• Yijie Zheng, Seonjin Lee, Xiaoliang Liang, Shuquan Wei, Hyung-Geun Moon, and Yang Jin.
• Division of Pulmonary and Critical Care, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
• J. Infect. Dis. 2013 Dec 1;208(11):1803-12.

BackgroundSepsis and sepsis-associated organ failure are devastating conditions. Understanding the detailed cellular/molecular mechanisms involved in sepsis should lead to the identification of novel therapeutic targets.MethodsCecal ligation and puncture (CLP) was used as a polymicrobial sepsis model in vivo to determine mortality and end-organ damage. Macrophages were adopted as the cellular model in vitro for mechanistic studies.ResultsPTRF+/- mice survived longer and suffered less organ damage after CLP. Reductions in nitric oxide (NO) and iNOS biosynthesis were observed in plasma, macrophages, and vital organs in the PTRF+/- mice. Using an acute sepsis model after CLP, we found that iNOS-/- mice had a comparable level of survival as the PTRF+/- mice. Similarly, polymerase I transcript release factor (PTRF) deficiency resulted in decreased iNOS and NO/ROS production in macrophages in vitro. Mechanistically, lipopolysaccharide (LPS) enhanced the co-localization and interaction between PTRF and TLR4 in lipid rafts. Deletion of PTRF blocked formation of the TLR4/Myd88 complex after LPS. Consistent with this, lack of PTRF impaired the TLR4 signaling, as shown by the decreased p-JNK, p-ERK, and p-p38, which are upstream factors involved in iNOS transcription.ConclusionPTRF is a crucial regulator of TLR4 signaling in the development of sepsis.

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