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

Author(s)

Leite, J. A. ^{[1, 2, 3]} ; Isaksen, T. J. ^[1] ; Heuck, A. ^[1] ; Scavone, C. ^[2] ; Lykke-Hartmann, K. ^{[1, 4, 5]}

Affiliation

^[1] Aarhus Univ, Dept Biomed, Aarhus - Denmark

^[2] Univ Sao Paulo, Inst Ciencias Biomed, Dept Pharmacol, Sao Paulo, SP - Brazil

^[3] Univ Fed Goias, Inst Ciencias Biol, Dept Pharmacol, Goiania, Go - Brazil

^[4] Aarhus Univ, Dept Clin Med, DK-8000 Aarhus C - Denmark

^[5] Aarhus Univ Hosp, Dept Clin Genet, DK-8200 Aarhus N - Denmark

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 10, n. 1 AUG 25 2020.
• Web of Science Citations: 0

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 (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)

• FAPESP's process: 16/07427-8 - Aging and neuroprotection: effects of Klotho protein in energetic metabolism, Na,K-ATPase signaling and adaptative response in central nervous system
• Grantee: Cristoforo Scavone
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/21343-1 - Effects of LPS analysed in mouse models harboring disease-mutations in the ±2- or ±3Na+/K+-ATPase, respectively
• Grantee: Jacqueline Alves Leite
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 14/10171-0 - Study of the molecular effect of OUA treatment on the HPA axis of rats exposed to chronic unpredictable stress
• Grantee: Jacqueline Alves Leite
• Support Opportunities: Scholarships in Brazil - Doctorate