Aquaporin 4: a player in cerebral edema and neuroinflammation

Abstract

Neuroinflammation is a common pathological event observed in many different brain diseases, frequently associated with blood brain barrier (BBB) dysfunction and followed by cerebral edema. Neuroinflammation is characterized with microglia activation and astrogliosis, which is a hypertrophy of the astrocytes. Astrocytes express aquaporin 4, the water channel protein, involved in water homeostasis and edema formation. Aside from its function in water homeostasis, recent studies started to show possible interrelations between aquaporin 4 and neuroinflammation. In this review the roles of aquaporin 4 in neuroinflammation associated with BBB disruption and cerebral edema will be discussed with recent studies in the field.

Figure 1

Structural organization of AQP4 in the astrocyte membrane. (A) Schematic drawing of the AQP4 homo-tetramer assembly within the lipid membrane from a lateral view resulting in a central pore permeable to cations and gases (green arrows) [16]. Each individual aquaporin facilitates bi-directional water movement that is dependent on the osmotic gradient (blue arrows) (modified from Badaut et al. [57]). (B) In normal brain, association between AQP4-m1 (red circles) and AQP4-m23 (blue circles) isoforms contribute to form orthogonal array of particles (OAPs). Higher expression of AQP4-m23 contributes to the formation of large OAPs, and should facilitate the gas, ion (green arrows), and water diffusion (water arrows) through the astrocyte membrane. (C) In brain injury, increase of AQP4-m1 [19] should contribute to disruption of OAPs (modified from Badaut et al. [57]). Changes in OAP size may decrease the number of central pore and possibly affect not only water movement but also the ion and gas movements.

Figure 2

Schematic summary of a beneficial role AQP4 upregulation plays during the edema resolution phase. The upregulation of AQP4 causes increased water clearance from the tissue, which in turn causes decreased BBB disruption because of decreased pressure, and there is less neutrophil infiltration and decreased pro-inflammatory cytokines. This cause decreased MMP production [62], which possibly results in less destruction of the basal lamina and tight junctions, causes an even greater decrease of the BBB. In another pathway (dotted lines), the increased water clearance from the tissue and extracellular space causes changes in the osmotic pressure, changing the activation state of the stretch activated ion channels expressed in microglia [86-88], causing less microglial activation, thus causing decreased pro-inflammatory cytokine. The resulting decrease in BBB disruption/permeability leads to decreased vasogenic edema or better edema resolution. Finally, this scheme outlines the potential link between AQP4, edema and neuroinflammation.

Figure 3

AQP4 distribution in the astrocyte in normal cortex and after brain injury. (A) Confocal picture of AQP4 immunostaining (red, arrow heads) in normal brain shows the presence of the water channel protein on the astrocyte endfoot (GFAP staining, green, arrow) in contact to the blood vessels in the cortex. (B) Confocal pictures of the AQP4 immunostaining (red) on reactive astrocytes revealed with GFAP immunolabelling (green) in the cortex after traumatic brain injury. The presence of the AQP4 staining is not only localized on the endfeet in contact to the blood vessels but also distributed in all astrocyte processes (arrows). Scale bar 10 μm.