Novel role of aquaporin-4 in CD4+ CD25+ T regulatory cell development and severity of Parkinson's disease.
Aquaporin-4 (AQP4) is highly expressed in mammalian brains and is involved in the pathophysiology of cerebral disorders, including stroke, tumors, infections, hydrocephalus, epilepsy, and traumatic brain injury. We found that AQP4-deficient mice were hypersensitive to stimulations such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or lipopolysaccharide compared to wild-type (WT) littermates. In a mouse model of MPTP-induced Parkinson's disease (PD), AQP4-deficient animals show more robust microglial inflammatory responses and more severe loss of dopaminergic neurons (DNs) compared with WT mice. However, a few studies have investigated the association of abnormal AQP4 levels with immune dysfunction. Here, for the first time, we report AQP4 expression in mouse thymus, spleen, and lymph nodes. Furthermore, the significantly lower numbers of CD4(+) CD25(+) regulatory T cells in AQP4-deficient mice compared to WT mice, perhaps resulting from impaired thymic generation, may be responsible for the uncontrolled microglial inflammatory responses and subsequent severe loss of DNs in the substantia nigra pars compacta in the MPTP-induced PD model. These novel findings suggest that AQP4 deficiency may disrupt immunosuppressive regulators, resulting in hyperactive immune responses and potentially contributing to the increased severity of PD or other immune-associated diseases.
Department of Pathogen Biology and Immunology, Jiangsu Key Laboratory of Pathogen Biology, Nanjing Medical University, China.
Ying
Y
Chi
Yi
Y
Fan
Lei
L
He
Wei
W
Liu
Xiaoyun
X
Wen
Sha
S
Zhou
Xuefeng
X
Wang
Cui
C
Zhang
Hui
H
Kong
Laura
L
Sonoda
Prem
P
Tripathi
Carrie J
CJ
Li
Michelle S
MS
Yu
Chuan
C
Su
Gang
G
Hu
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D051401:Aquaporin 4 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015704:CD4 Antigens / Q000032:analysis / Q000096:biosynthesis; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D013154:Spleen / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013950:Thymus Gland / Q000378:metabolism
D051401:Aquaporin 4; D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D008070:Lipopolysaccharides; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine