Aquaporin 4: A Player in Cerebral Edema and Neuroinflammation

Andrew M Fukuda; Jerome Badaut

Disclosures

J Neuroinflammation. 2012;9(279) 

In This Article

AQP4 and neuroinflammation in Autoimmune Diseases

Experimental Autoimmune Encephalomyelitis (EAE) and AQP4

Recent data in a model of experimental autoimmune encephalomyelitis (EAE) in which homogenized guinea-pig whole spinal cord was injected into rats showed upregulation of AQP4 starting at 10 days until the onset and peak of cerebellar enlargement. At these timepoints, significantly positive correlation was observed between AQP4 and BBB disruption in the cerebellum, associated with a decrease of tight junction proteins such as occludin.[7] This detrimental role of AQP4 in EAE is supported by a less severe clinical and tissue inflammation score after EAE and LPS-injection in AQP4−/− mice than WT animals.[1] This is most likely the cause of reduced production of the pro-inflammatory cytokines, TNFα and IL-6, observed in AQP4−/− mice astrocyte cultures.[1]

AQP4−/− mice studies have also suggested that AQP4 could be contributing to the production of CD4+ and CD25+ T regulator cells; and lack of AQP4 may be disrupting the immunosuppressive regulators in Parkinson's disease, leading to increased microglial activation and a worse outcome due to more dopaminergic neuronal loss after induction of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.[5] Interestingly, AQP4 expression is present in the spleen, lymph nodes, and thymus, hinting towards a more direct role of AQP4 in systemic immune responses, and perhaps not just confined to neuroinflammation.[5]

Neuromyelitis Optica (NMO) and AQP4

The possible link between neuroinflammation and AQP4 was advertised with neuromyelitis optica (NMO), a demyelinating disease. NMO is a pathological condition characterized by abnormal signals most often observed in the spinal cord and optic nerve, and in the form of blindness and paralysis. Interestingly, AQP4 has been identified as the target for NMO-IgG, a unique feature of the disease which differentiates it from multiple sclerosis,[43–45] making it a very useful differential diagnostic tool in the clinics. More specifically, there is plausible evidence that NMO-IgG specifically targets AQP4 within the OAP structures, rather than free AQP4 isoforms.[6,46,47] Whether the presence of an autoantibody against AQP4 is the cause of the disease or a collateral consequence of some secondary pathological mechanisms still lacks an unanimous answer, but studies performed where immunoglobulins taken from AQP4 antibody positive NMO patients were administered to rats with EAE showed NMO pathology seen in the clinics,[48,49] suggesting that the presence of AQP4 autoantibody in patients already suffering from neuroimmune disease worsens the condition and leads to the NMO pathology observed. Interestingly, several clinical observations have been reported in which patients with myasthenia gravis (MG) also suffer from auto-AQP4-antibody positive NMO simultaneously.[50–56] Thus pointing out the possibility of a common autoimmune origin for both diseases, or the aforementioned worsening effect of the AQP4 autoantibody in patients with pre-existing immune diseases; previously unrecognized because of the lack of knowledge about the NMO IgG auto-AQP4 antibody as a diagnostic tool for NMO. This link could point to the involvement of AQP4 in the peripheral immune system as well.

In summary, these recent data from NMO and AQP4−/− mice models are encouraging to propose that AQP4 is a player in inflammation and neuroinflammation. But considering AQP4 properties as a water channel, its function in these processes are still unclear.

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