Na/K-ATPase suppresses LPS-induced pro-inflammatory signaling through Lyn
Jue Zhang,
Jackie Chang,
Mirza Ahmar Beg,
Wenxin Huang,
Yiqiong Zhao,
Wen Dai,
Xiaopeng Wu,
Weiguo Cui,
Sneha S. Pillai,
Hari Vishal Lakhani,
Komal Sodhi,
Joseph I. Shapiro,
Daisy Sahoo,
Ze Zheng,
Roy L. Silverstein,
Yiliang Chen
Affiliations
Jue Zhang
Versiti Blood Research Institute, Milwaukee, WI 53226, USA
Jackie Chang
Versiti Blood Research Institute, Milwaukee, WI 53226, USA
Mirza Ahmar Beg
Versiti Blood Research Institute, Milwaukee, WI 53226, USA
Wenxin Huang
Versiti Blood Research Institute, Milwaukee, WI 53226, USA
Yiqiong Zhao
Versiti Blood Research Institute, Milwaukee, WI 53226, USA
Wen Dai
Versiti Blood Research Institute, Milwaukee, WI 53226, USA
Xiaopeng Wu
Versiti Blood Research Institute, Milwaukee, WI 53226, USA
Weiguo Cui
Versiti Blood Research Institute, Milwaukee, WI 53226, USA; Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Sneha S. Pillai
Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
Hari Vishal Lakhani
Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
Komal Sodhi
Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
Joseph I. Shapiro
Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25701, USA
Daisy Sahoo
Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Ze Zheng
Versiti Blood Research Institute, Milwaukee, WI 53226, USA; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Roy L. Silverstein
Versiti Blood Research Institute, Milwaukee, WI 53226, USA; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Yiliang Chen
Versiti Blood Research Institute, Milwaukee, WI 53226, USA; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Corresponding author
Summary: Na/K-ATPase (NKA), besides its ion transporter function, is a signal transducer by regulating Src family kinases (SFK). The signaling NKA contributes to oxidized LDL-induced macrophage foam cell formation and interacts with TLR4. However, its role in lipopolysaccharides (LPS)-induced signaling and glycolytic switch in macrophages remains unclear. Using peritoneal macrophages from NKA α1 haploinsufficient mice (NKA α1+/−), we found that NKA α1 haploinsufficiency led to enhanced LPS-stimulated NF-κB pathway, ROS signaling, and pro-inflammatory cytokines. Intraperitoneal injection of LPS resulted in more severe lung inflammation and injury with lower survival rate in NKA α1+/− mice. Additionally, LPS induced a higher extent of the metabolic switch from oxidative phosphorylation to glycolysis. Mechanistically, NKA α1 interacted with TLR4 and Lyn. The presence of NKA α1 in this complex attenuated Lyn activation by LPS, which subsequently restricted the downstream ROS and NF-κB signaling. In conclusion, we demonstrated that NKA α1 suppresses LPS-induced macrophage pro-inflammatory signaling through Lyn.