Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation

Article (PDF Available)inThe FASEB Journal 25(5):1556-66 · April 2011with35 Reads
DOI: 10.1096/fj.10-177279 · Source: PubMed
Abstract
Aquaporin-4 (AQP4) deficiency in mice reduces neuroinflammation in experimental autoimmune encephalomyelitis (EAE) produced by active immunization with myelin oligodendrocyte glycoprotein peptide (MOG). Potential mechanisms for the protective effect of AQP4 deficiency were investigated, including AQP4-dependent leukocyte and microglia cell function, immune cell entry in the central nervous system (CNS), intrinsic neuroinflammation, and humoral immune response. As we found with active-immunization EAE, neuroinflammation was greatly reduced in AQP4-knockout mice in adoptive-transfer EAE. AQP4 was absent in immune cells, including activated T lymphocytes. The CNS migration of fluorescently labeled, MOG-sensitized T lymphocytes was comparable in wild-type and AQP4-knockout mice. Microglia did not express AQP4. Serum anti-AQP4 antibodies were absent in EAE. Remarkably, intracerebral injection of LPS produced much greater neuroinflammation in wild-type than in AQP4-knockout mice, and cytokine (TNF-α and IL-6) secretion was reduced in astrocyte cultures from AQP4-knockout mice. Adenovirus-mediated expression of AQP4, or of an unrelated aquaporin, AQP1, increased cytokine secretion in astrocyte and nonastrocyte cell cultures, supporting the involvement of aquaporin water permeability in cytokine secretion. Our data suggest an intrinsic proinflammatory role of AQP4 involving AQP4-dependent astrocyte swelling and cytokine release. Reduction in AQP4 water transport may be protective in neuroinflammatory CNS diseases.

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    • "Since all properties are similar to wild type mice except absence of AQP4, AQP4 knockout mice are excellent candidates for AQP4 study. Numerous reports have revealeddifferentAQP4 functions through comparing AQP4 deletion mice with wild type mice [8][9][10][11][12]. There are mainly three research groups that have reported AQP4 knockout lines. "
    [Show abstract] [Hide abstract] ABSTRACT: Cerebrovascular diseases are conditions caused by problems with brain vasculature, which have a high morbidity and mortality. Aquaporin-4 (AQP4) is the most abundant water channel in the brain and crucial for the formation and resolution of brain edema. Considering brain edema is an important pathophysiological change after stoke, AQP4 is destined to have close relation with cerebrovascular diseases. However, this relation is not limited to brain edema due to other biological effects elicited by AQP4. Till now, multiple studies have investigated roles of AQP4 in cerebrovascular diseases. This review focuses on expression of AQP4 and the effects of AQP4 on brain edema and neural cells injuries in cerebrovascular diseases including cerebral ischemia, intracerebral hemorrhage and subarachnoid hemorrhage. In the current review, we pay more attention to the studies of recent years directly from cerebrovascular diseases animal models or patients, especially those using AQP4 gene knockout mice. This review also elucidates the potential of AQP4as an excellent therapeutic target.
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    • "Additionally, previous studies have indicated that AQP4 has an intrinsic proinflammatory role during astrocyte ac- tivation [20]. This view is further supported by reduced cytokine (IL-6 and TNF-α) secretion in AQP4 −/− astrocyte cultures exposed to LPS [19] . The present results also indicate that AQP4 knockout has a tendency to attenuate glial inflammation in 12 month-old APP/PS1 brain, reflected by significant decreases in IL-1β and nonsignficant decreases in IL-6 and TNF-α in hippocampal and cerebral samples. "
    [Show abstract] [Hide abstract] ABSTRACT: Preventing or reducing amyloid-beta (Aβ) accumulation in the brain is an important therapeutic strategy for Alzheimer’s disease (AD). Recent studies showed that the water channel aquaporin-4 (AQP4) mediates soluble Aβ clearance from the brain parenchyma along the paravascular pathway. However the direct evidence for roles of AQP4 in the pathophysiology of AD remains absent. Here, we reported that the deletion of AQP4 exacerbated cognitive deficits of 12-moth old APP/PS1 mice, with increases in Aβ accumulation, cerebral amyloid angiopathy and loss of synaptic protein and brain-derived neurotrophic factor in the hippocampus and cortex. Furthermore, AQP4 deficiency increased atrophy of astrocytes with significant decreases in interleukin-1 beta and nonsignficant decreases in interleukin-6 and tumor necrosis factor-alpha in hippocampal and cerebral samples. These results suggest that AQP4 attenuates Aβ pathogenesis despite its potentially inflammatory side-effects, thus serving as a promising target for treating AD.
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    Zhiqiang XuZhiqiang XuNa XiaoNa XiaoYali ChenYali Chen+1more author...[...]
    • "AQP4 deficiency may impair learning and memory, in part, through glutamate transporter-1 (GLT-1)444546. Furthermore, AQP4 knockout is involved in neuroinflammation and interferes with AD47484950. Ample evidence has indicated that the regulation of astrocyte functions via AQP4 may offer a new therapeutic option for AD [51]. "
    Article · Jan 2015 · Molecular Neurodegeneration
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