Novel role of aquaporin-4 in CD4+ CD25+ T regulatory cell development and severity of Parkinson’s disease

Abstract

Aquaporin-4 (AQP4) is highly expressed in mammalian brains and is involved in the pathophysiology of cerebral disorders, including stroke, tumors, infections, hydrocephalus, epilepsy, and traumatic brain injury. We found that AQP4-deficient mice were hypersensitive to stimulations such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or lipopolysaccharide compared to wild-type (WT) littermates. In a mouse model of MPTP-induced Parkinson's disease (PD), AQP4-deficient animals show more robust microglial inflammatory responses and more severe loss of dopaminergic neurons (DNs) compared with WT mice. However, a few studies have investigated the association of abnormal AQP4 levels with immune dysfunction. Here, for the first time, we report AQP4 expression in mouse thymus, spleen, and lymph nodes. Furthermore, the significantly lower numbers of CD4(+) CD25(+) regulatory T cells in AQP4-deficient mice compared to WT mice, perhaps resulting from impaired thymic generation, may be responsible for the uncontrolled microglial inflammatory responses and subsequent severe loss of DNs in the substantia nigra pars compacta in the MPTP-induced PD model. These novel findings suggest that AQP4 deficiency may disrupt immunosuppressive regulators, resulting in hyperactive immune responses and potentially contributing to the increased severity of PD or other immune-associated diseases.

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

“…Of note, none of these findings have been replicated by other groups. Moreover, their acute and chronic MPTP model produces a dopaminergic cell loss between 36.8-42% in WT animals (352)(353)(354)(355), which is not compatible with a model of PD ranging from 60-80% loss of dopaminergic cells (104,105). The authors further describe elevated expression of GFAP-positive cells, microglia and cytokines in Aqp4 -/-mice after treatment in the control condition saline (355).…”

“…Hence, these studies indicate that AQP4 is involved in neuroinflammation, probably through a cross-talk between astrocytes and microglia. The authors attribute the augmented dopaminergic cell loss in Aqp4 -/-mice to reduced proliferation and neurotrophic support from astroglia, as well as release of cytokines from astroglia (352)(353)(354)(355). Of note, none of these findings have been replicated by other groups.…”

“…Aqp4 -/-mice have exhibited reduced survival in vasogenic edema associated with tumor, cold brain injury and persistent ischemia compared to WTs (451, 458, 459), more severe signs of cerebral malaria (341), and less clearance of amyloid-β by the glymphatic system (320), indicating that AQP4 may contribute to plaque formation in AD. In four studies by the same group, Aqp4 -/-mice were more prone to MPTPinduced neurotoxicity in acute and chronic models of PD (352)(353)(354)(355). Aqp4 deficiency after MPTP exposure further resulted in reduced astroglial proliferation and GDNF protein synthesis (352), elevation of pro-inflammatory cytokines (354), hyperactive microglial and astroglial inflammatory responses in the SN (354) as well as in thymus, spleen and lymph nodes leading to loss of regulatory T-cells (353).…”

“…In four studies by the same group, Aqp4 -/-mice were more prone to MPTPinduced neurotoxicity in acute and chronic models of PD (352)(353)(354)(355). Aqp4 deficiency after MPTP exposure further resulted in reduced astroglial proliferation and GDNF protein synthesis (352), elevation of pro-inflammatory cytokines (354), hyperactive microglial and astroglial inflammatory responses in the SN (354) as well as in thymus, spleen and lymph nodes leading to loss of regulatory T-cells (353). On the other hand, they reported reduced leukocyte activation in Aqp4 -/-, in line with others who found a protective role of Aqp4 deletion (338).…”

“…Several studies on chronic neurodegenerative diseases have linked AQP4 to neuroinflammation (342, 343, 345, 346, 348-350, 364, 365), and MPTP models of PD have shown increased dopaminergic cell death and elevated activation of inflammatory factors in AQP4 deficient mice compared to controls (352)(353)(354)(355). However, the link between AQP4 and PD requires further experimental support in order to demonstrate whether AQP4 plays a beneficial or detrimental role in PD.…”