SENP3 in monocytes/macrophages up-regulates tissue factor and mediates lipopolysaccharide-induced acute lung injury by enhancing JNK phosphorylation |
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Authors: | Xuelian Chen Yimin Lao Jing Yi Jie Yang Shuangjun He Yi Chen |
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Institution: | 1. Emergency Department, South Campus, Renji Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China;2. Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Department of Biochemistry and Molecular Cell Biology, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China |
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Abstract: | The mechanisms underlying coagulation abnormalities in sepsis and septic acute lung injury remain unclear. Tissue factor (TF) initiates coagulation; its production can be regulated by reactive oxygen species (ROS); and monocytes/macrophages produce pathological TF during sepsis. The SUMO2/3 protease SENP3 is redox-sensitive, and SENP3 accumulation in lipopolysaccharide (LPS)-activated macrophages is ROS-dependent. To explore whether SENP3 contributes to LPS-activated coagulation, we used mice with Senp3 conditional knockout (cKO) in myeloid cells. In the model of LPS-induced sepsis, SENP3 cKO mice exhibited less severe acute lung injury than SENP3 fl/fl mice. SENP3 cKO mice exhibited decreased TF expression in monocytes and alveolar macrophages, with consequently compromised coagulation in their blood and lungs. In vitro results showed that ROS-induced SENP3 accumulation contributed to LPS-induced TF expression, which was reduced by JNK inhibitor SP600125. Furthermore, mice injected with LPS following SP600125 (75 mg/kg) treatment showed decreased monocytes/macrophages TF production and alleviated coagulation activation, with less severe lung injury and higher survival rates. Collectively, the results suggest that SENP3 mediates LPS-induced coagulation activation by up-regulating monocyte/macrophage TF production in a JNK-dependent manner. This work provides new insights into ROS regulation of LPS-activated coagulation and reveals a link between SUMOylation and coagulation. |
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Keywords: | coagulation macrophages monocytes reactive oxygen species SENP3 tissue factor |
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