气道上皮细胞（AEC）坏死性凋亡会导致气道过敏性炎症和哮喘恶化。靶向肿瘤坏死因子样配体 1 A (TL1A)/死亡受体 3 (DR3) 轴对哮喘气道炎症具有治疗作用。 TL1A 在介导卵清蛋白 (OVA) 攻击的 AEC 坏死性凋亡中的作用及其对气道炎症的贡献尚不清楚。我们评估了受体相互作用丝氨酸/苏氨酸蛋白激酶 3 (RIPK3) 和混合谱系激酶结构域的表达 -人血清和肺中的类蛋白（MLKL），并通过组织学验证了哮喘和 OVA 诱导小鼠肺组织中 MLKL 磷酸化的水平。接下来，我们使用MLKL敲除小鼠和RIPK3抑制剂GSK872，研究了TL1A通过激活实验性哮喘中的坏死性凋亡对气道炎症和气道屏障功能的影响。在哮喘患者的血清中观察到坏死性凋亡标志蛋白的高表达，并且坏死性凋亡在哮喘小鼠和 OVA 诱导小鼠的气道上皮细胞中均被激活。通过敲除 MLKL 或抑制 RIPK3 来阻止坏死性凋亡，可有效减轻支气管旁炎症、粘液分泌过多和气道胶原纤维积聚，同时还能抑制 2 型炎症因子的分泌。此外，在缺乏半胱天冬酶的情况下，通过在 HBE 细胞中沉默或过度表达 TL1A，TL1A/DR3 可以作为坏死性凋亡的死亡触发因素。此外，重组TL1A蛋白被发现可在体内诱导坏死性凋亡，敲除MLKL可部分逆转TL1A诱导的病理变化。 TL1A 诱导的坏死性凋亡通过降低紧密连接蛋白 zonula occlusionns-1 (ZO-1) 和 occludin 的表达来破坏气道屏障功能，这可能是通过激活 NF-κB 信号通路实现的。TL1A 诱导的气道上皮坏死性凋亡在在促进哮喘气道炎症和屏障功能障碍中发挥重要作用。抑制 TL1A 诱导的坏死性凋亡途径可能是一种有前途的治疗策略。© 2024。作者。

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.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.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.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.© 2024. The Author(s).