Ruoyao Xu, Yushuang Pan, Kaige Zheng, Muyan Chen, Chengyu Yin, Qimiao Hu, Jie Wang, Qing Yu, Peiyi Li, Yan Tai, Junfan Fang, Boyu Liu, Jianqiao Fang, Guihua Tian, Boyi Liu
{"title":"IL-33/ST2 induces macrophage-dependent ROS production and TRPA1 activation that mediate pain-like responses by skin incision in mice","authors":"Ruoyao Xu, Yushuang Pan, Kaige Zheng, Muyan Chen, Chengyu Yin, Qimiao Hu, Jie Wang, Qing Yu, Peiyi Li, Yan Tai, Junfan Fang, Boyu Liu, Jianqiao Fang, Guihua Tian, Boyi Liu","doi":"10.7150/thno.97856","DOIUrl":null,"url":null,"abstract":"<b>Background:</b> Insufficiently managed incisional (INC) pain severely affects patients' life quality and rehabilitation after a major operation. However, mechanisms underlying INC pain still remain poorly understood./n<b>Methods:</b> A mouse model of INC pain was established by skin plus deep muscle incision. Biochemistry assay, <i>in vivo</i> reactive oxygen species (ROS) imaging, Ca<sup>2+</sup> imaging combined with retrograde labelling, neuron tracing and nocifensive behavior test, etc. were utilized for mechanism investigation./n<b>Results:</b> We found pro-nociceptive cytokine interleukin -33 (IL-33) ranked among top up-regulated cytokines in incised tissues of INC pain model mice. IL-33 was predominantly expressed in keratinocytes around the incisional area. Neutralization of IL-33 or its receptor suppression of tumorigenicity 2 protein (ST2) or genetic deletion of <i>St2</i> gene (<i>St2</i><sup>-/-</sup>) remarkably ameliorated mechanical allodynia and improved gait impairments of model mice. IL-33 contributes to INC pain by recruiting macrophages, which subsequently release ROS in incised tissues via ST2-dependent mechanism. Transfer of excessive macrophages enhanced oxidative injury and reproduced mechanical allodynia in <i>St2</i><sup>-/-</sup> mice upon tissue incision. Overproduced ROS subsequently activated functionally up-regulated transient receptor potential ankyrin subtype-1 (TRPA1) channel innervating the incisional site to produce mechanical allodynia. Neither deleting <i>St2</i> nor attenuating ROS affected wound healing of model mice./n<b>Conclusions:</b> Our work uncovered a previously unrecognized contribution of IL-33/ST2 signaling in mediating mechanical allodynia and gait impairment of a mouse model of INC pain. Targeting IL-33/ST2 signaling could be a novel therapeutic approach for INC pain management.","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4000,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.97856","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Insufficiently managed incisional (INC) pain severely affects patients' life quality and rehabilitation after a major operation. However, mechanisms underlying INC pain still remain poorly understood./nMethods: A mouse model of INC pain was established by skin plus deep muscle incision. Biochemistry assay, in vivo reactive oxygen species (ROS) imaging, Ca2+ imaging combined with retrograde labelling, neuron tracing and nocifensive behavior test, etc. were utilized for mechanism investigation./nResults: We found pro-nociceptive cytokine interleukin -33 (IL-33) ranked among top up-regulated cytokines in incised tissues of INC pain model mice. IL-33 was predominantly expressed in keratinocytes around the incisional area. Neutralization of IL-33 or its receptor suppression of tumorigenicity 2 protein (ST2) or genetic deletion of St2 gene (St2-/-) remarkably ameliorated mechanical allodynia and improved gait impairments of model mice. IL-33 contributes to INC pain by recruiting macrophages, which subsequently release ROS in incised tissues via ST2-dependent mechanism. Transfer of excessive macrophages enhanced oxidative injury and reproduced mechanical allodynia in St2-/- mice upon tissue incision. Overproduced ROS subsequently activated functionally up-regulated transient receptor potential ankyrin subtype-1 (TRPA1) channel innervating the incisional site to produce mechanical allodynia. Neither deleting St2 nor attenuating ROS affected wound healing of model mice./nConclusions: Our work uncovered a previously unrecognized contribution of IL-33/ST2 signaling in mediating mechanical allodynia and gait impairment of a mouse model of INC pain. Targeting IL-33/ST2 signaling could be a novel therapeutic approach for INC pain management.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.