Activity of an innate defence regulator peptide to alleviate airway inflammation is mitigated by disruption of its central hydrophobic region

Innate defence regulator (IDR) peptides are synthetic peptides inspired by natural antimicrobial peptides. We examined the effects of an IDR peptide, IDR1002, in a house dust mite (HDM)-challenged murine model of asthma; IDR1002 (6 mg/kg) was administered (subcutaneous; ×3/week) in HDM-challenged adult BALB/c mice for two weeks. Airway hyperresponsiveness (AHR) was assessed by flexiVent™ small animal ventilator, cell differentials in bronchoalveolar lavage (BAL) by Wright-Giemsa staining, and cytokines production by ELISA. IDR1002 reduced HDM-induced AHR, accumulation of eosinophils and neutrophils, and production of cytokine IL-33 in lungs. It has been shown that disrupting a single amino acid tryptophan (W) within the hydrophobic region of IDR1002 sequence mitigates antimicrobial functions 1 . Thus, we examined the effects of the W-substituted analog, IDR1002(W/R), in HDM-challenged mice. IDR1002(W/R) did not suppress leukocyte accumulation or production of IL-33, but maintained capacity to reduce AHR in HDM-mice. Examining the immunomodulatory activity of the peptides in-vitro with human bronchial epithelial cells, we showed that IDR1002, but not IDR1002(W/R), enhanced production of anti-inflammatory mediators such as IL-1RA and stanniocalcin-1, and suppressed IFNγ-induced IL-33. Our results suggest that the ability of IDR1002 to alleviate airway inflammation is mitigated by disrupting its central hydrophobic region, without abrogating the peptide’s capacity to reduce AHR. This offers an opportunity to use these two peptides as probes to delineate disparate mechanisms associated with airway inflammation and AHR. 1 Peptides 2015; 71:276