Endothelial TLR4 Expression Mediates Vaso-Occlusive Crisis in Sickle Cell Disease.
Endothelial TLR4 Expression Mediates Vaso-Occlusive Crisis in Sickle Cell Disease.
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DOI：
10.3389/fimmu.2020.613278
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发表时间：
2020
影响因子：
7.3
通讯作者：
Vercellotti GM
中科院分区：
文献类型：
--
作者：
Beckman JD;Abdullah F;Chen C;Kirchner R;Rivera-Rodriguez D;Kiser ZM;Nguyen A;Zhang P;Nguyen J;Hebbel RP;Belcher JD;Vercellotti GM
镰状细胞病（SCD）患者红细胞释放的血红素与Toll样受体4（TLR 4）相互作用，激活NF-κB，导致细胞因子和粘附分子的产生，从而促进炎症、疼痛和血管闭塞。在SCD中，TLR 4抑制已显示调节血红素诱导的微血管停滞和肺损伤。我们试图通过开发TLR 4无效转基因镰状小鼠来描述内皮细胞与造血细胞TLR 4在SCD中的作用。我们将一个整体Tlr 4-/-缺陷状态培育成表达正常成人血红蛋白A的Townes-AA小鼠和表达镰状血红蛋白S的Townes-SS小鼠。SS-Tlr 4-/-具有与SS-Tlr 4 +/+小鼠相似的全血细胞计数和血清化学。然而，SS-Tlr 4-/-小鼠在响应血红素、脂多糖（LPS）和缺氧/复氧（H/R）的挑战时，在背部皮肤褶皱腔室中比SS-Tlr 4 +/+小鼠发生显著更少的微血管停滞。为了确定SS-Tlr 4-/-小鼠微血管淤滞减少的潜在机制，我们测量了血红素激发后肝脏中的促炎性NF-κB和粘附分子。与血红素激发的SS-Tlr 4 +/+肝脏相比，SS-Tlr 4-/-肝脏具有较低的粘附分子和细胞因子mRNA、NF-κB磷酸化p65和粘附分子蛋白表达。此外，肺P-选择素和血管性血友病因子免疫染色减少。接下来，为了确定内皮或造血细胞TLR 4信号传导是否对血管闭塞生理学至关重要，我们通过将SS-Tlr 4-/-或SS-Tlr 4 +/+骨髓移植到AA-Tlr 4-/-或AA-Tlr 4 +/+受体中来创建嵌合小鼠。当受体是AA-Tlr 4-/-时，血红素刺激的微血管停滞显著降低。这些数据表明，内皮细胞，而不是造血，TLR 4表达是必要的启动血管闭塞生理SS小鼠。
Heme, released from red blood cells in sickle cell disease (SCD), interacts with toll-like receptor 4 (TLR4) to activate NF-κB leading to the production of cytokines and adhesion molecules which promote inflammation, pain, and vaso-occlusion. In SCD, TLR4 inhibition has been shown to modulate heme-induced microvascular stasis and lung injury. We sought to delineate the role of endothelial verses hematopoietic TLR4 in SCD by developing a TLR4 null transgenic sickle mouse. We bred a global Tlr4-/- deficiency state into Townes-AA mice expressing normal human adult hemoglobin A and Townes-SS mice expressing sickle hemoglobin S. SS-Tlr4-/- had similar complete blood counts and serum chemistries as SS-Tlr4+/+ mice. However, SS-Tlr4-/- mice developed significantly less microvascular stasis in dorsal skin fold chambers than SS-Tlr4+/+ mice in response to challenges with heme, lipopolysaccharide (LPS), and hypoxia/reoxygenation (H/R). To define a potential mechanism for decreased microvascular stasis in SS-Tlr4-/- mice, we measured pro-inflammatory NF-κB and adhesion molecules in livers post-heme challenge. Compared to heme-challenged SS-Tlr4+/+ livers, SS-Tlr4-/- livers had lower adhesion molecule and cytokine mRNAs, NF-κB phospho-p65, and adhesion molecule protein expression. Furthermore, lung P-selectin and von Willebrand factor immunostaining was reduced. Next, to establish if endothelial or hematopoietic cell TLR4 signaling is critical to vaso-occlusive physiology, we created chimeric mice by transplanting SS-Tlr4-/- or SS-Tlr4+/+ bone marrow into AA-Tlr4-/- or AA-Tlr4+/+ recipients. Hemin-stimulated microvascular stasis was significantly decreased when the recipient was AA-Tlr4-/-. These data demonstrate that endothelial, but not hematopoietic, TLR4 expression is necessary to initiate vaso-occlusive physiology in SS mice.
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影响因子：
4.7
作者：
Belcher, John D.;Vineyard, Julie V.;Bruzzone, Carol M.;Chen, Chunsheng;Beckman, Joan D.;Nguyen, Julia;Steer, Clifford J.;Vercellotti, Gregory M.
通讯作者：
Vercellotti, Gregory M.
影响因子：
3.7
作者：
Belcher, John D.;Chen, Chunsheng;Vercellotti, Gregory M.
通讯作者：
Vercellotti, Gregory M.
影响因子：
6.6
作者：
Lei, Jianxun;Paul, Jinny;Gupta, Kalpna
通讯作者：
Gupta, Kalpna
影响因子：
4.4
作者：
Park, HS;Jung, HY;Bae, YS
通讯作者：
Bae, YS
影响因子：
7.3
作者：
Belcher, John D.;Zhang, Ping;Vercellotti, Gregory M.
通讯作者：
Vercellotti, Gregory M.