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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 2

IL-4 treatment primarily increases macrophage numbers at injured nerves.

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IL-4 treatment primarily increases macrophage numbers at injured nerves....
(A) Representative dot plots showing expression of all immune cells (CD45+), T lymphocytes (CD45+CD3+), neutrophils (CD45+Ly6g+), and macrophages (CD45+F4/80+). The blots represent the corresponding fluorescence minus one (FMO) negative controls (left), cells isolated from injured nerves after repetitive injection of vehicle (middle) or IL-4 (200 ng; right). Cells stained positive for the appropriate marker are shown inside the rectangular gates. (B) Quantification of the corresponding cell populations shown in A. **P < 0.01, ***P < 0.001 vs. vehicle; 2-tailed t test. Data are shown as individual data points and mean ± SEM. n = 8 samples per group. The cells were isolated 24 hours after the last injection of vehicle or IL-4, on day 22 after chronic constriction injury. The data were analyzed using flow cytometry and FlowJo software. The number of positively stained cells were calculated using absolute counting beads.
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