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 8

Tet-inducible selective overexpression of MCT1 in macrophages promotes the regeneration of injured peripheral nerves.

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Tet-inducible selective overexpression of MCT1 in macrophages promotes t...
(A) Transgenic mice with upregulation of MCT1 selectively in macrophages (LysM-Cre tTA+/– MCT1Over/+) were produced by crossing LysM-Cre mice with lox-stop-lox tTA mice (tet-off) and a tet-responsive MCT1-overexpressing mouse. (B) MCT1 overexpression was confirmed by evaluating MCT1 mRNA expression in peritoneal exudate macrophages using real-time RT-PCR (fold change relative to MCT1Over/WT littermate controls). n = 3–8 per group. ***P < 0.001, by unpaired, 2-tailed t test. (C) Lactate uptake in peritoneal exudate macrophages was assessed and is shown as the fold change relative to MCT1Over/WT mice. n = 3 per group. *P < 0.05, by unpaired, 2-tailed t test. (D) Motor NCV and (E) CMAP amplitude recoveries (percentage relative to pre-crush) of nerves after injury. n = 8 for MCT1Over/WT mice; n = 6 for LysM-Cre tTA+/– MCT1Over/WT mice. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA with Bonferroni’s multiple-comparison test. Vertical lines in D and E represent the overall statistical comparison between the data sets from mice of the 2 genotypes. (F) Representative photomicrographs of fluorescently labeled NMJs in gastrocnemius muscles 6 weeks after crush. Muscles were stained with BTX (red) and antibodies against neurofilaments (green) and synaptophysin (blue) to visualize AChRs and nerve terminals, respectively. Scale bars: 50 μm. (G) Fully reinnervated, partially reinnervated, and denervated AChR clusters 6 weeks after crush. n = 5 per group. **P <0 .01, by 2-way ANOVA with Bonferroni’s multiple-comparison test. (H) Representative photomicrographs and (I) myelinated axon counts in sural nerves from LysM-Cre tTA+/– MCT1Over/+ and MCT1Over/WT mice 6 weeks after sciatic nerve crush. Light microscope photomicrographs and subsequent analysis were done on toluidine blue–stained sections. n = 4–5 per group. *P < 0.05, by unpaired, 2-tailed t test. Scale bars: 20 μm. All data indicate the mean ± SEM.