Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Pediatric Respiratory, Xi'an Children's Hospital, Xi'an, China.
J Cell Physiol. 2023 Dec;238(12):2904-2923. doi: 10.1002/jcp.31141. Epub 2023 Oct 25.
Whether respiratory syncytial virus (RSV) infection in early life may induce orosomucoid 1-like protein 3 (ORMDL3) and lead to NOD-like receptor protein 3 (NLRP3) inflammasome overexpression in asthma, which could be alleviated by the inhibition of HAT p300. First, we explored the relationship between RSV, ORMDL3, and recurrent wheezing in the future through clinical data of infants with RSV-induced bronchiolitis. Then, we used bronchial epithelium transformed with Ad12-SV40 2B (BEAS-2B) and an asthmatic mouse model of repeated RSV infection and OVA sensitization and challenge (rRSV + OVA) in early life to assess the effects of ORMDL3 on NLRP3 inflammasome and that of histone acetylation on ORMDL3 regulation. ORMDL3 overexpression is the independent risk factor of recurrent wheezing in RSV-bronchiolitis follow-up. In BEAS-2B, ORMDL3-induced NLRP3 inflammasome expression. BEAS-2B infected by RSV resulted in overexpression of ORMDL3 and NLRP3 inflammasome and histone hyperacetylation, while ORMDL3-small interfering RNA and C646 interfered could decrease NLRP3 inflammasome. ORMDL3 overexpression in mouse lung increased NLRP3 inflammasome. The expression of ORMDL3 and NLRP3 inflammasome significantly increased, with histone hyperacetylation in the lung in rRSV + OVA mice. p300 and acetylH3 bound to ORMDL3 promoter. In C646 + rRSV + OVA mice, C646 alleviated lung inflammation and overexpression of ORMDL3 and NLRP3 inflammasome. RSV activated ORMDL3 overexpression through histone hyperacetylation and induced NLRP3 inflammasome expression.
无论是呼吸道合胞病毒（RSV）感染早期是否会诱导粘蛋白 1 样蛋白 3（ORMDL3）并导致 NOD 样受体蛋白 3（NLRP3）炎症小体过度表达，而 HAT p300 的抑制可能会缓解这种情况。首先，我们通过 RSV 引起的毛细支气管炎婴儿的临床数据探讨了 RSV、ORMDL3 与未来复发性喘息之间的关系。然后，我们使用 Ad12-SV40 2B 转化的支气管上皮细胞（BEAS-2B）和早期重复 RSV 感染和 OVA 致敏和激发（rRSV + OVA）的哮喘小鼠模型来评估 ORMDL3 对 NLRP3 炎症小体的影响以及组蛋白乙酰化对 ORMDL3 调节的影响。ORMDL3 过表达是 RSV 毛细支气管炎随访中复发性喘息的独立危险因素。在 BEAS-2B 中，ORMDL3 诱导 NLRP3 炎症小体表达。RSV 感染的 BEAS-2B 导致 ORMDL3 和 NLRP3 炎症小体以及组蛋白过度乙酰化表达，而 ORMDL3-siRNA 和 C646 干扰可以降低 NLRP3 炎症小体。小鼠肺中的 ORMDL3 过表达增加了 NLRP3 炎症小体。rRSV + OVA 小鼠肺中的 ORMDL3 和 NLRP3 炎症小体表达明显增加，组蛋白乙酰化增加。p300 和乙酰化 H3 与 ORMDL3 启动子结合。在 C646 + rRSV + OVA 小鼠中，C646 减轻了肺炎症和 ORMDL3 以及 NLRP3 炎症小体的过表达。RSV 通过组蛋白过度乙酰化激活 ORMDL3 过表达，并诱导 NLRP3 炎症小体表达。
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