TY - JOUR
T1 - Dorsal root ganglia macrophages maintain osteoarthritis pain
AU - Raoof, Ramin
AU - Gil, Christian Martin
AU - Lafeber, Floris P.J.G.
AU - De Visser, Huub
AU - Prado, Judith
AU - Versteeg, Sabine
AU - Pascha, Mirte N.
AU - Heinemans, Anne L.P.
AU - Adolfs, Youri
AU - Pasterkamp, Jeroen
AU - Wood, John N.
AU - Mastbergen, Simon C.
AU - Eijkelkamp, Niels
N1 - Funding Information:
This work was supported by the European Union Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie Grants 642720 and 814244. N.E. and J. Prado were supported by the Life Sciences Seed Grant from Utrecht University. F.L. and S.C.M. were supported by the Dutch Arthritis Association (Grant LLP-9), and R.J.P. was supported by the Netherlands Organization for Scientific Research. J.N.W. was supported by Versus Arthritis (grant 29150). We thank the University Medical Center Utrecht Multidisciplinary Investigation of Neural Disorders facility for help with light-sheet microscopy and iDISCO tissue clearing, Michiel van der Vlist for reading the manuscript and discussions, Roeland Lokhorst for help with the dynamic weight-bearing analysis, Mirjam Maas for isolation of bone marrow-derived macrophages, and Megan Opstal for technical assistance with stainings of DRGs.
Publisher Copyright:
Copyright © 2021 the authors.
PY - 2021/9/29
Y1 - 2021/9/29
N2 - 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 Nav1.8 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.
AB - 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 Nav1.8 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.
KW - Chronic pain
KW - Macrophage
KW - Osteoarthritis
KW - Sensory neuron
UR - http://www.scopus.com/inward/record.url?scp=85116162787&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.1787-20.2021
DO - 10.1523/JNEUROSCI.1787-20.2021
M3 - Article
C2 - 34400519
SN - 0270-6474
VL - 41
SP - 8249
EP - 8261
JO - The Journal of neuroscience : the official journal of the Society for Neuroscience
JF - The Journal of neuroscience : the official journal of the Society for Neuroscience
IS - 39
ER -