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

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 8

Sustained IL-4–induced analgesia is mediated by opioid peptides and receptors at damaged nerves.

Options: View larger image (or click on image) Download as PowerPoint
Sustained IL-4–induced analgesia is mediated by opioid peptides and rece...
(A) Reversibility of IL-4–induced (200 ng) analgesia by antibodies to opioid peptides, anti-ENK (2 μg), anti-END (2 μg), or anti-DYN (4 μg). (B) Reversibility of IL-4–induced (200 ng) analgesia by peripherally restricted opioid receptor antagonist NLXM (10 μg). (C) Reversibility of IL-4–induced (200 ng) analgesia by antagonists selective at δ (ICI 174,864; 8 μg), μ (CTOP; 2 μg), and κ receptors (norBNI; 20 μg). Antibodies and antagonists were injected 24 hours after the last IL-4 injection (on day 22 after chronic constriction injury [CCI]) and again 5 days after IL-4 injection (on day 26 after CCI). von Frey thresholds were determined before and 24 hours after each IL-4 injection (on days 14–21); before and 5–60 minutes after the first injection of antibodies and antagonists (on day 22); once on day 23 (24 hours after the first injection of antibodies and antagonists); and before and 5–60 minutes after the second injection of antibodies and antagonists (on day 26). The thresholds were measured in hind paws ipsilateral to CCI. Control groups were tested accordingly. Arrows indicate injections. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control (control IgG or vehicle); 2-way repeated-measures ANOVA, Bonferroni’s test. Data are represented as mean ± SEM. n = 9 animals per group. ENK, Met-enkephalin; END, β-endorphin; DYN, dynorphin A 1-17; NLXM, naloxone methiodide; ICI 174,864, N,N-diallyl-Tyr-Aib-Aib-Phe-Leu; CTOP, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2; norBNI, nor-binaltorphimine.