The alpha(2) Na+/K+-ATPase isoform mediates LPS-induced neuroinflammation

Na+/K+-ATPase is a transmembrane ion pump that is essential for the maintenance of ion gradients and regulation of multiple cellular functions. Na+/K+-ATPase has been associated with nuclear factor kappa B (NF kappa B) signalling, a signal associated with lipopolysaccharides (LPSs)-induced immune response in connection with activated Toll-like receptor 4 (TLR4) signalling. However, the contribution of Na+/K+-ATPase to regulating inflammatory responses remains elusive. We report that mice haploinsufficient for the astrocyte-enriched alpha Na-2(+)/K+-ATPase isoform (alpha(+/G301R)(2) mice) have a reduced proinflammatory response to LPS, accompanied by a reduced hypothermic reaction compared to wild type litter mates. Following intraperitoneal injection of LPS, gene expressions of Tnf-alpha, Il-1 beta, and Il-6 was reduced in the hypothalamus and hippocampus from alpha(+/G301R)(2) mice compared to alpha(+/+)(2) littermates. The alpha(+/G301R)(2) mice experienced increased expression of the gene encoding an antioxidant enzyme, NRF2, in hippocampal astrocytes. Our findings indicate that alpha Na-2(+)/K+-ATPase haploinsufficiency negatively modulates LPS-induced immune responses, highlighting a rational pharmacological target for reducing LPS-induced inflammation. (AU)