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IKKβ-mediated inflammatory myeloid cell activation exacerbates experimental autoimmune encephalomyelitis by potentiating Th1/Th17 cell activation and compromising blood brain barrier

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Authors
Lee, Min Jung; Bing, So Jin; Choi, Jonghee; Jang, Minhee; Lee, Gihyun; Lee, Hyunkyoung; Chang, Byung Soo; Jee, Youngheun; Lee, Sung Joong; Cho, Ik-Hyun
Issue Date
2016-07-22
Publisher
BioMed Central
Citation
Molecular Neurodegeneration, 11(1):54
Keywords
Myeloid cellIKKβ conditional deletionExperimental autoimmune encephalomyelitisT cellBlood brain barrier
Abstract
Background
The inflammatory myeloid cell activation is one of the hallmarks of experimental autoimmune encephalomyelitis (EAE), yet the in vivo role of the inflammatory myeloid cell activation in EAE has not been clearly resolved. It is well-known that IKK/NF-κB is a key signaling pathway that regulates inflammatory myeloid activation.

Methods
We investigated the in vivo role of inflammatory myeloid cell activation in myelin oligodendrocyte glycoprotein (MOG) peptides-induced EAE using myeloid cell type-specific ikkβ gene conditional knockout-mice (LysM-Cre/IkkβF/F).

Results
In our study, LysM-Cre/IkkβF/F mice had alleviated clinical signs of EAE corresponding to the decreased spinal demyelination, microglial activation, and immune cell infiltration in the spinal cord, compared to the wild-type mice (WT, IkkβF/F). Myeloid ikkβ gene deletion significantly reduced the percentage of CD4+/IFN-γ+ (Th1) and CD4+/IL-17+ (Th17) cells but increased the percentages of CD4+/CD25+/Foxp3+ (Treg) cells in the spinal cord and lymph nodes, corresponding to the altered mRNA expression of IFN-γ, IL-17, IL-23, and Foxp3 in the spinal cords of LysM-Cre/IkkβF/F EAE mice. Also, the beneficial effect of myeloid IKKβ deletion in EAE corresponded to the decreased permeability of the blood brain barrier (BBB).

Conclusions
Our findings strongly suggest that IKK/NF-kB-induced myeloid cell activation exacerbates EAE by activating Th1 and Th17 responses and compromising the BBB. The development of NF-κB inhibitory agents with high efficacy through specific targeting of IKKβ in myeloid cells might be of therapeutic potential in MS and other autoimmune disorders.
Language
English
URI
http://hdl.handle.net/10371/109844
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College of Dentistry/School of Dentistry (치과대학/치의학대학원)Dept. of Dentistry (치의학과)Journal Papers (저널논문_치의학과)
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