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 6

MCT1 determines the immune responses of macrophages potentially through ATF3.

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MCT1 determines the immune responses of macrophages potentially through ...
Cultures of peritoneal exudate macrophages from LysM-Cre MCT1fl/fl and littermate control MCT1fl/fl mice were treated with a M1 phenotype–inducer mixture (100 ng/mL LPS plus 50 U/mL IFN-γ) for 6 and 24 hours. (A) Protein levels of ATF3 were assessed by Western blotting. The full-length Western blots were used for densitometric quantification, and (B) ATF3 expression, normalized to β-actin, is presented as the fold change relative to untreated macrophages from MCT1fl/fl mice. n = 3 per group. **P < 0.01, by 2-way ANOVA with Bonferroni’s multiple-comparison test. (C and D) mRNA expression of Atf3 on post-injury days (C) 1 and (D) 10 in uncrushed and crushed sciatic nerves (distal to the site of injury) was evaluated by real-time RT-PCR. mRNA levels are shown as the fold change compared with uncrushed sciatic nerves isolated from MCT1fl/fl mice, normalized to their corresponding GAPDH mRNA levels. n = 3–7 per group. *P < 0 .05 and ***P < 0.001, by 2-way ANOVA with Bonferroni’s multiple-comparison test. (E) Schematic representation of the potential role of MCT1 in nerve regeneration after injury, suggesting that MCT1 deletion in macrophages decreases the expression of ATF3, which leads to increases in the expression of proinflammatory cytokines and impaired nerve regeneration. All data indicate the mean ± SEM.