclear receptors, including PPARγ and Nrf2.
“STAT6 further regulates macrophage fate through downstream activation of nuclear receptors, including PPARγ and Nrf2 (67).”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [67]
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Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages
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- Authors
- Tu, Y., Liu, J., Kong, D., Guo, X., Li, J., Long, Z., Peng, J., Wang, Z., Wu, H., Liu, P., Liu, R., Yu, W., & Li, W.
- Affiliations
- Shaanxi University of Chinese Medicine (CN)
- Air Force Medical University (CN)
- Corresponding author
- Liu, Jiangzheng
- Li, Jiawei
- Liu, Rui
- Yu, Weihua
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2023-05
- Volume
- 201
- Pages
- 98-110
- ISSN
- 0891-5849 (ISSN-L)
- OpenAlex
- W4327921897
- Cited by
- 89
- References
- 8
- Citations by year
- 2026: 39 · 2025: 31 · 2024: 13 · 2023: 6
- FWCI
- 10.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (32171231, 82173544)
- Key Research and Development Projects of Shaanxi Province (2022ZDLSF07-11)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- irisin, M2 macrophage polarization, PPARγ, Nrf2, integrin αvβ5, sepsis, lipopolysaccharide-induced inflammation, arginase-1, IL-10, antioxidant genes, myokines, bone marrow-derived macrophages
- MeSH terms
- Animals, Cell Differentiation, Fibronectins, Macrophage Activation, Macrophages, PPAR gamma, STAT6 Transcription Factor, NF-E2-Related Factor 2, Mice, Janus Kinase 2
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