Peripheral T cells derived from Alzheimer's disease patients overexpress CXCR2 contributing to its transendothelial migration, which is microglial TNF-alpha-dependent.
The mechanism of circulating T cells entry into the brain in Alzheimer's diseases (AD) remains unclear. Here, we showed that peripheral T cells derived from AD patients overexpress CXCR2 to enhance its transendothelial migration. T cells migration through in vitro blood-brain barrier model was effectively blocked by anti-CXCR2 antibody or IL-8 (a CXCR2 ligand) RNAi in human brain microvascular endothelial cells (HBMECs). Amyloid beta (Abeta) injection in rat hippocampus upregulated CXCR2 expression accompanied with increased T cells occurrence in the brain, and this enhanced T cells entry was effectively blocked by CXCR2 antagonist. Furthermore, anti-TNF-alpha antibody blocked IL-8 production in HBMECs and T cells transendothelial migration caused by the culture supernatant of microglia treated with Abeta. Blockage of intracerebral TNF-alpha abolished the upregulation of CXCR2 in peripheral T cells and the increased T cells occurrence in the brain induced by Abeta injection in rat hippocampus. These data suggest that CXCR2 overexpression in peripheral T cells is intracerebral microglial TNF-alpha-dependent and TNF-alpha primes T cells transendothelial migration in Alzheimer's diseases.
Liu
Yi-Jun
YJ
Department of Developmental Biology, Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang 110001, PR China.
Guo
Da-Wen
DW
Tian
Li
L
Shang
De-Shu
DS
Zhao
Wei-Dong
WD
Li
Bo
B
Fang
Wen-Gang
WG
Zhu
Li
L
Chen
Yu-Hua
YH
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001323:Autoantibodies / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D017628:Microglia / Q000378:metabolism; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D016229:Amyloid beta-Peptides; D001323:Autoantibodies; D016209:Interleukin-8; D023063:Receptors, Interleukin-8B; D014409:Tumor Necrosis Factor-alpha