Targeting epidermal fatty acid binding protein for treatment of experimental autoimmune encephalomyelitis.

Enyu Rao,Jill Suttles,Puja Singh,Yan Li,Bing Li,Young-In Chi,Yuwen Zhang

doi:10.1186/s12865-015-0091-2

Abstract

BackgroundMultiple sclerosis (MS) is an autoimmune disease in which dysregulated immune cells attack myelin in the central nervous system (CNS), leading to irreversible neuronal degeneration. Our previous studies have demonstrated that epidermal fatty acid binding protein (E-FABP), widely expressed in immune cells, in particular in dendritic cells (DCs) and T lymphocytes, fuels the overactive immune responses in the mouse model of experimental autoimmune encephalomyelitis (EAE).MethodsIn the present study, we conducted an intensive computational docking analysis to identify novel E-FABP inhibitors for regulation of immune cell functions and for treatment of EAE.ResultsWe demonstrate that compound [2-(4-acetylphenoxy)-9,10-dimethoxy-6,7-dihydropyrimido[6,1-a]isoquinolin-4-one; designated as EI-03] bound to the lipid binding pocket of E-FABP and enhanced the expression of peroxisome proliferator-activating receptor (PPAR) γ. Further in vitro experiments showed that EI-03 regulated DC functions by inhibition of TNFα production while promoting IL-10 secretion. Moreover, EI-03 treatment counterregulated T cell balance by decreasing effector T cell differentiation (e.g. Th17, Th1) while increasing regulatory T cell development. Most importantly, mice treated with this newly identified compound exhibited reduced clinical symptoms of EAE in mouse models.ConclusionsTaken together, we have identified a new compound which displays a potential therapeutic benefit for treatment of MS by targeting E-FABP.

Highlights

Multiple sclerosis (MS) is an autoimmune disease in which dysregulated immune cells attack myelin in the central nervous system (CNS), leading to irreversible neuronal degeneration
Since fatty acids function both as energy sources and as signaling molecules, Fatty acid binding proteins (FABPs) have been identified as central regulators of metabolic and inflammatory pathways [6,7,8,9] Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we have demonstrated that mice deficient of FABPs, in particular epidermal FABP (E-FABP), have protection from the development of EAE [10,11]
We have shown that CD4+ T cells deficient for epidermal fatty acid binding protein (E-FABP) exhibit increased expression of peroxisome proliferatoractivating receptor γ (PPARγ), which suppressed Th17 differentiation while enhancing regulatory T cell (Treg) development [10]

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune disease in which dysregulated immune cells attack myelin in the central nervous system (CNS), leading to irreversible neuronal degeneration. Our previous studies have demonstrated that epidermal fatty acid binding protein (E-FABP), widely expressed in immune cells, in particular in dendritic cells (DCs) and T lymphocytes, fuels the overactive immune responses in the mouse model of experimental autoimmune encephalomyelitis (EAE). Since fatty acids function both as energy sources and as signaling molecules, FABPs have been identified as central regulators of metabolic and inflammatory pathways [6,7,8,9] Using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we have demonstrated that mice deficient of FABPs, in particular epidermal FABP (E-FABP), have protection from the development of EAE [10,11].

Methods

Results

Conclusion