C16 Peptide Promotes Vascular Growth and Reduces Inflammation in a Neuromyelitis Optica Model.

Haohao Chen,Shu Han,Jinzhan Jiang,Xiaoxiao Fu

doi:10.3389/fphar.2019.01373

Haohao Chen, Shu Han + Show 2 more

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https://doi.org/10.3389/fphar.2019.01373

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Abstract

The goal of this study was to elucidate the mechanism of action of C16, a laminin-1 peptide that competes with αvβ3 for integrin binding, in treating neuromyelitis optica (NMO). A NMO rat model was established and specific inhibitors were used to investigate the effect of Tie2 kinase, integrin, and PI3K/Akt signaling pathways on C16 function in NMO using histological, immunohistochemical, immunofluorescence, Western blot, and ELISA assays. A total of 150 rats were divided into five groups: a control untreated group (n = 18) and four test groups (n = 33 per group) including vehicle-treated control, C16, Tie2 kinase inhibitor + C16, and PI3K/Akt inhibitor LY294002 + C16. We found that inhibiting Tie2 kinase resulted in partial loss of C16 peptide-mediated effects, while suppressing PI3K/Akt signaling reduced C16 peptide-mediated effects. In addition, activation of the αvβ3 integrin axis and Tie2 kinase promoted PI3K/Akt signaling. Our study showed that the Tie2-PI3K/Akt, Tie2 integrin, and integrin-PI3K/Akt signaling pathways regulate C16 peptide function in vascular growth and stabilization as well as inflammation in NMO.

Highlights

Disruption of the blood–brain barrier (BBB), which plays a crucial role in maintaining cerebral homeostasis, is the rate-determining step in the progression of inflammatory neurological diseases, such as multiple sclerosis (MS) and neuromyelitis optica (NMO) (Shimizu and Kanda, 2013)
NMO symptoms started manifesting at 3 days and peaked at 2 weeks P.I., and the clinical scores remained poor at 8 weeks P.I. in the vehicle control-treated group (Figure 1)
We previously showed that C16 inhibited the trans-endothelial migration of C8166-CD4 lymphoblast cells and significantly reduced the infiltration of leukocytes and macrophages in the spinal cord (SC) and brain in an experimental autoimmune encephalomyelitis (EAE) model, which is a frequently used MS animal model (Zhang et al, 2014; Wang et al, 2016; Tian et al, 2017)

Summary

Introduction

Disruption of the blood–brain barrier (BBB), which plays a crucial role in maintaining cerebral homeostasis, is the rate-determining step in the progression of inflammatory neurological diseases, such as multiple sclerosis (MS) and neuromyelitis optica (NMO) (Shimizu and Kanda, 2013). Characteristic pathological changes in NMO include loss of blood–SC barrier integrity, blood vessel leakiness, and inflammatory cell infiltration (Jiang et al, 2014). The increase in blood vessel permeability promotes NMO-IgG antibody invasion of the parenchyma tissues in the CNS, wherein the circulating anti-aquaporin 4 (AQP4) NMO-IgG binds selectively to AQP4 water channels localized at astrocytic foot processes at the BBB. This leads to AQP4 loss, further destruction of the BBB integrity, and NMO progression (Shimizu et al, 2012).

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