Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain
van der Vlist, Michiel; Raoof, Ramin; Willemen, Hanneke L.D.M.; Prado, Judith; Versteeg, Sabine; Martin Gil, Christian; Vos, Martijn; Lokhorst, Roeland E.; Pasterkamp, R. Jeroen; Kojima, Toshiyuki; Karasuyama, Hajime; Khoury-Hanold, William; Meyaard, Linde; Eijkelkamp, Niels
(2022) Neuron, volume 110, issue 4, pp. 613 - 626
(Article)
Abstract
The current paradigm is that inflammatory pain passively resolves following the cessation of inflammation. Yet, in a substantial proportion of patients with inflammatory diseases, resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain. Mechanistic insight into how inflammatory pain is resolved is lacking. Here, we show
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that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. The resolution of pain and the transfer of mitochondria requires expression of CD200 receptor (CD200R) on macrophages and the non-canonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain.
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Keywords: CD200r, chronic pain, inflammatory pain, isec1, macrophages, mitochondria, neuroimmunology, Pain resolution, sensory neurons, vesicles, General Neuroscience, Journal Article
ISSN: 0896-6273
Publisher: Cell Press
Note: Funding Information: The first three authors (R.R. M.V. and H.W.) contributed equally to this manuscript and are allowed to re-order the sequence of the first authors to represent this if needed in, for example, their CV. We would like to thank R.J. Soberman (Massachusetts General Hospital and Harvard Medical School) for sharing Cd200r−/− mice; W. Muller (University of Manchester) for providing us with the LysMcre × Il10rflox mice; B. Chan and J. Allen (University of Manchester) for Il4ra−/− bone marrow; Gerald Shadel and Zheng Wu (Salk Institute) for providing Tfam+/− bone marrow; F. Baixauli and E. Pearce (both Max Planck Institute of Immunobiology and Epigenetics) for MitoDendra2-expressing bone marrow; Y. Adolfs (UMC Utrecht) for assisting with light-sheet microscopy; P. Vader (UMC Utrecht) for help with particle analysis; L. van Vliet, M. Bruel, and J. Raemakers (all UMC Utrecht) for their help with the analysis of immunofluorescence pictures; B. Burgering (UMC Utrecht) and S. Kaech (Yale University) for access to the seahorse machines; R. Medzhitov (Yale University) and lab members for discussions; and M. Pascha (UMC Utrecht) for help with the macrophages cultures and setting up flow-cytometry protocols. This work has received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreements no. 642720 and 814244. M.V. H.W. R.J.P. and L.M. are supported by the Netherlands Organization for Scientific Research (NWO) (ALW grants 863.14.016, 821.02.025, and 016.VENI.192.053, NWO Vici 918.15.608, and Vici 865.14.004). N.E. and J.P. were partly funded by the Life Sciences Seed grant of the University Utrecht. Conceptualization, L.M. M.v.d.V. and N.E.; methodology, N.E. L.M. M.v.d.V. H.L.D.M.W. R.R. J.P. R.E.L. T.K. R.J.P. and H.K.; formal analysis, M.v.d.V. N.E. H.L.D.M.W. R.R. and J.P.; investigation, L.M. N.E. C.M.G. R.R. H.L.D.M.W. M.V. W.K.-H. M.v.d.V. S.V. and R.E.L.; resources, R.J.P. T.K. and H.K.; writing – original draft, M.v.d.V. N.E. and R.R.; writing – reviewing and editing, M.v.d.V. N.E. L.M. R.R. and H.L.D.M.W.; visualization, M.v.d.V. N.E. and R.R.; supervision, M.v.d.V. H.L.D.M.W. L.M. and N.E.; project administration, N.E. and L.M.; funding acquisition, H.L.D.M.W. M.v.d.V. L.M. and N.E. The authors declare no competing interests. Funding Information: The first three authors (R.R., M.V., and H.W.) contributed equally to this manuscript and are allowed to re-order the sequence of the first authors to represent this if needed in, for example, their CV. We would like to thank R.J. Soberman (Massachusetts General Hospital and Harvard Medical School) for sharing Cd200r −/− mice; W. Muller (University of Manchester) for providing us with the LysM cre × Il10r flox mice; B. Chan and J. Allen (University of Manchester) for Il4ra −/− bone marrow; Gerald Shadel and Zheng Wu (Salk Institute) for providing Tfam +/− bone marrow; F. Baixauli and E. Pearce (both Max Planck Institute of Immunobiology and Epigenetics) for MitoDendra2-expressing bone marrow; Y. Adolfs (UMC Utrecht) for assisting with light-sheet microscopy; P. Vader (UMC Utrecht) for help with particle analysis; L. van Vliet, M. Bruel, and J. Raemakers (all UMC Utrecht) for their help with the analysis of immunofluorescence pictures; B. Burgering (UMC Utrecht) and S. Kaech (Yale University) for access to the seahorse machines; R. Medzhitov (Yale University) and lab members for discussions; and M. Pascha (UMC Utrecht) for help with the macrophages cultures and setting up flow-cytometry protocols. This work has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreements no. 642720 and 814244 . M.V., H.W., R.J.P., and L.M. are supported by the Netherlands Organization for Scientific Research (NWO) (ALW grants 863.14.016 , 821.02.025 , and 016.VENI.192.053 , NWO Vici 918.15.608 , and Vici 865.14.004 ). N.E. and J.P. were partly funded by the Life Sciences Seed grant of the University Utrecht . Publisher Copyright: © 2022 The Authors
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