PDF(Pubmed)
Abstract：
BACKGROUND: Airway epithelial cell (AEC) necroptosis contributes to airway allergic inflammation and asthma exacerbation. Targeting the tumor necrosis factor-like ligand 1 A (TL1A)/death receptor 3 (DR3) axis has a therapeutic effect on asthmatic airway inflammation. The role of TL1A in mediating necroptosis of AECs challenged with ovalbumin (OVA) and its contribution to airway inflammation remains unclear.
METHODS: We evaluated the expression of the receptor-interacting serine/threonine-protein kinase 3(RIPK3) and the mixed lineage kinase domain-like protein (MLKL) in human serum and lung, and histologically verified the level of MLKL phosphorylation in lung tissue from asthmatics and OVA-induced mice. Next, using MLKL knockout mice and the RIPK3 inhibitor GSK872, we investigated the effects of TL1A on airway inflammation and airway barrier function through the activation of necroptosis in experimental asthma.
RESULTS: High expression of necroptosis marker proteins was observed in the serum of asthmatics, and necroptosis was activated in the airway epithelium of both asthmatics and OVA-induced mice. Blocking necroptosis through MLKL knockout or RIPK3 inhibition effectively attenuated parabronchial inflammation, mucus hypersecretion, and airway collagen fiber accumulation, while also suppressing type 2 inflammatory factors secretion. In addition, TL1A/ DR3 was shown to act as a death trigger for necroptosis in the absence of caspases by silencing or overexpressing TL1A in HBE cells. Furthermore, the recombinant TL1A protein was found to induce necroptosis in vivo, and knockout of MLKL partially reversed the pathological changes induced by TL1A. The necroptosis induced by TL1A disrupted the airway barrier function by decreasing the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin, possibly through the activation of the NF-κB signaling pathway.
CONCLUSIONS: TL1A-induced airway epithelial necroptosis plays a significant role in promoting airway inflammation and barrier dysfunction in asthma. Inhibition of the TL1A-induced necroptosis pathway could be a promising therapeutic strategy.
METHODS: We evaluated the expression of the receptor-interacting serine/threonine-protein kinase 3(RIPK3) and the mixed lineage kinase domain-like protein (MLKL) in human serum and lung, and histologically verified the level of MLKL phosphorylation in lung tissue from asthmatics and OVA-induced mice. Next, using MLKL knockout mice and the RIPK3 inhibitor GSK872, we investigated the effects of TL1A on airway inflammation and airway barrier function through the activation of necroptosis in experimental asthma.
RESULTS: High expression of necroptosis marker proteins was observed in the serum of asthmatics, and necroptosis was activated in the airway epithelium of both asthmatics and OVA-induced mice. Blocking necroptosis through MLKL knockout or RIPK3 inhibition effectively attenuated parabronchial inflammation, mucus hypersecretion, and airway collagen fiber accumulation, while also suppressing type 2 inflammatory factors secretion. In addition, TL1A/ DR3 was shown to act as a death trigger for necroptosis in the absence of caspases by silencing or overexpressing TL1A in HBE cells. Furthermore, the recombinant TL1A protein was found to induce necroptosis in vivo, and knockout of MLKL partially reversed the pathological changes induced by TL1A. The necroptosis induced by TL1A disrupted the airway barrier function by decreasing the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin, possibly through the activation of the NF-κB signaling pathway.
CONCLUSIONS: TL1A-induced airway epithelial necroptosis plays a significant role in promoting airway inflammation and barrier dysfunction in asthma. Inhibition of the TL1A-induced necroptosis pathway could be a promising therapeutic strategy.
摘要：
背景：气道上皮细胞（AEC）坏死导致气道过敏性炎症和哮喘加重。靶向肿瘤坏死因子样配体1A(TL1A)/死亡受体3(DR3)轴对哮喘气道炎症有治疗作用。TL1A在介导卵清蛋白（OVA）攻击的AECs坏死中的作用及其对气道炎症的贡献尚不清楚。
方法：我们评估了受体相互作用的丝氨酸/苏氨酸蛋白激酶3（RIPK3）和混合谱系激酶结构域样蛋白（MLKL）在人血清和肺中的表达，并在组织学上验证了哮喘和OVA诱导的小鼠肺组织中MLKL磷酸化的水平。接下来,使用MLKL基因敲除小鼠和RIPK3抑制剂GSK872,我们研究了TL1A通过激活实验性哮喘的坏死性凋亡对气道炎症和气道屏障功能的影响。
结果：在哮喘患者血清中观察到坏死标记蛋白的高表达，哮喘和OVA诱导的小鼠的气道上皮都激活了坏死。通过MLKL敲除或RIPK3抑制阻断坏死性凋亡可有效减轻支气管旁炎症，粘液分泌过多,和气道胶原纤维的积累，同时还抑制2型炎症因子的分泌。此外,通过在HBE细胞中沉默或过表达TL1A,TL1A/DR3显示在不存在胱天蛋白酶的情况下充当坏死的死亡触发因素。此外，发现重组TL1A蛋白在体内诱导坏死，MLKL的敲除部分逆转了TL1A诱导的病理变化。TL1A诱导的坏死通过降低紧密连接蛋白小带闭塞蛋白1（ZO-1）和闭塞蛋白的表达来破坏气道屏障功能，可能通过激活NF-κB信号通路。
结论：TL1A诱导的气道上皮坏死在促进哮喘气道炎症和屏障功能障碍中起重要作用。抑制TL1A诱导的坏死途径可能是一种有前途的治疗策略。
方法：我们评估了受体相互作用的丝氨酸/苏氨酸蛋白激酶3（RIPK3）和混合谱系激酶结构域样蛋白（MLKL）在人血清和肺中的表达，并在组织学上验证了哮喘和OVA诱导的小鼠肺组织中MLKL磷酸化的水平。接下来,使用MLKL基因敲除小鼠和RIPK3抑制剂GSK872,我们研究了TL1A通过激活实验性哮喘的坏死性凋亡对气道炎症和气道屏障功能的影响。
结果：在哮喘患者血清中观察到坏死标记蛋白的高表达，哮喘和OVA诱导的小鼠的气道上皮都激活了坏死。通过MLKL敲除或RIPK3抑制阻断坏死性凋亡可有效减轻支气管旁炎症，粘液分泌过多,和气道胶原纤维的积累，同时还抑制2型炎症因子的分泌。此外,通过在HBE细胞中沉默或过表达TL1A,TL1A/DR3显示在不存在胱天蛋白酶的情况下充当坏死的死亡触发因素。此外，发现重组TL1A蛋白在体内诱导坏死，MLKL的敲除部分逆转了TL1A诱导的病理变化。TL1A诱导的坏死通过降低紧密连接蛋白小带闭塞蛋白1（ZO-1）和闭塞蛋白的表达来破坏气道屏障功能，可能通过激活NF-κB信号通路。
结论：TL1A诱导的气道上皮坏死在促进哮喘气道炎症和屏障功能障碍中起重要作用。抑制TL1A诱导的坏死途径可能是一种有前途的治疗策略。
