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 α2Na+/K+-ATPase isoform (α2+/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 α2+/G301R mice compared to α2+/+ littermates. The α2+/G301R mice experienced increased expression of the gene encoding an antioxidant enzyme, NRF2, in hippocampal astrocytes. Our findings indicate that α2Na+/K+-ATPase haploinsufficiency negatively modulates LPS-induced immune responses, highlighting a rational pharmacological target for reducing LPS-induced inflammation.
Highlights
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
We observed a reduction in Tnf transcription in hippocampal astrocytes from α2+/G301R mice after the challenge with LPS (Fig. 5d), supporting the results that astrocytes in these areas of the brain are differentially affected by α2 haploinsufficiency. These results show that the lack of the tumour necrosis factor-α (TNF-α) response in the α2+/G301R mice is partly due to the lack of α2Na+/K+-ATPase expressing astrocytes that can sense LPS through induced Tlr[4] expression
Activation of the immune system by LPS leads to production and release of proinflammatory cytokines such as TNF-α, IL-1β that act on the periphery and central nervous system leading to symptoms such as immobility and/or lethargy, piloerection, drowsiness, and ptosis, this symptoms are knowing as sickness b ehavior[61], which may be accompanied by physiological changes such as hypothermia
Summary
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. It is important to highlight the isoforms of Na+/K+-ATPase are located in distinct regions in the plasma membrane of cells[14], which confer different physiological functions in the regulation of intracellular N a+ and Ca2+. Within this context, studies with different cell t ypes[15], such as aortic smooth muscle and astrocytes, have demonstrated the importance of the a 2Na+/K+-ATPase isoform in the maintenance of intracellular N a+, as well as the interaction of the α2 isoform with the Na+/Ca2+ exchanger for the reaction of intracellular Ca2+ levels and their signaling[16,17]. Functions, the α2 isoform is functional primarily in astrocytes and developing neurons and the α3 isoform is restricted to n eurons[19,20]
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