Immune-related GTPase Irgm1 exacerbates experimental auto-immune encephalomyelitis by promoting the disruption of blood-brain barrier and blood-cerebrospinal fluid barrier.
Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is a T cell-mediated autoimmune condition characterized by prominent inflammation in the CNS. In this model, autoreactive T cells are primed in peripheral lymph nodes and migrate into uninflamed CNS across blood-cerebrospinal fluid barrier (BCSFB) and blood-brain barrier (BBB) to initiate inflammation. However, the molecular mechanism controlling T cell migration remains to be determined. In an in vivo EAE mouse model, we have shown that Irgm1 (also known as LRG-47), a member of the immunity-related GTPase family, promotes the disruption of both BCSFB and BBB, and exacerbates the phenotypes of MOG-induced EAE. During EAE, Irgm1 was up-regulated in reactive astrocytes, ependymal cells and epithelial cells of the choroids plexus, which, in turn, promotes T cell infiltration into the CNS. Electron microscopy study showed that the MOG-induced disruption of both BBB and BCSFB was protected in the Irgm1(-/-) mice. Moreover, the expression of Claudin-5 (CLN-5), a major molecular determinant of BBB, in brain microvessel endothelial cells (BMVECs) was decreased in WT EAE mice while increased in Irgm1(-/-) mice. In addition, the expression of CC-chemokine ligand 20 (CCL-20), an important chemokine mediating lymphocyte trafficking across BCSFB, in the epithelial cells of choroids plexus was significantly suppressed in naïve and EAE-induced Irgm1(-/-) mice. These data suggest that Irgm1 is an important molecular regulator for the properties of both BBB and BCSFB, and a proinflammatory factor for EAE.
Department of Neurology, The Affiliated Sanming First Hospital of Fujian Medical University, Sanming 365000, Fujian, China. cdongwang@yahoo.com
Chaodong
C
Wang
Caihong
C
Wang
Haiyan
H
Dong
Xiao-Mu
XM
Wu
Chunyu
C
Wang
Fucan
F
Xia
Guimei
G
Li
Xiuzhi
X
Jia
Shuyu
S
He
Xiaoshu
X
Jiang
Huashun
H
Li
Hongwei
H
Xu
D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002555:Cerebrospinal Fluid; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005434:Flow Cytometry; D019204:GTP-Binding Proteins / Q000276:immunology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
C096000:Ifi1 protein, mouse; D019204:GTP-Binding Proteins