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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Astrocytes / metabolism
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Cells, Cultured
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Female
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Gene Expression Regulation / drug effects
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Gene Knock-In Techniques
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Heterozygote
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Hippocampus / metabolism
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Hippocampus / pathology*
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Hypothalamus / metabolism
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Hypothalamus / pathology*
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Hypothermia / chemically induced
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Hypothermia / enzymology
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Hypothermia / genetics
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Interleukin-1beta / biosynthesis
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Interleukin-1beta / blood
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Interleukin-1beta / genetics
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Interleukin-6 / biosynthesis
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Interleukin-6 / blood
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Interleukin-6 / genetics
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Lipopolysaccharides / toxicity*
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Macrophages / enzymology
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Mice
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Mice, Inbred C57BL
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Migraine with Aura / enzymology*
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Migraine with Aura / genetics
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Mutation, Missense
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NF-E2-Related Factor 2 / biosynthesis
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NF-E2-Related Factor 2 / genetics
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Sodium-Potassium-Exchanging ATPase / deficiency
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Sodium-Potassium-Exchanging ATPase / genetics
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Sodium-Potassium-Exchanging ATPase / physiology*
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / blood
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Tumor Necrosis Factor-alpha / genetics
Substances
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Interleukin-1beta
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Interleukin-6
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Lipopolysaccharides
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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Tumor Necrosis Factor-alpha
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interleukin-6, mouse
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lipopolysaccharide, Escherichia coli O111 B4
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Atp1a2 protein, mouse
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Sodium-Potassium-Exchanging ATPase
Supplementary concepts
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Hemiplegic migraine, familial type 2