Samuel B. Chivers , Mary Ann Andrade , Cassandra L. McLay , Kristopher L. Wieland , Pankil K. Shah , Glenn M. Toney , Nathaniel A. Jeske
{"title":"Chronic intermittent hypoxia drives M1 macrophage polarization in dorsal root ganglia","authors":"Samuel B. Chivers , Mary Ann Andrade , Cassandra L. McLay , Kristopher L. Wieland , Pankil K. Shah , Glenn M. Toney , Nathaniel A. Jeske","doi":"10.1016/j.bbi.2025.06.028","DOIUrl":null,"url":null,"abstract":"<div><div>Immune cells play a crucial role in maintaining the health of all body tissues. When chemical signals are released into the local environment from injured or infected cells, tissue-specific immune cells become attracted and migrate to that area. Upon arrival, they begin releasing their own signals that produce a cascade of effects, including pain modulation. However, little is known about how systemic hypoxia influences immune modulation of pain in the peripheral nervous system. We sought to identify the unique role of macrophages in peripheral sensory ganglia by using a translational model of sleep apnea. Mice were exposed to chronic intermittent hypoxia (CIH) for 14 days and L4-L6 dorsal root ganglia were removed for analyses of macrophage content. Immunofluorescence histochemistry and fluorescence-activated cell sorting indicate a prevalence of M1 macrophage markers and a reduction of M2 macrophage markers in DRG tissues taken from CIH mice. Total RNA-seq identified multiple genes upregulated in DRG macrophages following CIH exposure, including toll-like receptor 9 (TLR9). In vitro treatment of primary macrophage cultures with the FDA-approved TLR9 antagonist hydroxychloroquine (HCQ) inhibited M1 macrophage polarization. Calcium imaging of DRG neurons taken from CIH-exposed mice revealed hypersensitivity to KCL that was prevented by HCQ co-treatment. Furthermore, HCQ acutely abated hyperalgesic priming behavior in mice exposed to CIH. Together, these results identify TLR9 as a druggable target capable of reducing nociceptor sensitization in CIH, with implications for exaggerated pain sensitivity in patients with sleep apnea.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"129 ","pages":"Pages 442-452"},"PeriodicalIF":8.8000,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Brain, Behavior, and Immunity","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0889159125002454","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Immune cells play a crucial role in maintaining the health of all body tissues. When chemical signals are released into the local environment from injured or infected cells, tissue-specific immune cells become attracted and migrate to that area. Upon arrival, they begin releasing their own signals that produce a cascade of effects, including pain modulation. However, little is known about how systemic hypoxia influences immune modulation of pain in the peripheral nervous system. We sought to identify the unique role of macrophages in peripheral sensory ganglia by using a translational model of sleep apnea. Mice were exposed to chronic intermittent hypoxia (CIH) for 14 days and L4-L6 dorsal root ganglia were removed for analyses of macrophage content. Immunofluorescence histochemistry and fluorescence-activated cell sorting indicate a prevalence of M1 macrophage markers and a reduction of M2 macrophage markers in DRG tissues taken from CIH mice. Total RNA-seq identified multiple genes upregulated in DRG macrophages following CIH exposure, including toll-like receptor 9 (TLR9). In vitro treatment of primary macrophage cultures with the FDA-approved TLR9 antagonist hydroxychloroquine (HCQ) inhibited M1 macrophage polarization. Calcium imaging of DRG neurons taken from CIH-exposed mice revealed hypersensitivity to KCL that was prevented by HCQ co-treatment. Furthermore, HCQ acutely abated hyperalgesic priming behavior in mice exposed to CIH. Together, these results identify TLR9 as a druggable target capable of reducing nociceptor sensitization in CIH, with implications for exaggerated pain sensitivity in patients with sleep apnea.
期刊介绍:
Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals.
As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.