Peripheral nerve regeneration: New research findings revealed!

Aqsa, Jamia Millia Islamia

The peripheral nerves can regenerate following an injury. Schwann plays a vital role in the regeneration of these nerves. They release myelin, de-differentiate, and proliferate. But the rate at which they regenerate is about 1 mm/day in humans, which is extremely slow. It often leads to incomplete recovery or disability in patients.

Recent research at Johns Hopkins Medicine on transgenic mice revealed that macrophages play a vital role in the regeneration of the injured peripheral nerves. They help by contributing to axonal regeneration by removing inhibitory myelin and axonal debris. Macrophages secrete cytokines and factors that trigger growth and facilitate SC migration and axon regeneration.

Other than influencing intracellular metabolism, macrophages are capable of influencing metabolism in surrounding SCs. Monocarboxylate transporters (MCTs) are recently recognized to be critical for regulating diverse immune cell functions. They are recognized in increasing macrophage intracellular metabolism and improving peripheral nerve response to injury.

Research Findings:

• Macrophages are crucial for tissue repair and regeneration of peripheral nerves. When Schwann cells get disrupted due to nerve injury it results in the production of chemokines and cytokines. As a result, resident nerve macrophages get activated and recruit circulating macrophages. They remove cell debris and help in promoting regeneration. Monocarboxylate transporters in macrophages also contribute to macrophage phenotype and the cytokine microenvironment of injured nerves.
• MCT1 is a protein that contributes to the metabolic function of macrophages. They help in defining the macrophage phenotype and function. The effect of MCT1 in macrophage metabolism was studied with and without MCT1. To study this without MCT1, the gene encoding this transporter protein was deleted. The study revealed that MCT1 removal in macrophages affects both glycolytic and mitochondrial functions negatively. It resulted in reduced ATP production and affected metabolic operations.
• Further investigations on the role of MCT1 reveal its role in macrophage metabolism and phenotype. Research suggests that MCT1 deficiency in macrophages alters the signaling cascade. When this signaling cascade gets disturbed, it affects the recognition of apoptotic cells by phagocyte receptors. MCT1 plays an important role in determining macrophage phenotype. It affects the cytokine microenvironment, which is vital for the phagocytic activity of macrophages.
• Another molecule that indirectly affects MCT1-regulated macrophage phenotypes and functions in injured nerves is ATF3. It is an injury-inducible transcription factor. The findings revealed that the expression of ATF3 gets decreased on the deletion of MCT1. It results in increased pro-inflammatory cytokines and impaired nerve regeneration.
• After a complete understanding of the importance of MCT1 in macrophage metabolism and phenotype, it was then tested for cell transfer in patients. Cell transfer of macrophages with MCT1 helps in nerve regeneration in mice without macrophage-specific MCT1. The positive outcome of the result suggests that this therapy can be used for treating nerve injuries in patients.
• The overexpression of MCT1 in macrophages also helps in accelerating peripheral nerve regeneration. The experiments in transgenic mice indicated an increase in nerve regeneration after increasing the expression of MCT1 in macrophages.

Significance of the study:

The research findings conclude the vital role of MCT1 in macrophage metabolism and phenotype determination. In addition, its upregulation in macrophages increased the recovery of peripheral injured nerves.

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Reference:

1. Jha, M. K., Passero, J. V., Rawat, A., Ament, X. H., Yang, F., Vidensky, S., Collins, S. L., Horton, M. R., Hoke, A., Rutter, G. A., Latremoliere, A., Rothstein, J. D., & Morrison, B. M. (2021). Macrophage monocarboxylate transporter 1 promotes peripheral nerve regeneration after injury in mice. Journal of Clinical Investigation. https://doi.org/10.1172/JCI141964

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