Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising/recruitment
  • Contact
IL-4 induces M2 macrophages to produce sustained analgesia via opioids
Melih Ö. Celik, … , Rainer Glauben, Halina Machelska
Melih Ö. Celik, … , Rainer Glauben, Halina Machelska
Published February 27, 2020
Citation Information: JCI Insight. 2020;5(4):e133093. https://doi.org/10.1172/jci.insight.133093.
View: Text | PDF
Research Article Neuroscience

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

  • Text
  • PDF
Abstract

IL-4 is a pleiotropic antiinflammatory cytokine, which can be neuroprotective after nervous system injury. The beneficial actions of IL-4 are thought to result from the blunting of action of inflammatory mediators, such as proinflammatory cytokines. Here, we demonstrate that IL-4 induces M2 macrophages to continuously produce opioid peptides and ameliorate pain. IL-4 application at injured nerves in mice shifted F4/80+ macrophages from the proinflammatory M1 to the antiinflammatory M2 phenotype, which synthesized opioid peptides (Met-enkephalin, β-endorphin, and dynorphin A 1-17). These effects were accompanied by a long-lasting attenuation of neuropathy-induced mechanical hypersensitivity, beyond the IL-4 treatment. This IL-4-induced analgesia was decreased by opioid peptide antibodies and opioid receptor (δ, μ, κ) antagonists applied at injured nerves, which confirms the involvement of the local opioid system. The participation of M2 macrophages was supported by analgesia in recipient mice injected at injured nerves with F4/80+ macrophages from IL-4–treated donors. Together, IL-4–induced M2 macrophages at injured nerves produced opioid peptides, which activated peripheral opioid receptors to diminish pain. Fostering the opioid-mediated actions of intrinsic M2 macrophages may be a strategy to tackle pathological pain.

Authors

Melih Ö. Celik, Dominika Labuz, Jacqueline Keye, Rainer Glauben, Halina Machelska

×

Figure 1

IL-4 application at damaged nerves produces long-lasting attenuation of mechanical hypersensitivity.

Options: View larger image (or click on image) Download as PowerPoint
IL-4 application at damaged nerves produces long-lasting attenuation of ...
(A) Time course of IL-4–induced analgesia. IL-4 (200 ng) was injected daily on days 14–21 after chronic constriction injury (CCI) at the CCI site. Mechanical von Frey thresholds were measured before, 5–60 minutes after, and 24 hours after each injection until day 22 and then on day 23 (48 hours after the last injection) and on day 26 after CCI (120 hours after the last injection). (B) Involvement of IL-4R in IL-4–induced analgesia. Anti-IL-4Rα (6 μg) was injected with IL-4 (200 ng) on day 21 after CCI (when IL-4 was applied last time), and again alone (without IL-4) on days 22 and 26 after CCI. von Frey thresholds were measured before and 24 hours after each IL-4 injection (on days 14–21); 5 minutes after IL-4 and anti-IL-4Rα co-injection (on day 21); before and 5–60 minutes after (on day 22) and 24 hours after (on day 23) the second anti-IL-4Rα injection; and before and 5–30 minutes after the third anti-IL-4Rα injection (on day 26). The thresholds were measured in hind paws ipsilateral to CCI. Control groups were tested accordingly. Arrows indicate injections. **P < 0.01, ***P < 0.001 vs. control (vehicle or control IgG); 2-way repeated-measures ANOVA and Bonferroni’s test. Data are represented as mean ± SEM. n = 9 animals per group.
Follow JCI Insight:
Copyright © 2021 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts