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Na/K-ATPase suppresses LPS-induced pro-inflammatory signaling through Lyn

Jue Zhang1, Jackie Chang1, Mirza Ahmar Beg1

  • 1Versiti Blood Research Institute, Milwaukee, WI 53226, USA.

Iscience
|September 8, 2022
PubMed

Insights

Sodium-Potassium ATPase (NKA) alpha1 subunit suppresses lipopolysaccharide (LPS)-induced inflammation in macrophages. NKA alpha1 limits inflammatory signaling pathways, reducing pro-inflammatory cytokine production and improving survival in LPS-challenged mice.

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • The Sodium-Potassium ATPase (NKA) functions as both an ion transporter and a signal transducer, regulating Src family kinases (SFK).
  • Signaling NKA is implicated in macrophage foam cell formation and interacts with Toll-like receptor 4 (TLR4).
  • The role of NKA in lipopolysaccharide (LPS)-induced signaling and metabolic shifts in macrophages is not fully understood.

Purpose of the Study:

  • To investigate the role of NKA alpha1 in LPS-induced signaling pathways and metabolic reprogramming in macrophages.
  • To determine the impact of NKA alpha1 deficiency on LPS-induced inflammation and macrophage responses.
  • To elucidate the molecular mechanisms by which NKA alpha1 regulates LPS-induced signaling.

Main Methods:

  • Utilized peritoneal macrophages from NKA alpha1 haploinsufficient (NKA α1+/-) mice.
  • Administered LPS to mice and assessed inflammatory responses, lung injury, and survival rates.
  • Analyzed NF-κB pathway activation, reactive oxygen species (ROS) signaling, pro-inflammatory cytokine production, and metabolic shifts.
  • Investigated the interaction of NKA α1 with TLR4 and Lyn kinase using co-immunoprecipitation.

Main Results:

  • NKA α1 haploinsufficiency exacerbated LPS-stimulated NF-κB pathway activation, ROS signaling, and pro-inflammatory cytokine release.
  • LPS challenge led to more severe lung inflammation, injury, and reduced survival in NKA α1+/- mice.
  • LPS induced a greater metabolic switch from oxidative phosphorylation to glycolysis in NKA α1+/- macrophages.
  • NKA α1 was found to interact with TLR4 and Lyn, with NKA α1 attenuating Lyn activation by LPS.

Conclusions:

  • NKA α1 plays a critical suppressive role in LPS-induced pro-inflammatory signaling in macrophages.
  • NKA α1 acts by inhibiting Lyn activation within the TLR4 signaling complex, thereby restricting downstream ROS and NF-κB activation.
  • These findings highlight NKA α1 as a potential therapeutic target for inflammatory conditions driven by LPS exposure.
Keywords:
Biological sciencesimmunologymolecular biology

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