Journal article
Acid-sensing ion channel 3 in macrophages, but not sensory neurons, mediates development of activity-induced muscle pain
Brain, behavior, and immunity, Vol.130, 106122
11/2025
DOI: 10.1016/j.bbi.2025.106122
PMID: 41027498
Abstract
Activity-induced pain is a significant symptom for people with chronic pain and reduces participation in daily activities and effective exercise programs. We previously showed that pharmacological blockade of ASIC3 locally in muscle, but not downregulation of ASIC3 in sensory neurons, prevents development of activity-induced muscle pain. Further, depleting macrophages from muscle prevents activity-induced pain. We therefore hypothesized that ASIC3 expression in muscle macrophages is necessary for development of activity-induced muscle pain by promoting release of pro-inflammatory cytokines. We developed a conditional ASIC3 knockout mouse (ASIC3fl/fl) to test if removal of ASIC3 from macrophages prevents development of activity-induced pain. Cx3cr1Cre+/ASIC3fl/fl mice do not develop activity-induced pain; however, AdvCre+/ASIC3fl/fl had no effect on activity-induced pain. In contrast, carrageenan-induced muscle pain was prevented in both Cx3cr1Cre+/ASIC3fl/fl and AdvCre+/ASIC3fl/fl mice. Further, removal of ASIC3 from muscle macrophages, using a lentivirus expressing CRE injected into muscle from ASIC3fl/fl mice, attenuated activity-induced pain. Flow cytometry revealed the proportion of muscle macrophages in muscle was decreased in Cx3cr1Cre+/ASIC3fl/fl compared to controls (Cx3cr1Cre-/ASIC3fl/fl), despite overall increases in myeloid cells and T-cells. Further in Cx3cr1Cre+/ASIC3fl/fl there was an attenuated release of the inflammatory cytokines GM-csf and TNFα from cultured macrophages treated with ATP and pH 6.5 when compared to controls. Together these data show that ASIC3 in muscle macrophages plays a critical role in development of activity-induced muscle pain by modulating release of inflammatory cytokines.
Details
- Title: Subtitle
- Acid-sensing ion channel 3 in macrophages, but not sensory neurons, mediates development of activity-induced muscle pain
- Creators
- Kazuhiro Hayashi - University of IowaJoseph B Lesnak - University of IowaAshley N Plumb - University of IowaAdam J Janowski - University of IowaLynn A Rasmussen - University of IowaHeath Vignes - University of IowaRobert Flanagan - University of IowaGiovanni Berardi - University of IowaWilliam J Paradee - University of IowaKathleen A Sluka - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Brain, behavior, and immunity, Vol.130, 106122
- DOI
- 10.1016/j.bbi.2025.106122
- PMID
- 41027498
- NLM abbreviation
- Brain Behav Immun
- ISSN
- 0889-1591
- eISSN
- 1090-2139
- Publisher
- ACADEMIC PRESS INC ELSEVIER SCIENCE
- Grant note
- National Institutes of Health: AR073187 Japan Society for the Promotion of Science
Funding This study is supported by the National Institutes of Health AR073187. Dr. Hayashi is supported by Japan Society for the Promotion of Science. The funders played no role in the design, conduct, or reporting of this study. There was no additional external funding received for this study.
- Language
- English
- Electronic publication date
- 09/28/2025
- Date published
- 11/2025
- Academic Unit
- Iowa Neuroscience Institute; Nursing; Physical Therapy and Rehabilitation Science; Neuroscience and Pharmacology; Medicine Administration
- Record Identifier
- 9984969112202771
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