61. Peripheral monocytes/macrophages promote resolution of acute inflammatory pain via an IL-10 dependent pathway

Chronic pain is a major clinical problem, and understanding mechanisms underlying the transition from acute to chronic pain is needed. We investigated the contribution of peripheral monocytes/macrophages to the transition from acute to persistent IL-1beta induced hyperalgesia. As a model, we used LysM-GRK2+/− mice that develop prolonged hyperalgesia in response to IL-1β due to a cell specific reduction in G protein-coupled receptor kinase 2 (GRK2) in lysozyme M-positive microglia/macrophages. In wild type (WT) mice, peripheral monocyte/macrophage depletion prolonged intraplantar IL-1β -induced hyperalgesia from 8 days. In LysM-GRK2+/− mice that develop persistent IL-1β hyperalgesia, monocyte/macrophage depletion did not have any effect. Adoptive transfer of WT bone marrow derived monocytes (BMDM), but not of GRK2+/− BMDM, to LysM-GRK2+/− mice prevented the transition to persistent IL-1β-induced hyperalgesia. In search for the mechanism, we show that GRK2-deficient macrophages produce less IL-10 in vitro and intrathecal IL-10 adminisration attenuated IL-1β-induced hyperalgesia in LysM-GRK2+/− mice. Moreover, in WT mice intrathecal anti-IL10 prolonged IL-1β-induced hyperalgesia. Finally, adoptive transfer of IL-10−/− BMDM did not normalize the IL-1β-induced hyperalgesia in LysM-GRK2+/− mice. In conclusion, we uncovered a key role for peripheral monocytes/macrophages in promoting resolution of inflammatory hyperalgesia via a mechanism dependent of IL-10 signaling. The decreased capacity of GRK2-deficient monocytes/macrophages to produce IL-10 underlies their inability to promote resolution of inflammatory pain. Supported by NIH grants NS073939 and NS074999.