Deficiency of the novel high mobility group protein HMGXB4 protects against systemic inflammation-induced endotoxemia in mice
Xiangqin He, Kunzhe Dong, Jian Shen, Guoqing Hu, Jinhua Liu, Xiuhua Kang, Liang Wang, Reem T. Atawia, Islam Osman, Robert W. Caldwell, Meixiang Xiang, Wei Zhang, Zeqi Zheng, Liwu Li, David Fulton, Keyu Deng, Hongbo Xin, Jiliang Zhou
Abstract
Significance Sepsis is a life-threatening disorder triggered by systemic inflammation. Currently, there are no effective therapies targeting immune dysfunction in sepsis. The high mobility group (HMG) proteins are chromosomal proteins with important roles in regulating gene transcription. We found that the HMGXB4 protein is strongly induced by lipopolysaccharide. Knockout of Hmgxb4 protected against endotoxemia-induced lethality in mice. Mechanistically, HMGXB4 promoted expression of the proinflammatory genes, Nos2 and Icam1 . Increased NOS2 expression promotes excessive NO that causes tissue damage, and increased ICAM1 encourages monocyte attachment to endothelial cells. Our study reveals a critical role of HMGXB4 in endotoxemia via excessive NO production and increased monocyte adhesion which advances the concept that strategies targeting HMGXB4 may be effective for the treatment of sepsis.