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

Abstract

BackgroundThe 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.MethodsWe 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).ResultsIn 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).ConclusionsOur 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0116-1) contains supplementary material, which is available to authorized users.

Blockade of Arginine Vasopressin receptors prevents blood-brain barrier breakdown in Experimental Autoimmune Encephalomyelitis

“…During neuroinflammation, leukocytes migrate and trigger inflammatory reactions in the CNS, causing BBB impairment. It has been widely described that the BBB plays an important pathophysiological role in neuroinflammatory diseases, such as multiple sclerosis (MS) [3][4][5] . MS is an autoimmune inflammatory demyelinating disease with different immune cells involved in its pathogenesis and T cells are the most recognized cell type 6 , and one of its most studied animal models is experimental autoimmune encephalomyelitis (EAE) 5 .…”

“…It has been widely described that the BBB plays an important pathophysiological role in neuroinflammatory diseases, such as multiple sclerosis (MS) [3][4][5] . MS is an autoimmune inflammatory demyelinating disease with different immune cells involved in its pathogenesis and T cells are the most recognized cell type 6 , and one of its most studied animal models is experimental autoimmune encephalomyelitis (EAE) 5 . CNS migration and accumulation of autoreactive myelin-specific T lymphocytes as well as BBB breakdown are the basic pathological hallmarks of both MS and EAE 7 .…”

T‐lymphocyte–specific knockout of IKK‐2 or NEMO induces T h 17 cells in an experimental nephrotoxic nephritis mouse model

“…It has been shown that depletion of NEMO accelerated T-cell receptor-induced cytoskeleton translocation of IKK-2 (41). Lee et al (42) demonstrated that the inhibition of NF-kB activation by conditional deletion of IKK-2 in myeloid cells results in alleviated clinical signs of experimental autoimmune encephalomyelitis, compared with WT mice. It has been shown that conditional deletion of the p100 gene Nfkb2 in T reg cells results in massive inflammation because of the impaired suppressive function of Nfkb2-deficient T reg cells (39).The canonical or noncanonical NF-kB pathway play different roles in T h 17-cell development, as IKK-1 was reported as a key transcriptional regulator of the T h 17 lineage, and T cells expressing a nonactivated form of IKK-1 were significantly compromised in their ability to produce IL-17 and to initiate neural inflammation (43).…”

Oriental Medicine Samhwangsasim-tang Alleviates Experimental Autoimmune Encephalomyelitis by Suppressing Th1 Cell Responses and Upregulating Treg Cell Responses

“…Lumbar spinal cords were removed, fixed using 4% PFA for a day, incubated overnight in 30% sucrose solution, and then cut into 10-μm thick by previously described (Lee et al, 2016a,b). The sections were stained with luxol fast blue (LFB) and counterstained by hematoxylin to evaluate demyelination and immune cell infiltration, respectively.…”