De Volder Joyceline, Bontinck Annelies, Haelterman Valerie, Boon Louis, Joos Guy F, Brusselle Guy G, Maes Tania
Department of Respiratory Medicine, Laboratory for Translational Research in Obstructive Pulmonary Diseases, Medical Research Building (MRB) II, Ghent University Hospital, 2 Floor, Corneel Heymanslaan 10, 9000, Ghent, Belgium.
JJP Biologics, Warsaw, Poland.
Respir Res. 2025 Jan 28;26(1):43. doi: 10.1186/s12931-024-03082-9.
Diesel exhaust particles (DEP) have been proven to aggravate asthma pathogenesis. We previously demonstrated that concurrent exposure to house dust mite (HDM) and DEP in mice increases both eosinophils and neutrophils in bronchoalveolar lavage fluid (BALF) and also results in higher levels of neutrophil-recruiting chemokines and neutrophil extracellular trap (NET) formation compared to sole HDM, sole DEP or saline exposure. We aimed to evaluate whether treatment with anti-IL-5 can alleviate the asthmatic features in this mixed granulocytic asthma model. Moreover, we aimed to unravel whether neutrophils modulate the DEP-aggravated eosinophilic airway inflammation.
Female C57BL6/J mice were intranasally exposed to saline or HDM and DEP for 3 weeks (subacute model). Interference with eosinophils was performed by intraperitoneal administration of anti-IL-5 (TRFK5), which neutralizes IL-5. Interference with neutrophils and neutrophil elastase was performed by intraperitoneal anti-Ly6G and sivelestat administration, respectively. Outcome parameters included eosinophils subsets (homeostatic EOS and inflammatory EOS), proinflammatory cytokines, goblet cell hyperplasia and airway hyperresponsiveness.
The administration of anti-IL-5 significantly decreased eosinophilic responses, affecting both inflammatory and homeostatic eosinophil subsets, upon subacute HDM + DEP exposure while BAL neutrophils, NET formation and other asthma features remained present. Neutrophils were significantly reduced after anti-Ly6G administration in BALF, lung and blood without affecting the eosinophilic inflammation upon HDM + DEP exposure. Sivelestat treatment tended to decrease BALF inflammation, including eosinophils, upon HDM + DEP exposure, but did not affect lung inflammation.
Inhibition of IL-5 signalling, but not neutrophil interventions, significantly attenuates eosinophilic inflammation in a mouse model of mixed granulocytic asthma, elicited by air pollution exposure.
柴油废气颗粒（DEP）已被证实会加重哮喘的发病机制。我们之前证明，小鼠同时暴露于屋尘螨（HDM）和DEP中，与单独暴露于HDM、单独暴露于DEP或生理盐水相比，支气管肺泡灌洗液（BALF）中的嗜酸性粒细胞和中性粒细胞都会增加，并且还会导致更高水平的中性粒细胞趋化因子和中性粒细胞胞外陷阱（NET）形成。我们旨在评估抗IL-5治疗是否能减轻这种混合粒细胞性哮喘模型中的哮喘特征。此外，我们旨在阐明中性粒细胞是否调节DEP加重的嗜酸性气道炎症。
雌性C57BL6/J小鼠经鼻暴露于生理盐水、HDM或DEP 3周（亚急性模型）。通过腹腔注射抗IL-5（TRFK5）来干扰嗜酸性粒细胞，抗IL-5可中和IL-5。分别通过腹腔注射抗Ly6G和西维来司他来干扰中性粒细胞和中性粒细胞弹性蛋白酶。结果参数包括嗜酸性粒细胞亚群（稳态嗜酸性粒细胞和炎症性嗜酸性粒细胞）、促炎细胞因子、杯状细胞增生和气道高反应性。
在亚急性HDM + DEP暴露后，抗IL-5的给药显著降低了嗜酸性反应，影响了炎症性和稳态嗜酸性粒细胞亚群，而BAL中的中性粒细胞、NET形成和其他哮喘特征仍然存在。在HDM + DEP暴露后，腹腔注射抗Ly6G后，BALF、肺和血液中的中性粒细胞显著减少，而不影响嗜酸性炎症。西维来司他治疗在HDM + DEP暴露后倾向于减少BALF炎症，包括嗜酸性粒细胞，但不影响肺部炎症。
在空气污染引发的混合粒细胞性哮喘小鼠模型中，抑制IL-5信号通路而非中性粒细胞干预可显著减轻嗜酸性炎症。
