Immunomodulation by dimethyl fumarate treatment improves mouse sciatic nerve regeneration.

Publication date: Apr 16, 2020

Traumatic injury to the peripheral nervous system (PNS) often generates sensorimotor deficits that impair the quality of life of the patient. The success of nerve regeneration is related to tissue clearance and the formation of a microenvironment that sustains and stimulates axon growth up to the target. In this sense, macrophages are important for axon and myelin debris removal, neovascularization and the production of neurotrophic factors. Macrophage activation is improved by T helper (Th) lymphocytes, whose role remains few explored upon traumatic nerve injuries. Dimethyl fumarate (DMF) is the first-line drug for the treatment of multiple sclerosis due to its neuroprotective, anti-inflammatory and immunomodulatory properties. DMF improves nerve regeneration via antioxidant and cytoprotective cell signaling pathways. However, the direct activity on the cell immune response following nerve axotomy requires further investigation. In the present study, we evaluated DMF activity on Th cells and macrophage polarization, axonal regeneration and motor recovery following sciatic nerve crush in mice. For this aim, operated animals received DMF or vehicle once a day, starting at 3 days postinjury (dpi). Using an in vivo cell migration assay, we observed reduced lymphocyte infiltration in the nerves of DMF-treated mice at 7 dpi. Flow cytometry revealed DMF-responsive lymphocyte polarization from the pro- (Th1) to anti-inflammatory (Th2) phenotype at 7 dpi but not at 14 dpi. No effect was observed on macrophage polarization (from M1 to M2), although DMF reduced the frequency of the proinflammatory M1 subset from 7 to 14 dpi. Quantification of neurofilament (axon marker) and growth-associated protein 43 (GAP-43) immunolabeling showed improved axonal regeneration under DMF treatment at 14 dpi. Better motor recovery was observed in the DMF-treated group, as verified by an automated walking track test. Overall, our data reinforce the pro-regenerative capacity of DMF after traumatic nerve injury based on downmodulation of the proinflammatory immune response.

Concepts Keywords
Antioxidant Branches of biology
Assay Organ systems
Axon Neurophysiology
Axonal Regeneration Nerve injury
Dimethyl DMF
DMF Dimethyl fumarate
Flow Cytometry Axotomy
Frequency Neuroregeneration
Fumarate Wallerian degeneration
GAP Axon
Immune Response Myelin
Immunomodulatory
Lymphocyte
Lymphocytes
Macrophage
Macrophages
Mice
Microenvironment
Multiple Sclerosis
Myelin
Neovascularization
Nerve
Nerve Injury
Nerve Regeneration
Neurofilament
Neuroprotective
Neurotrophic Factors
Peripheral Nervous System
Phenotype
Polarization
Sciatic Nerve
Th1
Th2
Traumatic Injury
Vivo

Semantics

Type Source Name
drug DRUGBANK Dimethyl fumarate
drug DRUGBANK Spinosad
disease MESH multiple sclerosis
disease MESH growth
drug DRUGBANK Tropicamide
disease MESH Wallerian degeneration

Original Article

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