An ανβ3 Integrin-Binding Peptide Ameliorates Symptoms of Chronic Progressive Experimental Autoimmune Encephalomyelitis by Alleviating Neuroinflammatory Responses in Mice

Abstract

MOG35-55 triggers chronic, progressive experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, and the clinical course of EAE in this model is characterized by macrophage infiltration, axonal demyelination/damage, and progressive paralysis. These stages are usually associated with inflammatory responses in the central nervous system (CNS). This study was designed to investigate the effects of C16, an ανβ3 integrin-binding peptide that targets integrins involved in the transendothelial migration of extravasating inflammatory cells. C16 was applied for only 2weeks, but the benefits of this therapy lasted at least 8weeks. Multiple histological and immunohistochemical staining studies, western blotting, enzyme-linked immunosorbent assays, electron microscopy, and cortical somatosensory-evoked potential (c-SEP) electrophysiological tests were employed to assess the degree of inflammation, axonal loss, white matter demyelination, neuronal apoptosis, extent of gliosis, expression of pro-inflammatory cytokines, and functional recovery of differently treated EAE model mice. The results showed that C16 treatment inhibited extensive leukocyte and macrophage accumulation and infiltration, reduced the expression of pro-inflammatory cytokines (tumor necrosis factor-α and interferon-γ), and thereby attenuated and delayed the progression of EAE. Moreover, astrogliosis, demyelination, and axonal and neuronal loss were all alleviated in C16-treated EAE animals, contributing to the improvement of function. These data suggest that the C16 peptide may act as a protective agent by reducing neuroinflammatory responses and improving the microenvironment.