LRR domain of NLRX1 protein delivery by dNP2 inhibits T cell functions and alleviates autoimmune encephalomyelitisopen access
- Authors
- Koo, Ja-Hyun; Kim, Do-Hyun; Cha, Donghun; Kang, Min-Jong; Choi, Je-Min
- Issue Date
- Feb-2020
- Publisher
- IVYSPRING INT PUBL
- Keywords
- NOD-like receptor family member X1; T cell; BBB-penetrating peptide; dNP2; experimental autoimmune encephalomyelitis
- Citation
- THERANOSTICS, v.10, no.7, pp.3138 - 3150
- Indexed
- SCIE
SCOPUS
- Journal Title
- THERANOSTICS
- Volume
- 10
- Number
- 7
- Start Page
- 3138
- End Page
- 3150
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/10732
- DOI
- 10.7150/thno.43441
- ISSN
- 1838-7640
- Abstract
- Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system (CNS), which is a chronic progressive disease and is caused by uncontrolled activation of myelin antigen specific T cells. It has high unmet medical needs due to the difficulty of efficient drug delivery into the CNS to control tissue inflammation. In this study, we demonstrate that a fusion protein of NOD-like receptor family member X1 (NLRX1) and blood brain barrier (BBB)-permeable peptide, dNP2 ameliorates experimental autoimmune encephalomyelitis (EAE). Methods: We purified recombinant LRR or NBD regions of NLRX1 protein conjugated with dNP2. To examine intracellular delivery efficiency of the recombinant protein, we incubated the proteins with Jurkat T cells or murine splenic T cells and their delivery efficiency was analyzed by flow cytometry. To investigate the therapeutic efficacy in an EAE model, we injected the recombinant protein into mice with 3 different treatment schemes e.g., prevention, semi-therapeutic, and therapeutic. To analyze their functional roles in T cells, we treated MACS-sorted naive CD4 T cells with the proteins during their activation and differentiation into Th1, Th17, and Treg cells. Results: dNP2-LRR protein treatment showed significantly higher delivery efficiency than TAT-LRR or LRR alone in Jurkat T cells and mouse splenic T cells. In all three treatment schemes of EAE experiments, dNP2-LRR administration showed ameliorated tissue inflammation and disease severity with reduced number of infiltrating T cells producing inflammatory cytokines such as IFN gamma. In addition, dNP2-LRR inhibited T cell activation, cytokine production, and Th1 differentiation. Conclusion: These results suggest that dNP2-LRR is a novel agent, which regulates effector T cell functions and could be a promising molecule for the treatment of CNS autoimmune diseases such as multiple sclerosis.
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