Chronic intermittent hypoxia drives M1 macrophage polarization in dorsal root ganglia

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

Chronic intermittent hypoxia drives M1 macrophage polarization in dorsal root ganglia

Brain Behav Immun. 2025 Jun 20:129:442-452. doi: 10.1016/j.bbi.2025.06.028. Online ahead of print.

Authors

Samuel B Chivers¹, Mary Ann Andrade², Cassandra L McLay¹, Kristopher L Wieland¹, Pankil K Shah³, Glenn M Toney⁴, Nathaniel A Jeske⁵

Affiliations

¹ Departments of Oral and Maxillofacial Surgery, University of Texas Health San Antonio, TX 78229, United States.
² Departments of Physiology, University of Texas Health San Antonio, TX 78229, United States; Department of Medical Physiology, Texas A & M University, College of Medicine, Bryan, TX 77807, United States.
³ Departments of Medicine, University of Texas Health San Antonio, TX 78229, United States.
⁴ Departments of Physiology, University of Texas Health San Antonio, TX 78229, United States; Departments of Pharmacology, University of Texas Health San Antonio, TX 78229, United States; Department of Medical Physiology, Texas A & M University, College of Medicine, Bryan, TX 77807, United States.
⁵ Departments of Oral and Maxillofacial Surgery, University of Texas Health San Antonio, TX 78229, United States; Departments of Physiology, University of Texas Health San Antonio, TX 78229, United States; Departments of Pharmacology, University of Texas Health San Antonio, TX 78229, United States. Electronic address: jeske@uthscsa.edu.

PMID: 40545150
DOI: 10.1016/j.bbi.2025.06.028

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.

Keywords: Apnea; Hyperalgesic; Macrophage; Pain; Sleep; Tlr9.