The α2 Na+/K+-ATPase isoform mediates LPS-induced neuroinflammation
Jacqueline Alves Leite, Toke Jost Isaksen, Anders Heuck, Cristóforo Scavone, Karin Lykke‐Hartmann
Abstract
Abstract 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 (NFκB) 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 α 2 Na + /K + -ATPase isoform (α 2 +/G301R 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-α , Il-1β , and Il-6 was reduced in the hypothalamus and hippocampus from α 2 +/G301R mice compared to α 2 +/+ littermates. The α 2 +/G301R mice experienced increased expression of the gene encoding an antioxidant enzyme, NRF2, in hippocampal astrocytes. Our findings indicate that α 2 Na + /K + -ATPase haploinsufficiency negatively modulates LPS-induced immune responses, highlighting a rational pharmacological target for reducing LPS-induced inflammation.