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DOI10.1073/pnas.2021862118
Deficiency of the novel high mobility group protein HMGXB4 protects against systemic inflammation-induced endotoxemia in mice
He X.; Dong K.; Shen J.; Hu G.; Liu J.; Kang X.; Wang L.; Atawia R.T.; Osman I.; Caldwell R.W.; Xiang M.; Zhang W.; Zheng Z.; Li L.; Fulton D.J.R.; Deng K.; Xin H.; Zhou J.
发表日期2021
ISSN00278424
卷号118期号:7
英文摘要Sepsis is a major cause of mortality in intensive care units, which results from a severely dysregulated inflammatory response that ultimately leads to organ failure. While antibiotics can help in the early stages, effective strategies to curtail inflammation remain limited. The high mobility group (HMG) proteins are chromosomal proteins with important roles in regulating gene transcription. While HMGB1 has been shown to play a role in sepsis, the role of other family members including HMGXB4 remains unknown. We found that expression of HMGXB4 is strongly induced in response to lipopolysaccharide (LPS)-elicited inflammation in murine peritoneal macrophages. Genetic deletion of Hmgxb4 protected against LPS-induced lung injury and lethality and cecal ligation and puncture (CLP)-induced lethality in mice, and attenuated LPS-induced proinflammatory gene expression in cultured macrophages. By integrating genome-wide transcriptome profiling and a publicly available ChIP-seq dataset, we identified HMGXB4 as a transcriptional activator that regulates the expression of the proinflammatory gene, Nos2 (inducible nitric oxide synthase 2) by binding to its promoter region, leading to NOS2 induction and excessive NO production and tissue damage. Similar to Hmgxb4 ablation in mice, administration of a pharmacological inhibitor of NOS2 robustly decreased LPS-induced pulmonary vascular permeability and lethality in mice. Additionally, we identified the cell adhesion molecule, ICAM1, as a target of HMGXB4 in endothelial cells that facilitates inflammation by promoting monocyte attachment. In summary, our study reveals a critical role of HMGXB4 in exacerbating endotoxemia via transcriptional induction of Nos2 and Icam1 gene expression and thus targeting HMGXB4 may be an effective therapeutic strategy for the treatment of sepsis. © 2021 National Academy of Sciences. All rights reserved.
语种英语
来源期刊Proceedings of the National Academy of Sciences of the United States of America
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/180620
作者单位National Engineering Research Center for Bioengineering Drugs and Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi 330031, China; School of Life Sciences, Nanchang University, Nanchang, Jiangxi 330031, China; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States; Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Department of Respiratory Medicine, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Department of Cardiology, First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, China; Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0910, United States; Vascular Biology Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, United States
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He X.,Dong K.,Shen J.,et al. Deficiency of the novel high mobility group protein HMGXB4 protects against systemic inflammation-induced endotoxemia in mice[J],2021,118(7).
APA He X..,Dong K..,Shen J..,Hu G..,Liu J..,...&Zhou J..(2021).Deficiency of the novel high mobility group protein HMGXB4 protects against systemic inflammation-induced endotoxemia in mice.Proceedings of the National Academy of Sciences of the United States of America,118(7).
MLA He X.,et al."Deficiency of the novel high mobility group protein HMGXB4 protects against systemic inflammation-induced endotoxemia in mice".Proceedings of the National Academy of Sciences of the United States of America 118.7(2021).
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