Dorsal Root Ganglia Macrophages Maintain Osteoarthritis Pain.

Autor: Raoof R; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Martin Gil C; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Lafeber FPJG; Department of Rheumatology and Clinical Immunology, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., de Visser H; Department of Rheumatology and Clinical Immunology, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Prado J; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Versteeg S; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Pascha MN; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Heinemans ALP; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Adolfs Y; Department of Translational Neuroscience, Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Pasterkamp J; Department of Translational Neuroscience, Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Wood JN; Molecular Nociception Group, Department of Biology, University College London, London WC1E 6BT, England., Mastbergen SC; Department of Rheumatology and Clinical Immunology, Regenerative Medicine Center, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands., Eijkelkamp N; Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands n.eijkelkamp@umcutrecht.nl.
Jazyk: angličtina
Zdroj: The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2021 Sep 29; Vol. 41 (39), pp. 8249-8261. Date of Electronic Publication: 2021 Aug 16.
DOI: 10.1523/JNEUROSCI.1787-20.2021
Abstrakt: Pain is the major debilitating symptom of osteoarthritis (OA), which is difficult to treat. In OA patients joint tissue damage only poorly associates with pain, indicating other mechanisms contribute to OA pain. Immune cells regulate the sensory system, but little is known about the involvement of immune cells in OA pain. Here, we report that macrophages accumulate in the dorsal root ganglia (DRG) distant from the site of injury in two rodent models of OA. DRG macrophages acquired an M1-like phenotype, and depletion of DRG macrophages resolved OA pain in male and female mice. Sensory neurons innervating the damaged knee joint shape DRG macrophages into an M1-like phenotype. Persisting OA pain, accumulation of DRG macrophages, and programming of DRG macrophages into an M1-like phenotype were independent of Na v 1.8 nociceptors. Inhibition of M1-like macrophages in the DRG by intrathecal injection of an IL4-IL10 fusion protein or M2-like macrophages resolved persistent OA pain. In conclusion, these findings reveal a crucial role for macrophages in maintaining OA pain independent of the joint damage and suggest a new direction to treat OA pain. SIGNIFICANCE STATEMENT In OA patients pain poorly correlates with joint tissue changes indicating mechanisms other than only tissue damage that cause pain in OA. We identified that DRG containing the somata of sensory neurons innervating the damaged knee are infiltrated with macrophages that are shaped into an M1-like phenotype by sensory neurons. We show that these DRG macrophages actively maintain OA pain remotely and independent of joint damage. The phenotype of these macrophages is crucial for a pain-promoting role. Targeting the phenotype of DRG macrophages with either M2-like macrophages or a cytokine fusion protein that skews macrophages into an M2-like phenotype resolves OA pain. Our work reveals a mechanism that contributes to the maintenance of OA pain distant from the affected knee joint and suggests that dorsal root ganglia macrophages are a target to treat osteoarthritis chronic pain.
(Copyright © 2021 the authors.)
Databáze: MEDLINE
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