Monocytes/macrophages control resolution of transient inflammatory pain

Hanneke L.D.M. Willemen, Niels Eijkelkamp, Anibal Garza Carbajal, Huijing Wang, Matthias Mack, Jitske Zijlstra, Cobi J. Heijnen, Annemieke Kavelaars

Research output: Contribution to journalArticle

38 Scopus citations


Insights into mechanisms governing resolution of inflammatory pain are of great importance for many chronic pain-associated diseases. Here we investigate the role of macrophages/monocytes and the anti-inflammatory cytokine interleukin-10 (IL-10) in the resolution of transient inflammatory pain. Depletion of mice from peripheral monocytes/macrophages delayed resolution of intraplantar IL-1β- and carrageenan-induced inflammatory hyperalgesia from 1 to 3 days to >1 week. Intrathecal administration of a neutralizing IL-10 antibody also markedly delayed resolution of IL-1β- and carrageenan-induced inflammatory hyperalgesia. Recently, we showed that IL-1β- and carrageenan-induced hyperalgesia is significantly prolonged in LysM-GRK2 +/- mice, which have reduced levels of G-protein-coupled receptor kinase 2 (GRK2) in LysM+ myeloid cells. Here we show that adoptive transfer of wild-type, but not of GRK2+/-, bone marrow-derived monocytes normalizes the resolution of IL-1β-induced hyperalgesia in LysM-GRK2+/- mice. Adoptive transfer of IL-10-/- bone marrow-derived monocytes failed to normalize the duration of IL-1β-induced hyperalgesia in LysM-GRK2+/- mice. Mechanistically, we show that GRK2+/- macrophages produce less IL-10 in vitro. In addition, intrathecal IL-10 administration attenuated IL-1β-induced hyperalgesia in LysM-GRK2+/- mice, whereas it had no effect in wild-type mice. Our data uncover a key role for monocytes/macrophages in promoting resolution of inflammatory hyperalgesia via a mechanism dependent on IL-10 signaling in dorsal root ganglia. Perspective We show that IL-10-producing monocytes/macrophages promote resolution of transient inflammatory hyperalgesia. Additionally, we show that reduced monocyte/macrophage GRK2 impairs resolution of hyperalgesia and reduces IL-10 production. We propose that low GRK2 expression and/or impaired IL-10 production by monocytes/macrophages represent peripheral biomarkers for the risk of developing chronic pain after inflammation.

Original languageEnglish (US)
Pages (from-to)496-506
Number of pages11
JournalJournal of Pain
Issue number5
StatePublished - May 2014


  • G-protein-coupled receptor kinase 2
  • Monocytes/macrophages
  • inflammatory pain
  • interleukin-10

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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  • Cite this

    Willemen, H. L. D. M., Eijkelkamp, N., Garza Carbajal, A., Wang, H., Mack, M., Zijlstra, J., Heijnen, C. J., & Kavelaars, A. (2014). Monocytes/macrophages control resolution of transient inflammatory pain. Journal of Pain, 15(5), 496-506.