Background Exacerbation in asthma is associated with decreased expression of specific host defence peptides (HDPs) in the lungs. We examined the effects of a synthetic derivative of HDP, innate defence regulator (IDR) peptide IDR-1002, in house dust mite (HDM)-challenged murine model of asthma, in interleukin (IL)-33-challenged mice and in human primary bronchial epithelial cells (PBECs).
Methods IDR-1002 (6 mg/kg per mouse) was administered (subcutaneously) in HDM-challenged and/or IL-33-challenged BALB/c mice. Lung function analysis was performed with increasing dose of methacholine by flexiVent small animal ventilator, cell differentials in bronchoalveolar lavage performed by modified Wright-Giemsa staining, and cytokines monitored by MesoScale Discovery assay and ELISA. PBECs stimulated with tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), with or without IDR-1002, were analysed by western blots.
Results IDR-1002 blunted HDM challenge-induced airway hyper-responsiveness (AHR), and lung leucocyte accumulation including that of eosinophils and neutrophils, in HDM-challenged mice. Concomitantly, IDR-1002 suppressed HDM-induced IL-33 in the lungs. IFN-γ/TNF-α-induced IL-33 production was abrogated by IDR-1002 in PBECs. Administration of IL-33 in HDM-challenged mice, or challenge with IL-33 alone, mitigated the ability of IDR-1002 to control leucocyte accumulation in the lungs, suggesting that the suppression of IL-33 is essential for the anti-inflammatory activity of IDR-1002. In contrast, the peptide significantly reduced either HDM, IL-33 or HDM+IL-33 co-challenge-induced AHR in vivo.
Conclusion This study demonstrates that an immunomodulatory IDR peptide controls the pathophysiology of asthma in a murine model. As IL-33 is implicated in steroid-refractory severe asthma, our findings on the effects of IDR-1002 may contribute to the development of novel therapies for steroid-refractory severe asthma.
- airway epithelium
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Contributors HP performed majority of the experiments and data analyses, contributed to the development of the scientific concepts and wrote the manuscript. MH and AA performed various assays for monitoring endpoint responses and cytokine production in the animal tissues. SB performed the murine lung function analyses. AJH provided significant intellectual input in the development of this study and extensively edited the manuscript. AMvdD provided extensive intellectual support in the design of the experiments using human primary cells. PSH provided significant intellectual input and directly supervised the experiments using primary human cells. NM conceived and directly supervised the study and extensively edited the manuscript. All authors reviewed and edited the manuscript.
Funding Funding support for this study was obtained from the Manitoba Health Research Council (MHRC); The Dr Paul T. Thorlakson Foundation, Winnipeg, MB, Canada; the Canadian Respiratory Research Network (CRRN) and the Children’s Hospital Research Institute of Manitoba (CHRIM). HP and AA were supported by studentships from MHRC.
Competing interests NM and HP are inventors on a patent application filed with Canadian Intellectual Property Office (WO2015077888) that incorporates aspects of the findings described in this manuscript. Other authors have no competing interest to declare.
Patient consent Not required.
Ethics approval University of Manitoba Animal Care Ethics Board.
Provenance and peer review Not commissioned; externally peer reviewed.
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