The role of aquaporin-4 in cerebral edema and neuroinflammation
| September 17, 2013
Aquaporin belongs to the family of water-channel proteins and is commonly expressed in different cell types and organisms. The aquaporin family has a six-membrane-spanning alpha-helical domain and a consensus motif consisting of asparagine-proline-alanine, which constitutes part of the pore.
Aquaporin-4 (AQP4) plays a significant role in potassium homeostasis and facilitates the water diffusion through potassium gradient for brain activity. AQP4 might also be involved in cell adhesion, migration and neuroinflammation. The neuroinflammation is an acute phase after brain injury, along with edema, and brain diseases like multiple sclerosis. Neuroinflammation involves several molecular and cellular changes among various brain diseases and injuries.
It is important to determine the activation status of both astrocytes and microglia, along with cytokine and chemokine secretion levels to understand neuroinflammation. The activated microglia are responsible for producing cytokines such as IL-1ß, IL-6, TNFa, IL-4, IL-10, and TFGß. Activated astrocytes also play a key role in neuroinflammation due to their involvement in astrogliosis, which involves the hypertrophy of the astrocytes in injury. The absence of AQP4 in the astrocytes might decrease the astrocyte hypertrophy due to a decrease in the water entry and migration toward the injury site. Activated microglia might also release the chemokines and cytokines involved in blood-brain barrier (BBB) disruption and vasogenic edema.
AQP4 was found to be upregulated in the vasogenic edema resolution phase as visualized by the normalization of the magnetic resonance signals in several disease models. Furthermore, AQP4 has been presented in reactive microglia after intranigral injection of lipopolysaccharide in rats. The changes in AQP4 during the inflammatory process suggested some changes in the water movement in relation with the neuroinflammation.
Recently, in an animal model of autoimmune encephalomyelitis (EAE), the homogenized guinea pig whole spinal cord was injected into rats. They showed an up regulation of AQP4 starting on day 10 until the onset and the peak of cerebellar enlargement. A positive correlation was observed between AQP4 and BBB disruption in the cerebellum, which was associated with a decrease in the tight junction proteins, such as occluding.
The detrimental role of AQP4 in EAE has been supported by a less severe clinical and tissue inflammation score after EAE and LPS-injection in the AQP4 -/- mice as compared to the wild type animals. This could be the reason for a reduced production of pro-inflammatory cytokines, TNFa, and ILs observed in the AQP4 -/- mice astrocyte cultures.
The possible link between neuroinflammation and AQP4 was observed with neuromyelitis optica (NMO), a demyelinating disease. NMO is a pathological condition characterized by abnormal signals in the spinal cord and optic nerve in the form of blindness and paralysis, respectively. Various studies have suggested the presence of an AQP4 auto antibody in the patients suffering from a neuroimmune disease that worsens the condition and leads to an NMO pathology.
AQP4 is a key player in the edema formation and resolution, and its expression is observed to be increased after the injury. Edema is observed after different brain injuries and is associated with BBB disruption. The BBB disruption could lead to a plasma protein leakage and extravascular fluid accumulation, which could be a part of a neuroinflammatory response. In cases with a decreased BBB disruption, there will be less proinflammatory cytokines, matrix metalloproteases and edema.
In summary, the role of AQP4, either beneficial or detrimental in brain injuries, depends on the time point and injury models. In vasogenic edema, AQP4 plays a beneficial role in removing water from the central nervous system. Edema is associated with neuroinflammation, activation of the microglia and astrogliosis. The upregulation of AQP4 might contribute to the neuroinflammatory process in astrogliosis and microglia inactivation.
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