Monocytes/Macrophages Control Resolution of Transient Inflammatory Pain

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• 作者：Hanneke L.D.M. Willemen^&lowast ; ; Niels Eijkelkamp^&lowast ; ; Anibal Garza Carbajal^&lowast ; ; ^§ ; ; Huijing Wang^&lowast ; ; Matthias Mack^&dagger ; ; Jitske Zijlstra^&lowast ; ; Cobi J. Heijnen^&lowast ; ; ^&Dagger ; ; Annemieke Kavelaars^&lowast ; ; ^&Dagger ; ; ^{akavelaars@mdanderson.org" class="auth_mail}
• 关键词：Monocytes/macrophages ; G-protein-coupled receptor kinase 2 ; interleukin-10 ; inflammatory pain
• 刊名：The Journal of Pain
• 出版年：May 2014
• 年：2014
• 卷：15
• 期：5
• 页码：496-506
• 全文大小：1675 K

文摘

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-1尾- 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-1尾- and carrageenan-induced inflammatory hyperalgesia. Recently, we showed that IL-1尾- 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-1尾-induced hyperalgesia in LysM-GRK2^+/− mice. Adoptive transfer of IL-10^−/− bone marrow-derived monocytes failed to normalize the duration of IL-1尾-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-1尾-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.