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

Melih Ö Celik1, Dominika Labuz1, Jacqueline Keye2

  • 1Department of Experimental Anesthesiology and.

JCI Insight
|February 28, 2020
PubMed

Insights

Interleukin-4 (IL-4) prompts M2 macrophages to produce natural opioids, reducing nerve injury pain. This IL-4-induced analgesia involves local opioid peptides and receptors, offering a new pain management strategy.

Area of Science:

  • Neuroimmunology
  • Pain Research
  • Cytokine Signaling

Background:

  • Interleukin-4 (IL-4) is an anti-inflammatory cytokine with known neuroprotective effects following nervous system injury.
  • Its beneficial actions are attributed to suppressing inflammatory mediators, including pro-inflammatory cytokines.
  • The precise mechanisms underlying IL-4's pain-ameliorating effects require further elucidation.

Purpose of the Study:

  • To investigate the role of IL-4 in modulating macrophage phenotype and function at sites of nerve injury.
  • To determine if IL-4-induced macrophages produce endogenous opioid peptides.
  • To assess the contribution of these opioid peptides and peripheral opioid receptors to IL-4-mediated analgesia.

Main Methods:

  • Administration of IL-4 to injured nerves in a mouse model of neuropathy.
  • Flow cytometry and immunohistochemistry to characterize macrophage phenotypes (M1 vs. M2).
  • Measurement of opioid peptide synthesis (Met-enkephalin, β-endorphin, dynorphin A 1-17) in macrophages.
  • Assessment of mechanical hypersensitivity and the effect of opioid antagonists and antibodies.
  • Adoptive transfer of M2 macrophages to evaluate their role in analgesia.

Main Results:

  • IL-4 treatment shifted macrophages from M1 to M2 phenotype at injured nerves.
  • M2 macrophages synthesized and released significant amounts of opioid peptides.
  • IL-4 administration resulted in long-lasting attenuation of mechanical hypersensitivity.
  • Analgesia was reduced by opioid peptide antibodies and antagonists, confirming opioid system involvement.
  • Adoptive transfer of IL-4-induced M2 macrophages conferred analgesia to recipient mice.

Conclusions:

  • IL-4 induces M2 macrophages at injured nerves to produce opioid peptides.
  • These opioid peptides activate peripheral opioid receptors, leading to pain reduction.
  • Targeting IL-4-induced M2 macrophage opioid production presents a potential therapeutic strategy for pathological pain.
Keywords:
CytokinesMacrophagesNeurosciencePain

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