TY - JOUR
T1 - Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice
AU - Jha, Mithilesh Kumar
AU - Passero, Joseph V.
AU - Rawat, Atul
AU - Ament, Xanthe Heifetz
AU - Yang, Fang
AU - Vidensky, Svetlana
AU - Collins, Samuel L.
AU - Horton, Maureen R.
AU - Hoke, Ahmet
AU - Rutter, Guy A.
AU - Latremoliere, Alban
AU - Rothstein, Jeffrey D.
AU - Morrison, Brett M.
N1 - Funding Information:
The authors would like to thank Mohamed Farah, Kimberly Brown, Carol Cooke, and the Johns Hopkins Neurology Electron Microscopy Core staff for their assistance in processing embedded nerve tissue for toluidine blue staining, electron microscopy, and image interpretation. We would also like to thank Weiran Chen, Research Associate at the Johns Hopkins School of Medicine, and Yagendra Nadava, Visiting Assistant Professor at the University of Maryland School of Medicine, for their assistance in generating and interpreting the Seahorse Bioanalyzer data. Financial support was provided by the NIH (NS086818-01, to BMM and R01NS112266, to AL). GAR was supported by a Wellcome Trust Investigator Award (WT212625/Z/18/Z) and a Medical Research Council (MRC) Programme grant (MR/R022259/1).
Publisher Copyright:
© 2021, American Society for Clinical Investigation.
PY - 2021/11
Y1 - 2021/11
N2 - Peripheral nerves have the capacity for regeneration, but the rate of regeneration is so slow that many nerve injuries lead to incomplete recovery and permanent disability for patients. Macrophages play a critical role in the peripheral nerve response to injury, contributing to both Wallerian degeneration and nerve regeneration, and their function has recently been shown to be dependent on intracellular metabolism. To date, the impact of their intracellular metabolism on peripheral nerve regeneration has not been studied. We examined conditional transgenic mice with selective ablation in macrophages of solute carrier family 16, member 1 (Slc16a1), which encodes monocarboxylate transporter 1 (MCT1), and found that MCT1 contributed to macrophage metabolism, phenotype, and function, specifically in regard to phagocytosis and peripheral nerve regeneration. Adoptive cell transfer of wild-type macrophages ameliorated the impaired nerve regeneration in macrophage-selective MCT1-null mice. We also developed a mouse model that overexpressed MCT1 in macrophages and found that peripheral nerves in these mice regenerated more rapidly than in control mice. Our study provides further evidence that MCT1 has an important biological role in macrophages and that manipulations of macrophage metabolism can enhance recovery from peripheral nerve injuries, for which there are currently no approved medical therapies.
AB - Peripheral nerves have the capacity for regeneration, but the rate of regeneration is so slow that many nerve injuries lead to incomplete recovery and permanent disability for patients. Macrophages play a critical role in the peripheral nerve response to injury, contributing to both Wallerian degeneration and nerve regeneration, and their function has recently been shown to be dependent on intracellular metabolism. To date, the impact of their intracellular metabolism on peripheral nerve regeneration has not been studied. We examined conditional transgenic mice with selective ablation in macrophages of solute carrier family 16, member 1 (Slc16a1), which encodes monocarboxylate transporter 1 (MCT1), and found that MCT1 contributed to macrophage metabolism, phenotype, and function, specifically in regard to phagocytosis and peripheral nerve regeneration. Adoptive cell transfer of wild-type macrophages ameliorated the impaired nerve regeneration in macrophage-selective MCT1-null mice. We also developed a mouse model that overexpressed MCT1 in macrophages and found that peripheral nerves in these mice regenerated more rapidly than in control mice. Our study provides further evidence that MCT1 has an important biological role in macrophages and that manipulations of macrophage metabolism can enhance recovery from peripheral nerve injuries, for which there are currently no approved medical therapies.
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U2 - 10.1172/JCI141964
DO - 10.1172/JCI141964
M3 - Article
C2 - 34491913
AN - SCOPUS:85118490810
VL - 131
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 21
M1 - e141964
ER -