title: Monocytes/Macrophages control resolution of transient inflammatory pain.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Hanneke L D M
authors.initials: HL
authors.lastname: Willemen
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: Eijkelkamp
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands; Department for Molecular Human Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Anibal
authors.initials: A
authors.lastname: Garza Carbajal
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Huijing
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine II, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mack
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Jitske
authors.initials: J
authors.lastname: Zijlstra
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
authors.affiliation: Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Symptom Research, University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: akavelaars@mdanderson.org.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
mesh_terms: D000818:Animals; D002351:Carrageenan; D002478:Cells, Cultured; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000235:genetics / Q000378:metabolism; D055786:Gene Knockout Techniques; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology*; D007249:Inflammation / Q000503:physiopathology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta; D008264:Macrophages / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000502:physiology*; D010146:Pain / Q000503:physiopathology*; D014110:Touch
chemical_list: C556062:IL10 protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D016753:Interleukin-10; D002351:Carrageenan; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2
keywords: G-protein-coupled receptor kinase 2; Monocytes/macrophages; inflammatory pain; interleukin-10