重度和非重度哮喘中炎症小体反应的特征和抑制
2024/01/26
摘要
背景：气道中NLRP3炎症小体介导的IL-1β反应的增加可能是严重中性粒细胞性哮喘的基础。然而，增加的炎症小体活化是否仅存在于严重哮喘，是否是所有炎症型严重哮喘中免疫细胞的普遍特征，以及在患者中是否可以通过治疗性抑制炎症小体活化，这些问题仍然不清楚。
目的：研究哮喘患者免疫细胞中炎症小体介导的IL-1β反应的激活和抑制。
方法：从非严重哮喘（n = 59）和严重哮喘患者（n = 36 稳定期，n = 17 恶化期）以及健康受试者（n = 39）中分离外周血单个核细胞（PBMCs）。使用尼日利亚菌素或脂多糖（LPS）单独或组合（LPS + 尼日利亚菌素）刺激PBMCs，有无NLRP3抑制剂MCC950，并评估对IL-1β释放的影响。
结果：与健康受试者相比，非严重或严重哮喘患者的PBMCs对尼日利亚菌素的IL-1β反应更强。与非严重哮喘患者相比，严重哮喘患者的PBMCs对LPS + 尼日利亚菌素的IL-1β释放更多。与稳定期相比，严重哮喘患者的PBMCs在恶化期对炎症小体诱导的IL-1β释放并未增加。炎症小体诱导的IL-1β释放在男性和女性、或肥胖和非肥胖患者之间没有差异，并且与气道嗜酸性粒细胞和中性粒细胞数量相关。MCC950有效地抑制了所有组中PBMCs对LPS、尼日利亚菌素和LPS + 尼日利亚菌素诱导的IL-1β释放。
结论：炎症小体的启动和/或活化能力在严重和非严重哮喘患者的系统免疫细胞中普遍增加，强调了通过炎症小体抑制作为不同亚型疾病的通用治疗方法。
Horvat JC, Kim RY, Weaver N, Augood C, Brown AC, Donovan C, Dupre P, Gunawardhana L, Mayall JR, Hansbro NG, Robertson AAB, O'Neill LAJ, Cooper MA, Holliday EG, Hansbro PM, Gibson PG.
Abstract
Background:Increased airway NLRP3 inflammasome-mediated IL-1β responses may underpin severe neutrophilic asthma. However, whether increased inflammasome activation is unique to severe asthma, is a common feature of immune cells in all inflammatory types of severe asthma, and whether inflammasome activation can be therapeutically targeted in patients, remains unknown.
Objective:To investigate the activation and inhibition of inflammasome-mediated IL-1β responses in immune cells from patients with asthma.
Methods:Peripheral blood mononuclear cells (PBMCs) were isolated from patients with non-severe (n = 59) and severe (n = 36 stable, n = 17 exacerbating) asthma and healthy subjects (n = 39). PBMCs were stimulated with nigericin or lipopolysaccharide (LPS) alone, or in combination (LPS + nigericin), with or without the NLRP3 inhibitor MCC950, and the effects on IL-1β release were assessed.
Results:PBMCs from patients with non-severe or severe asthma produced more IL-1β in response to nigericin than those from healthy subjects. PBMCs from patients with severe asthma released more IL-1β in response to LPS + nigericin than those from non-severe asthma. Inflammasome-induced IL-1β release from PBMCs from patients with severe asthma was not increased during exacerbation compared to when stable. Inflammasome-induced IL-1β release was not different between male and female, or obese and non-obese patients and correlated with eosinophil and neutrophil numbers in the airways. MCC950 effectively suppressed LPS-, nigericin-, and LPS + nigericin-induced IL-1β release from PBMCs from all groups.
Conclusion:An increased ability for inflammasome priming and/or activation is a common feature of systemic immune cells in both severe and non-severe asthma, highlighting inflammasome inhibition as a universal therapy for different subtypes of disease.
背景：气道中NLRP3炎症小体介导的IL-1β反应的增加可能是严重中性粒细胞性哮喘的基础。然而，增加的炎症小体活化是否仅存在于严重哮喘，是否是所有炎症型严重哮喘中免疫细胞的普遍特征，以及在患者中是否可以通过治疗性抑制炎症小体活化，这些问题仍然不清楚。
目的：研究哮喘患者免疫细胞中炎症小体介导的IL-1β反应的激活和抑制。
方法：从非严重哮喘（n = 59）和严重哮喘患者（n = 36 稳定期，n = 17 恶化期）以及健康受试者（n = 39）中分离外周血单个核细胞（PBMCs）。使用尼日利亚菌素或脂多糖（LPS）单独或组合（LPS + 尼日利亚菌素）刺激PBMCs，有无NLRP3抑制剂MCC950，并评估对IL-1β释放的影响。
结果：与健康受试者相比，非严重或严重哮喘患者的PBMCs对尼日利亚菌素的IL-1β反应更强。与非严重哮喘患者相比，严重哮喘患者的PBMCs对LPS + 尼日利亚菌素的IL-1β释放更多。与稳定期相比，严重哮喘患者的PBMCs在恶化期对炎症小体诱导的IL-1β释放并未增加。炎症小体诱导的IL-1β释放在男性和女性、或肥胖和非肥胖患者之间没有差异，并且与气道嗜酸性粒细胞和中性粒细胞数量相关。MCC950有效地抑制了所有组中PBMCs对LPS、尼日利亚菌素和LPS + 尼日利亚菌素诱导的IL-1β释放。
结论：炎症小体的启动和/或活化能力在严重和非严重哮喘患者的系统免疫细胞中普遍增加，强调了通过炎症小体抑制作为不同亚型疾病的通用治疗方法。
(中日友好医院呼吸与危重症医学科 沈焜路 摘译 林江涛 审校)
(Respir Res. 2023 Dec 4; DOI: 10.1186/s12931-023-02603-2)
Characterization and inhibition of inflammasome responses in severe and non-severe asthma (Respir Res. 2023 Dec 4; DOI: 10.1186/s12931-023-02603-2)
Horvat JC, Kim RY, Weaver N, Augood C, Brown AC, Donovan C, Dupre P, Gunawardhana L, Mayall JR, Hansbro NG, Robertson AAB, O'Neill LAJ, Cooper MA, Holliday EG, Hansbro PM, Gibson PG.
Abstract
Background:Increased airway NLRP3 inflammasome-mediated IL-1β responses may underpin severe neutrophilic asthma. However, whether increased inflammasome activation is unique to severe asthma, is a common feature of immune cells in all inflammatory types of severe asthma, and whether inflammasome activation can be therapeutically targeted in patients, remains unknown.
Objective:To investigate the activation and inhibition of inflammasome-mediated IL-1β responses in immune cells from patients with asthma.
Methods:Peripheral blood mononuclear cells (PBMCs) were isolated from patients with non-severe (n = 59) and severe (n = 36 stable, n = 17 exacerbating) asthma and healthy subjects (n = 39). PBMCs were stimulated with nigericin or lipopolysaccharide (LPS) alone, or in combination (LPS + nigericin), with or without the NLRP3 inhibitor MCC950, and the effects on IL-1β release were assessed.
Results:PBMCs from patients with non-severe or severe asthma produced more IL-1β in response to nigericin than those from healthy subjects. PBMCs from patients with severe asthma released more IL-1β in response to LPS + nigericin than those from non-severe asthma. Inflammasome-induced IL-1β release from PBMCs from patients with severe asthma was not increased during exacerbation compared to when stable. Inflammasome-induced IL-1β release was not different between male and female, or obese and non-obese patients and correlated with eosinophil and neutrophil numbers in the airways. MCC950 effectively suppressed LPS-, nigericin-, and LPS + nigericin-induced IL-1β release from PBMCs from all groups.
Conclusion:An increased ability for inflammasome priming and/or activation is a common feature of systemic immune cells in both severe and non-severe asthma, highlighting inflammasome inhibition as a universal therapy for different subtypes of disease.
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气道高反应性与哮喘气道TSLP相关，独立于嗜酸性粒细胞炎症
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反式-IL-6 信号的上皮基因特征定义了 2 型低度哮喘亚群
