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Repeated exposure of house dust mite induces progressive airway inflammation in mice: Differential roles of CCL17 and IL-13.

ABSTRACT: We conducted a systematic evaluation of lung inflammation indued by repeated intranasal exposure (for 10 consecutive days) to a human aeroallergen, house dust mite (HDM) in BALB/c mice. Peak influx of neutrophils, monocytes/lymphocytes, and eosinophils was observed in bronchoalveolar lavage (BAL) on days 1, 7 and 11, respectively, and normalized to baseline by day 21. Peak elevations of Th2, myeloid-derived cytokines/chemokines and serum IgE were seen both in BAL and lung tissue homogenates between days 7 and 11, and declined thereafter; however, IL-33 levels remained elevated from day 7 to day 21. Airway hyperreactivity to inhaled methacholine was significantly increased by day 11 and decreased to baseline by day 21. The lung tissue showed perivascular and peribronchial cuffing, epithelial hypertrophy and hyperplasia and goblet cell formation in airways by day 11, and resolution by day 21. Levels of soluble collagen and tissue inhibitors of metalloproteinases (TIMP) also increased reflecting tissue remodeling in the lung. Microarray analysis demonstrated a significant time-dependent up-regulation of several genes including IL-33, CLCA3, CCL17, CD4, CD10, CD27, IL-13, Foxa3, IL-4, IL-10, and CD19, in BAL cells as well as the lung. Pre-treatment of HDM challenged mice with CCL17 and IL-13 antibodies reduced BAL cellularity, airway hyper-responsiveness (AHR), and histopathological changes. Notably, anti-IL-13, but not anti-CCL17 monoclonal antibodies (mAbs) reduced BAL neutrophilia while both mAbs attenuated eosinophilia. These results suggest that CCL17 has an overlapping, yet distinct profile versus IL-13 in the HDM model of pulmonary inflammation and potential for CCL17-based therapeutics in treating Th2 inflammation.

SUBMITTER: Malaviya R

PROVIDER: S-EPMC8085917 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Repeated exposure of house dust mite induces progressive airway inflammation in mice: Differential roles of CCL17 and IL-13.

Malaviya Ravi R Zhou Zhao Z Raymond Holly H Wertheimer Josh J Jones Brian B Bunting Rachel R Wilkinson Patrick P Madireddy Lohith L Hall LeRoy L Ryan Mary M Rao Tadimeti S TS

Pharmacology research & perspectives 20210501 3

We conducted a systematic evaluation of lung inflammation indued by repeated intranasal exposure (for 10 consecutive days) to a human aeroallergen, house dust mite (HDM) in BALB/c mice. Peak influx of neutrophils, monocytes/lymphocytes, and eosinophils was observed in bronchoalveolar lavage (BAL) on days 1, 7 and 11, respectively, and normalized to baseline by day 21. Peak elevations of Th2, myeloid-derived cytokines/chemokines and serum IgE were seen both in BAL and lung tissue homogenates betw ...[more]

PMID: 33929099

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Project description:BackgroundThe airway epithelial barrier function is disrupted in the airways of asthmatic patients. Abnormal mitochondrial biogenesis is reportedly involved in the pathogenesis of asthma. However, the role of mitochondrial biogenesis in the airway barrier dysfunction has not been elucidated yet. This study aimed to clarify whether the peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α), a central regulator of mitochondrial biogenesis, is involved in the disruption of the airway barrier function induced by aeroallergens.MethodsBEAS-2B cells were exposed to house dust mite (HDM) and the expressions of PGC-1α and E-cadherin, a junctional protein, were examined by immunoblotting. The effect of SRT1720, a PGC-1α activator, was investigated by immunoblotting, immunocytochemistry, and measuring the transepithelial electrical resistance (TEER) on the HDM-induced reduction in mitochondrial biogenesis markers and junctional proteins in airway bronchial epithelial cells. Furthermore,the effects of protease activated receptor 2 (PAR2) inhibitor, GB83, Toll-like receptor 4 (TLR4) inhibitor, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS), protease inhibitors including E64 and 4-(2-Aminoethyl) benzenesulfonyl fluoride hydrochloride (AEBSF) on the HDM-induced barrier dysfunction were investigated.ResultsThe amounts of PGC-1α and E-cadherin in the HDM-treated cells were significantly decreased compared to the vehicle-treated cells. SRT1720 restored the expressions of PGC-1α and E-cadherin reduced by HDM in BEAS-2B cells. Treatment with SRT1720 also significantly ameliorated the HDM-induced reduction in TEER. In addition, GB83, LPS-RS, E64 and AEBSF prevented the HDM-induced reduction in the expression of PGC1α and E-cadherin.ConclusionsThe current study demonstrated that HDM disrupted the airway barrier function through the PAR2/TLR4/PGC-1α-dependent pathway. The modulation of this pathway could be a new approach for the treatment of asthma.

Dataset Information

Repeated exposure of house dust mite induces progressive airway inflammation in mice: Differential roles of CCL17 and IL-13.

Publications

Repeated exposure of house dust mite induces progressive airway inflammation in mice: Differential roles of CCL17 and IL-13.

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