Cabral Fatima, Al-Rahem Mustafa, Skaggs John, Thomas Thushara A, Kumar Naresh, Wu Qian, Fadda Paolo, Yu Lianbo, Robinson John M, Kim Jonghan, Pandey Ekta, Sun Xinghui, Jarjour Wael N, Rajaram Murugesan V S, Harris Edward N, Ganesan Latha P
Department of Biochemistry, University of Nebraska, Lincoln, NE 68588, USA.
Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
iScience. 2021 Oct 25;24(11):103337. doi: 10.1016/j.isci.2021.103337. eCollection 2021 Nov 19.
Lipopolysaccharides (LPSs) cause lethal endotoxemia if not rapidly cleared from blood circulation. Liver sinusoidal endothelial cells (LSEC) systemically clear LPS by unknown mechanisms. We discovered that LPS clearance through LSEC involves endocytosis and lysosomal inactivation via Stabilin-1 and 2 (Stab1 and Stab2) but does not involve TLR4. Cytokine production was inversely related to clearance/endocytosis of LPS by LSEC. When exposed to LPS, Stabilin double knockout mice (Stab DK) and Stab1 KO, but not Stab2 KO, showed significantly enhanced systemic inflammatory cytokine production and early death compared with WT mice. Stab1 KO is not significantly different from Stab DK in circulatory LPS clearance, LPS uptake and endocytosis by LSEC, and cytokine production. These data indicate that (1) Stab1 receptor primarily facilitates the proactive clearance of LPS and limits TLR4-mediated inflammation and (2) TLR4 and Stab1 are functionally opposing LPS receptors. These findings suggest that endotoxemia can be controlled by optimizing LPS clearance by Stab1.
如果脂多糖（LPSs）不能从血液循环中迅速清除，就会导致致命的内毒素血症。肝窦内皮细胞（LSEC）通过未知机制系统性清除LPS。我们发现，通过LSEC清除LPS涉及经由稳定素-1和2（Stab1和Stab2）的内吞作用和溶酶体失活，但不涉及Toll样受体4（TLR4）。细胞因子的产生与LSEC对LPS的清除/内吞作用呈负相关。与野生型小鼠相比，当暴露于LPS时，稳定素双敲除小鼠（Stab DK）和Stab1基因敲除小鼠（Stab1 KO），而非Stab2基因敲除小鼠（Stab2 KO），表现出全身炎性细胞因子产生显著增强和早期死亡。在循环LPS清除、LSEC对LPS的摄取和内吞作用以及细胞因子产生方面，Stab1 KO与Stab DK没有显著差异。这些数据表明：（1）Stab1受体主要促进LPS的主动清除并限制TLR4介导的炎症；（2）TLR4和Stab1是功能相反的LPS受体。这些发现提示，内毒素血症可通过优化Stab1介导的LPS清除来控制。
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