Department of Toxicology, Shaanxi Provincial Key Lab of Free Radical Biology and Medicine, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China; School of Public Health, Shaanxi University of Traditional Chinese Medicine, Xianyang, 712000, China.
Department of Toxicology, Shaanxi Provincial Key Lab of Free Radical Biology and Medicine, Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an, 710032, China.
Free Radic Biol Med. 2023 May 20;201:98-110. doi: 10.1016/j.freeradbiomed.2023.03.014. Epub 2023 Mar 20.
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.
鸢尾素是一种运动诱导的肌因子，可减轻炎症和肥胖。诱导抗炎（M2）巨噬细胞有助于治疗败血症和相关的肺损伤。然而，鸢尾素是否驱动巨噬细胞 M2 极化尚不清楚。在这里，我们使用 LPS 诱导的败血症小鼠模型和 RAW64.7 细胞和骨髓来源的巨噬细胞（BMDMs）在体内和体外发现鸢尾素诱导巨噬细胞抗炎分化。鸢尾素还促进过氧化物酶体增殖物激活受体γ（PPAR-γ）和核因子红细胞 2 相关因子 2（Nrf2）的表达、磷酸化和核易位。PPAR-γ 和 Nrf2 的抑制或敲低消除了鸢尾素诱导的 M2 巨噬细胞标志物（如白细胞介素（IL）-10 和精氨酸酶 1）的积累。此外，双荧光素酶报告基因和染色质免疫沉淀定量 PCR（ChIP-qPCR）实验证实 STAT6 通过与鸢尾素刺激的巨噬细胞中其 DNA 启动子结合来增强 PPAR-γ 和 Nrf2 的转录。相反，STAT6 shRNA 阻断了鸢尾素诱导的 Pparγ、Nrf2 和相关下游基因的激活。此外，鸢尾素与其配体整合素αVβ5 的相互作用显着促进了 Janus 激酶 2（JAK2）磷酸化，而整合素αVβ5 和 JAK2 的抑制或敲低减弱了 STAT6、PPAR-γ 和 Nrf2 信号的激活。有趣的是，免疫沉淀（Co-IP）实验还表明，JAK2 和整合素αVβ5 之间的结合对于通过增强 JAK2-STAT6 途径的激活来促进鸢尾素诱导的巨噬细胞抗炎分化至关重要。总之，鸢尾素通过诱导 JAK2-STAT6 依赖性转录激活 PPAR-γ 相关抗炎系统和 Nrf2 相关抗氧化基因来促进 M2 巨噬细胞分化。这项研究的结果表明，给予鸢尾素是治疗感染和炎症性疾病的一种新的有前途的治疗策略。
