Tumor necrosis factor superfamily 14 (LIGHT) controls thymic stromal lymphopoietin to drive pulmonary fibrosis.
Tumor necrosis factor superfamily 14 (LIGHT) controls thymic stromal lymphopoietin to drive pulmonary fibrosis.
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DOI：
10.1016/j.jaci.2014.12.1936
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Croft M
中科院分区：
文献类型：
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作者：
Herro R;Da Silva Antunes R;Aguilera AR;Tamada K;Croft M
肺纤维化的特征在于肺中胶原蛋白和α-平滑肌肌动蛋白（aSMA）的过度积聚。促进这些表型的关键分子具有临床意义。在哮喘和特发性肺纤维化患者中发现TSLP处于高水平，并且TSLP已被认为是肺纤维化疾病的主要驱动因素。我们询问TNFSF 14（aka LIGHT）是否控制TSLP产生以引发纤维化。在LIGHT缺陷的小鼠中评估TSLP的表达和博莱霉素诱导的肺纤维化的起始。还测定了向未处理的小鼠气管内给予重组LIGHT促进TSLP和纤维化的能力。LIGHT的基因缺失消除了博莱霉素驱动的肺TSLP表达，伴随着肺胶原蛋白和aSMA的积累几乎完全缺失。此外，在没有其他炎症刺激的情况下，体内施用重组LIGHT诱导TSLP的肺表达，并且以TSLP依赖性方式显著再现博来霉素驱动的疾病的主要特征。阻断LIGHT与其受体HVEM和LTβR的结合，可抑制肺纤维化的临床症状，相应地，在人支气管上皮细胞（TSLP的主要来源）上发现了这两种受体。此外，LIGHT直接在人支气管上皮细胞中诱导TSLP，并在体内与IL-13和TGF-β协同作用以促进肺中的TSLP并驱动纤维化。这些结果表明，LIGHT是一种促纤维化细胞因子，可能是肺纤维化疾病发生和发展过程中TSLP产生的关键驱动因素。
Pulmonary fibrosis is characterized by excessive accumulation of collagen and α-smooth muscle actin (aSMA) in the lung. The key molecules that promote these phenotypes are of clinical interest. TSLP has been found at high levels in patients with asthma and idiopathic pulmonary fibrosis, and TSLP has been proposed as a primary driver of lung fibrotic disease. We asked whether TNFSF14 (aka LIGHT) controls TSLP production to initiate fibrosis. Expression of TSLP and initiation of pulmonary fibrosis induced by bleomycin were assessed in mice deficient in LIGHT. The ability of recombinant LIGHT, given intratracheally to naïve mice, to promote TSLP and fibrosis was also determined. Genetic deletion of LIGHT abolished lung TSLP expression driven by bleomycin, accompanied by near-complete absence of accumulation of lung collagen and aSMA. Furthermore, recombinant LIGHT administered in vivo induced lung expression of TSLP in the absence of other inflammatory stimuli, and strikingly reproduced the primary features of bleomycin-driven disease in a TSLP-dependent manner. Blockade of LIGHT binding to either of its receptors, HVEM and LTβR, inhibited clinical symptoms of pulmonary fibrosis, and correspondingly both receptors were found on human bronchial epithelial cells, a primary source of TSLP. Moreover, LIGHT induced TSLP directly in human bronchial epithelial cells and synergized with IL-13 and TGF-β in vivo to promote TSLP in the lungs and drive fibrosis. These results show that LIGHT is a profibrogenic cytokine that may be a key driver of TSLP production during the initiation and development of lung fibrotic disease.