Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice
Mithilesh Kumar Jha, … , Jeffrey D. Rothstein, Brett M. Morrison
Mithilesh Kumar Jha, … , Jeffrey D. Rothstein, Brett M. Morrison
Published September 7, 2021
Citation Information: J Clin Invest. 2021;131(21):e141964. https://doi.org/10.1172/JCI141964.
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Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice

Abstract

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.

Authors

Mithilesh Kumar Jha, Joseph V. Passero, Atul Rawat, Xanthe Heifetz Ament, Fang Yang, Svetlana Vidensky, Samuel L. Collins, Maureen R. Horton, Ahmet Hoke, Guy A. Rutter, Alban Latremoliere, Jeffrey D. Rothstein, Brett M. Morrison

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Figure 7

Adoptive cell transfer of macrophages with intact MCT1 ameliorates delayed nerve regeneration in macrophage-specific MCT1-deficient mice.

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Adoptive cell transfer of macrophages with intact MCT1 ameliorates delay...
(A) Schematic showing i.v. tail-vein injection of BMDMs genetically manipulated to express GFP 3 days after sciatic nerve crush and processing of the nerves for immunohistochemical analysis 7 days after injection. Both donor and recipient mice used in these studies were on a C57BL/BJ background. BMDMs targeted the injured sciatic nerve (B, lower panel), but not the uninjured sciatic nerve (B, upper panel) following the i.v. injection. Scale bars: 100 μm. (C) High-magnification images of nerve samples harvested 7 days after tail-vein injection showed that many of the GFP-positive cells (left panel) expressed F4/80 (red; middle panel), a specific macrophage marker, as shown in merged image (right panel). Images are representative confocal micrographs of 3 independent experiments. Scale bars: 20 μm. (D) Schematic showing i.v. tail-vein injection of BMDMs from wild-type mice with intact MCT1 (Mϕ with MCT1) 3 days after sciatic nerve crush and quantification of nerve regeneration by electrophysiology over a 6-week period in C57Bl6 macrophage–selective MCT1-null (B6 LysM-Cre MCT1fl/fl) and wild-type (B6 MCT1WT) mice. Both donor and recipient mice used in these studies were on a C57BL/6J background. (E) Motor NCV and (F) CMAP amplitude recovery of nerves after injury in B6 MCT1WT, B6 LysM-Cre MCT1fl/fl, and B6 MCT1WT mice following tail-vein injection of BMDMs isolated from B6 MCT1WT mice (B6 MCT1WT + Mϕ with MCT1), and after injury in B6 LysM-Cre MCT1fl/fl mice following tail-vein injection of BMDMs isolated from MCT1WT mice (B6 LysM-Cre MCT1fl/fl + Mϕ with MCT1). Recoveries are presented as the percentage relative to pre-crush conditions. n = 4 per group. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA with Bonferroni’s multiple-comparison test. All data indicate the mean ± SEM.