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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.
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Research Article Neuroscience

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

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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

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Figure 5

IL-4–induced macrophages at damaged nerves produce opioid peptides.

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IL-4–induced macrophages at damaged nerves produce opioid peptides.
(A) ...
(A) Quantitative mRNA expression of opioid peptide precursors Penk, Pomc, and Pdyn in F4/80+ macrophages from injured nerves. Data were acquired by qRT-PCR, represent relative mRNA expression levels normalized to Gapdh and are expressed as fold change vs. vehicle. (B) Intracellular content of opioid peptides ENK, END, and DYN in F4/80+ macrophages from injured nerves, measured by enzyme immunoassays. F4/80+ macrophages were isolated by IMS from nerves 24 hours after the last injection of vehicle or IL-4 (200 ng) at the chronic constriction injury (CCI) site, on day 22 after CCI. +P < 0.05, ++P < 0.01 (Mann-Whitney U test), **P < 0.01, ***P < 0.001 (2-tailed t test) vs. vehicle. Data are shown as individual data points and mean ± SEM. n = 8 samples per group. ENK, Met-enkephalin; END, β-endorphin; DYN, dynorphin A 1-17.
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