@article{ad0259784c4f45c09502deacc9cc1bf1,
title = "Na/K-ATPase suppresses LPS-induced pro-inflammatory signaling through Lyn",
abstract = "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.",
keywords = "Biological sciences, immunology, molecular biology",
author = "Jue Zhang and Jackie Chang and Beg, {Mirza Ahmar} and Wenxin Huang and Yiqiong Zhao and Wen Dai and Xiaopeng Wu and Weiguo Cui and Pillai, {Sneha S.} and Lakhani, {Hari Vishal} and Komal Sodhi and Shapiro, {Joseph I.} and Daisy Sahoo and Ze Zheng and Silverstein, {Roy L.} and Yiliang Chen",
note = "Funding Information: We would like to thank Dr. Michael P. Murphy (University of Cambridge) and Richard C. Hartley (University of Glasgow) for providing MitoNeoD, Dr. Kathryn J. Moore (New York University) for providing the THP-1 Dual cell line. We thank Dr. Marie Schulte from the Versiti Blood Research Institute, Northwestern Mutual Microscopy Core for the technical support of FV1000 Olympus Laser Scanning Confocal and Multiphoton Microscope. In addition, we thank Liang Wu for helping with the high-resolution figure preparation. This work is supported by National Institutes of Health grants R01 HL153397 (to R.L. Silverstein, W. Cui, and Y. Chen), 1R15HL150721 (to K.Sodhi.), 5R01HL058012 (to D.Sahoo.), the BrickStreet Foundation (to J.I.Shapiro.), the Huntington Foundation (to J.I.Shapiro.) and American Heart Association Scientist Development Grant 17SDG661117 (to Y. Chen), Career Development Award 19CDA34660043 (to Z. Zheng) and MCW New Faculty Startup Fund (to Y. Chen and Z. Zheng). Graphical abstract was created with BioRender.com. Y.C. and J.Z. conceived the study, designed and performed the experiments, analyzed the data, and wrote the article. J.C. performed the FACS experiments. M.A.B. W.D. and Y.Z. analyzed the data. W.H. conducted the qRT-PCR experiments on peritoneal macrophages. X.W. carried out spleen studies. S.S.P. H.V.L. and K.S. carried out histopathological experiments and qRT-PCR in lung tissues. W.C. Z.Z. J.S. D.S. and R.L.S. provided valuable ideas and suggestions and edited the article. The authors have declared that no conflict of interest exists. We worked to ensure sex balance in the selection of non-human subjects. While citing references scientifically relevant for this work, we also actively worked to promote gender balance in our reference list. Funding Information: We would like to thank Dr. Michael P. Murphy (University of Cambridge) and Richard C. Hartley (University of Glasgow) for providing MitoNeoD, Dr. Kathryn J. Moore (New York University) for providing the THP-1 Dual cell line. We thank Dr. Marie Schulte from the Versiti Blood Research Institute, Northwestern Mutual Microscopy Core for the technical support of FV1000 Olympus Laser Scanning Confocal and Multiphoton Microscope. In addition, we thank Liang Wu for helping with the high-resolution figure preparation. This work is supported by National Institutes of Health grants R01 HL153397 (to R.L. Silverstein, W. Cui, and Y. Chen), 1R15HL150721 (to K.Sodhi.), 5R01HL058012 (to D.Sahoo.), the BrickStreet Foundation (to J.I.Shapiro.), the Huntington Foundation (to J.I.Shapiro.) and American Heart Association Scientist Development Grant 17SDG661117 (to Y. Chen), Career Development Award 19CDA34660043 (to Z. Zheng) and MCW New Faculty Startup Fund (to Y. Chen and Z. Zheng). Graphical abstract was created with BioRender.com . Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = sep,
day = "16",
doi = "10.1016/j.isci.2022.104963",
language = "English (US)",
volume = "25",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "9",
}