Immunomodulatory innate defence regulator (IDR) peptide alleviates airway inflammation and hyper-responsiveness.

Abstract

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.

• Authors: Hadeesha Piyadasa, Mahadevappa Hemshekhar, Anthony Altieri, Sujata Basu, Anne M van der Does, Andrew J Halayko, Pieter S Hiemstra, Neeloffer Mookherjee
• Journal: Thorax (Thorax) Vol. 73 Issue 10 Pg. 908-917 (10 2018) ISSN: 1468-3296 [Electronic] England
• PMID: 29853649 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Chemical References

• Antimicrobial Cationic Peptides
• Cytokines
• IDR 1002
• Methacholine Chloride

Topics

• Animals
• Antimicrobial Cationic Peptides (pharmacology)
• Asthma (drug therapy, immunology, metabolism)
• Blotting, Western
• Bronchoalveolar Lavage Fluid (cytology)
• Cell Culture Techniques
• Cytokines (metabolism)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Epithelial Cells (drug effects, immunology)
• Female
• Humans
• Immunomodulation (drug effects)
• Lung (metabolism, pathology)
• Methacholine Chloride (pharmacology)
• Mice
• Mice, Inbred BALB C
• Pyroglyphidae (immunology)
• Respiratory Hypersensitivity (drug therapy, immunology, metabolism)