PMID- 36940733
OWN - NLM
STAT- MEDLINE
DCOM- 20230531
LR  - 20230531
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 201
DP  - 2023 May 20
TI  - Irisin drives macrophage anti-inflammatory differentiation via 
      JAK2-STAT6-dependent activation of PPARgamma and Nrf2 signaling.
PG  - 98-110
LID - S0891-5849(23)00121-1 [pii]
LID - 10.1016/j.freeradbiomed.2023.03.014 [doi]
AB  - 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-gamma) and nuclear 
      factor-erythroid 2-related factor 2 (Nrf2). Inhibition or knockdown of PPAR-gamma 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-gamma and Nrf2 transcription by binding to their DNA promoters in 
      irisin-stimulated macrophages. In contrast, STAT6 shRNA blocked the 
      irisin-induced activation of Ppargamma, Nrf2, and related downstream genes. Moreover, 
      the interaction of irisin with its ligand integrin alphaVbeta5 remarkably promoted Janus 
      kinase 2 (JAK2) phosphorylation, while inhibition or knockdown of integrin alphaVbeta5 
      and JAK2 attenuated the activation of STAT6, PPAR-gamma, and Nrf2 signaling. 
      Interestingly, co-immunoprecipitation (Co-IP) assay also revealed that the 
      binding between JAK2 and integrin alphaVbeta5 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-gamma-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.
CI  - Copyright (c) 2023. Published by Elsevier Inc.
FAU - Tu, Yongmei
AU  - Tu Y
AD  - 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. Electronic address: 
      2296828447@qq.com.
FAU - Liu, Jiangzheng
AU  - Liu J
AD  - 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. Electronic address: liujiangzh@fmmu.edu.cn.
FAU - Kong, Deqin
AU  - Kong D
AD  - 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. Electronic address: kongdeqin@fmmu.edu.cn.
FAU - Guo, Xiaojie
AU  - Guo X
AD  - 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. Electronic address: 18340021966@163.com.
FAU - Li, Jiawei
AU  - Li J
AD  - 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. Electronic address: 352836025@qq.com.
FAU - Long, Zi
AU  - Long Z
AD  - 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. Electronic address: luoze0317@126.com.
FAU - Peng, Jie
AU  - Peng J
AD  - 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. Electronic address: 57865778@qq.com.
FAU - Wang, Zhao
AU  - Wang Z
AD  - 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. Electronic address: jassonwang1130@163.com.
FAU - Wu, Hao
AU  - Wu H
AD  - 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. Electronic address: robot0422@sina.com.
FAU - Liu, Penghui
AU  - Liu P
AD  - 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. Electronic address: 1604364184@qq.com.
FAU - Liu, Rui
AU  - Liu R
AD  - 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. Electronic address: liurui123@fmmu.edu.cn.
FAU - Yu, Weihua
AU  - Yu W
AD  - 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. Electronic address: yuweihua1@fmmu.edu.cn.
FAU - Li, Wenli
AU  - Li W
AD  - 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. Electronic address: liwenli@fmmu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230320
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Fibronectins)
RN  - EC 2.7.10.2 (Janus Kinase 2)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (PPAR gamma)
RN  - 0 (Stat6 protein, mouse)
RN  - 0 (STAT6 Transcription Factor)
RN  - 0 (FNDC5 protein, mouse)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Cell Differentiation
MH  - *Fibronectins/genetics/metabolism
MH  - Janus Kinase 2/genetics/metabolism
MH  - Macrophage Activation
MH  - Macrophages/metabolism
MH  - NF-E2-Related Factor 2/genetics/metabolism
MH  - *PPAR gamma/genetics/metabolism
MH  - STAT6 Transcription Factor/genetics/metabolism
OTO - NOTNLM
OT  - Irisin
OT  - JAK2
OT  - Macrophage anti-inflammatory differentiation
OT  - Nrf2
OT  - PPAR-gamma
OT  - STAT6
COIS- Declaration of competing interest The authors declare no financial interest 
      conflicts.
EDAT- 2023/03/21 06:00
MHDA- 2023/05/29 06:41
CRDT- 2023/03/20 20:21
PHST- 2023/02/16 00:00 [received]
PHST- 2023/03/11 00:00 [revised]
PHST- 2023/03/15 00:00 [accepted]
PHST- 2023/05/29 06:41 [medline]
PHST- 2023/03/21 06:00 [pubmed]
PHST- 2023/03/20 20:21 [entrez]
AID - S0891-5849(23)00121-1 [pii]
AID - 10.1016/j.freeradbiomed.2023.03.014 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2023 May 20;201:98-110. doi: 
      10.1016/j.freeradbiomed.2023.03.014. Epub 2023 Mar 20.