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CCR2 monocytes as therapeutic targets for acute disc herniation and radiculopathy in mouse models.

Authors
  • Jin, Li1
  • Xiao, Li1
  • Manley, Brock J1
  • Oh, Eunha G1
  • Huang, Wendy1
  • Zhang, Yi1
  • Chi, Jialun1
  • Shi, Weibin2
  • Kerrigan, Jason R3
  • Sung, Sun-Sang J4
  • Kuan, Chia-Yi5
  • Li, Xudong6
  • 1 Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA 22908, USA.
  • 2 Department of Radiology and Medical Imaging, Charlottesville, VA 22908, USA; Department of Biochemistry and Molecular Genetics, Charlottesville, VA 22908, USA.
  • 3 Department of Mechanical and Aerospace Engineering, Center of Applied Biomechanics, University of Virginia, Charlottesville, VA 22904, USA.
  • 4 Department of Medicine, Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908, USA.
  • 5 Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA 22908, USA.
  • 6 Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA 22908, USA; Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22904, USA. Electronic address: [email protected].
Type
Published Article
Journal
Osteoarthritis and Cartilage
Publisher
Elsevier
Publication Date
Jan 01, 2024
Volume
32
Issue
1
Pages
52–65
Identifiers
DOI: 10.1016/j.joca.2023.08.014
PMID: 37802464
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Back pain and radiculopathy caused by disc herniation are major health issues worldwide. While macrophages are key players in disc herniation induced inflammation, their roles and origins in disease progression remain unclear. We aim to study the roles of monocytes and derivatives in a mouse model of disc herniation. Using a CCR2-CreER; R26R-EGFP (Ai6) transgenic mouse strain, we fate-mapped C-C chemokine receptor type 2 (CCR2) expressing monocytes and derivatives at disc herniation sites, and employed a CCR2RFP/RFP mouse strain and a CCR2-specific antagonist to study the effects of CCR2+ monocytes on local inflammatory responses, pain level, and disc degeneration by immunostaining, flow cytometry, and histology. CCR2+ monocytes (GFP+) increased at the sites of disc hernia over postoperative day 4, 6, and 9 in CCR2-CreER; Ai6 mice. F4/80+ cells increased, and meanwhile, CD11b+ cells trended downward. Co-localization analysis revealed that both GFP+CD11b+ and GFP+F4/80+ constituted the majority of CD11b+ and F4/80+ cells at disc hernia sites. Fluorescence activated cell sorter purified GFP+ cells exhibited higher cytokine expressions than GFP- cells. Inhibition of CCR2 signaling reduced infiltration of monocytes and macrophages, alleviated pain, maintained disc height, and reduced osteoclast activity in adjacent cortical bone for up to 1 month. Our findings suggest that circulating CCR2+ monocytes play important roles in initiating and promoting the local inflammatory responses, pain sensitization, and degenerative changes after disc herniation, and thus may serve as therapeutic targets for disc herniation induced back and leg pain. Copyright © 2023 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

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