NLRP3 Inflammasome Deficiency Alleviates Inflammation and Oxidative Stress by Promoting PINK1/Parkin-Mediated Mitophagy in Allergic Rhinitis Mice and Nasal Epithelial Cells

IF 3.7 3区医学 Q2 ALLERGY

Journal of Asthma and Allergy Pub Date : 2024-08-01 DOI:10.2147/jaa.s467774

Hong Ding, Xiaofan Lu, Huimin Wang, Wenming Chen, Bing Niu

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引用次数: 0

Abstract

Purpose: Accumulating evidence indicates that oxidative stress and inflammation are the pathological basis of allergic diseases. Inhibition of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome could ameliorate allergic rhinitis (AR). Here, we explored the effects and mechanisms that underlie NLRP3 inhibition on oxidative stress and inflammation in AR.
Methods: Ovalbumin (OVA)-induced AR murine model was established using wild-type (WT) and NLRP3-deficient mice. HNEpCs were stimulated with interleukin (IL)-13 with MCC950 pretreatment or PTEN-induced putative kinase 1 (PINK1) siRNA. The indicators of oxidative stress, inflammation, apoptosis, and mitophagy were determined both in vivo and in vitro.
Results: NLRP3 knockout (KO) reduced the frequency of nasal rubbing and sneezing, the infiltration of eosinophils, the number of mast cells, and the accumulation of goblet cells in AR mice after OVA stimulation. The NLRP3 KO AR mice exhibited the increased concentrations of OVA-specific immunoglobulin E (OVA-sIgE), IL-1β, IL-4, IL-13, IL-6, TNF-α, and the upregulated level of IFN-γ. NLRP3 KO significantly inhibited oxidative stress, and also markedly decreased apoptosis in the nasal mucosa of AR mice. Moreover, evaluated protein expressions of PINK1, enzyme 3 (E3) ubiquitin ligase PRKN (Parkin), and LC3 II, decreased expression of TOM20, as well as the increased colocalization of LC3 with mitochondria were observed in NLRP3 KO AR mice. In vitro, IL-13 exposure increased the levels of NLRP3 and IL-1β. Inhibition of NLRP3 using MCC950 enhanced PINK1/Parkin-mediated mitophagy but attenuated inflammation, oxidative stress, and apoptosis. However, PINK1 knockdown abrogated mitophagy and also reversed the protective effects of MCC950 on inflammation, oxidative stress, and apoptosis in HNEpCs stimulated with IL-13.
Conclusion: Inhibition of NLRP3 inflammasome exerts the protective effects on AR by facilitating mitophagy regulated by PINK1/Parkin signaling pathway.

Keywords: NLRP3, mitophagy, inflammation, oxidative stress, PINK1/Parkin

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缺乏 NLRP3 炎症小体可通过促进 PINK1/Parkin 介导的丝裂细胞吞噬缓解过敏性鼻炎小鼠和鼻腔上皮细胞的炎症和氧化应激反应

目的：越来越多的证据表明，氧化应激和炎症是过敏性疾病的病理基础。抑制 NOD 样受体家族含 pyrin 结构域的 3（NLRP3）炎性体可以改善过敏性鼻炎（AR）。在此，我们探讨了抑制 NLRP3 对 AR 中氧化应激和炎症的影响及其机制：方法：使用野生型（WT）和 NLRP3 缺陷型小鼠建立了卵清蛋白（OVA）诱导的 AR 小鼠模型。用白细胞介素（IL）-13刺激HNEpCs，并使用MCC950预处理或PTEN诱导的推定激酶1（PINK1）siRNA。在体内和体外测定了氧化应激、炎症、细胞凋亡和有丝分裂的指标：结果：NLRP3基因敲除（KO）减少了OVA刺激后AR小鼠揉鼻和打喷嚏的频率、嗜酸性粒细胞的浸润、肥大细胞的数量以及鹅口疮细胞的堆积。NLRP3 KO AR小鼠的OVA特异性免疫球蛋白E（OVA-sIgE）、IL-1β、IL-4、IL-13、IL-6、TNF-α浓度升高，IFN-γ水平上调。NLRP3 KO 能明显抑制氧化应激，还能显著减少 AR 小鼠鼻黏膜的细胞凋亡。此外，在 NLRP3 KO 的 AR 小鼠中还观察到 PINK1、酶 3（E3）泛素连接酶 PRKN（Parkin）和 LC3 II 蛋白表达量的评估、TOM20 表达量的降低以及 LC3 与线粒体共定位的增加。在体外，IL-13 的暴露增加了 NLRP3 和 IL-1β 的水平。使用 MCC950 抑制 NLRP3 可增强 PINK1/Parkin 介导的有丝分裂，但会减轻炎症、氧化应激和细胞凋亡。然而，PINK1基因敲除会减弱有丝分裂，也会逆转MCC950对受到IL-13刺激的HNEpCs的炎症、氧化应激和细胞凋亡的保护作用：结论：抑制NLRP3炎性体通过促进PINK1/Parkin信号通路调控的有丝分裂对AR具有保护作用：NLRP3、有丝分裂、炎症、氧化应激、PINK1/Parkin

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来源期刊

Journal of Asthma and Allergy Medicine-Immunology and Allergy

CiteScore

5.30

自引率

6.20%

发文量

185

审稿时长

16 weeks

期刊介绍： An international, peer-reviewed journal publishing original research, reports, editorials and commentaries on the following topics: Asthma; Pulmonary physiology; Asthma related clinical health; Clinical immunology and the immunological basis of disease; Pharmacological interventions and new therapies. Although the main focus of the journal will be to publish research and clinical results in humans, preclinical, animal and in vitro studies will be published where they shed light on disease processes and potential new therapies.