Crosstalk Between Transforming Growth Factor Beta-2 and Toll-Like Receptor 4 in the Trabecular Meshwork.
Crosstalk Between Transforming Growth Factor Beta-2 and Toll-Like Receptor 4 in the Trabecular Meshwork.
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DOI：
10.1167/iovs.16-21331
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发表时间：
2017-03-01
影响因子：
4.4
通讯作者：
McDowell CM
中科院分区：
文献类型：
--
作者：
Hernandez H;Medina-Ortiz WE;Luan T;Clark AF;McDowell CM
小梁网络参与房水流出和眼压调节。转化生长因子β-2信号通路对TM细胞外基质的调节已被广泛研究。最近的证据表明，Toll样受体4(TLR4)参与调节ECM和肝、肾、肺和皮肤的纤维化形成。在此，我们研究了转化生长因子β2-TLR4信号串扰在TM和高眼压中细胞外基质调节中的作用。用人供体眼、原代培养的人TM细胞和解剖的小鼠TM环的横截面来确定TM中TLR4的表达。培养的小梁细胞用转化生长因子β2(5 ng/mL)、TLR4抑制剂(TAK242，15μM)和TLR4配体(细胞纤维连接蛋白亚型-EDA)处理。A/J(n=13)、AKR/J(n=7)、BALBC/J(n=8)、C3H/HeJ(n=20)和C3H/HeOuJ(n=10)小鼠玻璃体腔注射腺病毒5型(Ad5)，其中1只眼注射人转化生长因子β2c226s/c228s，对侧眼作为对照。使用TonoLab眼压计进行有意识的眼压测量。Toll样受体4在人和小鼠的TM中表达。在转化生长因子β-2存在的情况下，抑制TLR4信号转导会减少纤维连接蛋白的表达。在转化生长因子β-2存在的情况下，CFN-EDA激活TLR4进一步增加纤维连接蛋白、层粘连蛋白和胶原-1的表达，TLR4信号抑制可阻断这一作用。Ad5.hTGFβ2c226s/c228s可诱导野生型小鼠高眼压，但对突变型(C3H/HeJ)小鼠无明显影响。这些研究证实转化生长因子β2-TLR4串扰是参与TM和高眼压中细胞外基质调节的新途径。这些数据进一步解释了青光眼TM损害发生的复杂机制。
The trabecular meshwork (TM) is involved in the outflow of aqueous humor and intraocular pressure (IOP) regulation. Regulation of the extracellular matrix (ECM) by TGFβ2 signaling pathways in the TM has been extensively studied. Recent evidence has implicated toll-like receptor 4 (TLR4) in the regulation of ECM and fibrogenesis in liver, kidney, lung, and skin. Here, we investigated the role of TGFβ2–TLR4 signaling crosstalk in the regulation of the ECM in the TM and ocular hypertension. Cross sections of human donor eyes, primary human TM cells in culture, and dissected mouse TM rings were used to determine Tlr4 expression in the TM. Trabecular meshwork cells in culture were treated with TGFβ2 (5 ng/mL), TLR4 inhibitor (TAK-242, 15 μM), and a TLR4 ligand (cellular fibronectin isoform [cFN]-EDA). A/J (n = 13), AKR/J (n = 7), BALBc/J (n = 8), C3H/HeJ (n = 20), and C3H/HeOuJ (n = 10) mice were injected intravitreally with adenovirus 5 (Ad5).hTGFβ2c226s/c228s in one eye, with the uninjected contralateral eye serving as a control. Conscious IOP measurements were taken using a TonoLab rebound tonometer. Toll-like receptor 4 is expressed in the human and mouse TM. Inhibition of TLR4 signaling in the presence of TGFβ2 decreases fibronectin expression. Activation of TLR4 by cFN-EDA in the presence of TGFβ2 further increases fibronectin, laminin, and collagen-1 expression, and TLR4 signaling inhibition blocks this effect. Ad5.hTGFβ2c226s/c228s induces ocular hypertension in wild-type mice but has no effect in Tlr4 mutant (C3H/HeJ) mice. These studies identify TGFβ2–TLR4 crosstalk as a novel pathway involved in ECM regulation in the TM and ocular hypertension. These data further explain the complex mechanisms involved in the development of glaucomatous TM damage.