Abstract
BackgroundThe involvement of astrocyte water channel aquaporin-4 (AQP4) in autoimmune diseases of the central nervous system has been suggested following the identification of AQP4 autoantibodies in neuromyelitis optica, an inflammatory demyelinating disease.ResultsWe investigated the involvement of AQP4 in disease severity in an established mouse model of experimental autoimmune encephalomyelitis (EAE) produced by immunization with myelin oligodendrocyte glycoprotein (MOG35–55) peptide. EAE was remarkably attenuated in AQP4 null mice compared to identically treated wildtype mice. Whereas most wildtype mice developed progressive tail and hindlimb paralysis, clinical signs were virtually absent in AQP4 null mice. Brain and spinal cords from AQP1 null mice showed greatly reduced mononuclear cell infiltration compared to wildtype mice, with relatively little myelin loss and axonal degeneration.ConclusionThe reduced severity of autoimmune encephalomyelitis in AQP4 deficiency suggests AQP4 as a novel determinant in autoimmune inflammatory diseases of the central nervous system and hence a potential drug target.
Highlights
The involvement of astrocyte water channel aquaporin-4 (AQP4) in autoimmune diseases of the central nervous system has been suggested following the identification of AQP4 autoantibodies in neuromyelitis optica, an inflammatory demyelinating disease
Aquaporin-4 (AQP4) is a water-selective channel expressed in plasma membranes of astrocytes throughout the central nervous system (CNS), at astrocyte foot processes at the blood-brain barrier and brain-cerebrospinal fluid interfaces [1,2]
Motivated by the potential involvement of AQP4 in an inflammatory demyelinating CNS disease, we investigated the role of AQP4 in EAE using a well-established mouse model of EAE produced by immunization with a peptide against myelin oligodendrocyte glycoprotein (MOG) [17]
Summary
The involvement of astrocyte water channel aquaporin-4 (AQP4) in autoimmune diseases of the central nervous system has been suggested following the identification of AQP4 autoantibodies in neuromyelitis optica, an inflammatory demyelinating disease. Structural data on AQP4 from electron crystallography suggested a possible new role of AQP4 in cell-cell adhesion [9,10], though subsequent experimental studies did not confirm this role [11]. Another potential new role for AQP4 that is unrelated to its cell membrane water transport function was suggested by the discovery of circulating autoantibodies against AQP4 in most patients with the inflammatory demyelinating disease neuromyelitis optica (NMO) [12]. How circulating NMO-IgG and CNS AQP4 expression promote inflammation and cause demyelinating lesions in the central nerv-
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