Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice
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
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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Research Article Metabolism Neuroscience

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 4

MCT1 ablation in macrophages does not affect the infiltration of Iba1-positive cells but critically modulates inflammatory cytokine expression in injured sciatic nerves.

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MCT1 ablation in macrophages does not affect the infiltration of Iba1-po...
On day 3 (A and B, left panels) and day 7 (B, right panels) after nerve crush, the number of Iba1-positive macrophages infiltrating into the nerves (B shows representative images from at least 4 independent experiments) from mice of both genotypes was unchanged. Total Iba1-positive macrophage counts were obtained from Z-stack images of 20 μm thick complete nerve cross-sections. n = 4–7 per group. Two-way ANOVA with Bonferroni’s multiple-comparison test. Scale bars: 200 μm (A) and 50 μm (B). (C) No change in mRNA Ly6G expression in uncrushed and crushed sciatic nerves (distal to the site of injury) was detected in LysM-Cre MCT1fl/fl mice compared with expression in littermate control MCT1fl/fl mice, as evaluated by real-time reverse transcriptase PCR (RT-PCR). Day-1 post-crush (1 d crush) mRNA levels are shown as the fold change compared with mRNA levels in crushed sciatic nerves isolated from MCT1fl/fl mice, normalized to the corresponding GAPDH mRNA levels. n = 5–8 per group. ND, not detected. Unpaired, 2-tailed t test. (D–I) mRNA expression levels of (D) IL-1β and (E) TNF-α on day 1 after crush; (F) IL-1β and (G) Ym-1 on day 3 after crush; and (H) Ym-1 and (I) Arg-1 on day 10 after crush in uncrushed and crushed sciatic nerves (distal to the site of injury) were evaluated by real-time RT-PCR. mRNAs 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 = 3–9 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.