Tuftsin Combines With Remyelinating Therapy and Improves Outcomes in Models of CNS Demyelinating Disease.

Kaitlyn K Thompson,Amanda Pretory,Stella E Tsirka,Jillian C Nissen

doi:10.3389/fimmu.2018.02784

Abstract

Though promoting remyelination in multiple sclerosis (MS) has emerged as a promising therapeutic strategy, it does not address inflammatory signals that continue to induce neuronal damage and inhibit effectiveness of repair mechanisms. Our lab has previously characterized the immunomodulatory tetrapeptide, tuftsin, which induces an anti-inflammatory shift in microglia and macrophages. This targeted anti-inflammatory agent improves physical deficits in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we sought to determine whether tuftsin is also effective in combination with benztropine, an FDA-approved drug that stimulates remyelination, in both EAE and in the cuprizone model of demyelination. We show that combining these two agents to promote anti-inflammatory and remyelinating mechanisms alleviates symptoms in EAE and lessens pathological hallmarks in both MS models. Importantly, tuftsin is required to transform the inflammatory CNS environment normally present in EAE/MS into one of an anti-inflammatory nature, and benztropine is required in the cuprizone model to improve remyelination. Our data further support tuftsin's beneficial immunomodulatory activity in the context of EAE, and show that when studying remyelination in the absence of an autoimmune insult, tuftsin still activated microglia toward an anti-inflammatory fate, but benztropine was necessary for significant repair of the damaged myelin. Overall, tuftsin effectively combined with benztropine to significantly improve MS-like pathologies in both models.

Highlights

Multiple sclerosis (MS) is a chronic, demyelinating autoimmune disease of the central nervous system (CNS) and one of the most common causes of disability among young adults, affecting ∼2.5 million people worldwide [1,2,3]
We report that targeting microglia/macrophages with tuftsin alone was not enough to facilitate remyelination and that benztropine was necessary to observe improvements
Due to significantly less demyelination evident in benztropineand combination-treated mice, we examined the numbers of immature oligodendrocyte precursor cell (OPC) and mature OLs, as benztropine has previously been seen to induce a shift in favor of higher OL numbers through promoting OPC differentiation [15]

Summary

Introduction

Multiple sclerosis (MS) is a chronic, demyelinating autoimmune disease of the central nervous system (CNS) and one of the most common causes of disability among young adults, affecting ∼2.5 million people worldwide [1,2,3]. MS is characterized by demyelinated, inflammatory lesions accompanied by blood-brain barrier disruption, usually in the white matter of the brain and spinal cord [1] Within these lesions, both immune and glial cell types actively contribute to neuronal damage. ∼15% of patients are diagnosed with primary progressive MS (PPMS), which consists of continually worsening symptoms from the time of onset [1, 6,7,8] During these progressive phases, it appears that inflammation diminishes and neurodegeneration predominates due to inefficient CNS plasticity that compensates for already damaged axons and ineffective remyelination and failure to repair and protect naked axons [3, 9]

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