Human β‐defensin‐2 suppresses key features of asthma in murine models of allergic airways disease

Abstract

Background: Asthma is an airway inflammatory disease and a major health problem worldwide. Anti-inflammatory steroids and bronchodilators are the gold-standard therapy for asthma. However, they do not prevent the development of the disease, and critically, a subset of asthmatics are resistant to steroid therapy. Objective: To elucidate the therapeutic potential of human β-defensins (hBD), such as hBD2 mild to moderate and severe asthma. Methods: We investigated the role of hBD2 in a steroid-sensitive, house dust miteinduced allergic airways disease (AAD) model and a steroid-insensitive model combining ovalbumin-induced AAD with C muridarum (Cmu) respiratory infection. Results: In both models, we demonstrated that therapeutic intranasal application of hBD2 significantly reduced the influx of inflammatory cells into the bronchoalveolar lavage fluid. Furthermore, key type 2 asthma-related cytokines IL-9 and IL-13, as well as additional immunomodulating cytokines, were significantly decreased after administration of hBD2 in the steroid-sensitive model. The suppression of inflammation was associated with improvements in airway physiology and treatment also suppressed airway hyper-responsiveness (AHR) in terms of airway resistance and compliance to methacholine challenge. Conclusions and Clinical relevance: These data indicate that hBD2 reduces the hallmark features and has potential as a new therapeutic agent in allergic and especially steroid-resistant asthma.

Molecular dynamics simulations and functional studies reveal that hBD-2 binds SARS-CoV-2 spike RBD and blocks viral entry into ACE2 expressing cells

“…In vivo application of hBD-2 has proven successful in addressing a number of diseases. This includes a recent study demonstrating efficacy in experimental colitis in a mouse model (Koeninger et al, 2020) and therapeutic intranasal application of hBD-2 to reduce the influx of inflammatory cells into bronchoalveolar lavage fluid (Pinkerton et al, 2020). Of relevance to our study is the use of smaller hBD fragments; i.e., mimetics, of mouse beta defensin 4 (mBD-4) (Zhao et al, 2016), the ortholog of hBD-2, that when administered intra-nasally, rescued 100% of mice from the lethal challenge of human and avian influenza A, SARS-CoV and MERS-CoV (LeMessurier et al, 2016).…”

Human β-Defensin 2 Mutations Are Associated With Asthma and Atopy in Children and Its Application Prevents Atopic Asthma in a Mouse Model

“…To completely rule out this possibility, an additional control group, treated with a peptide of similar but random amino acid composition like hBD-2, could be included in future experiments. While intranasal administration of hBD-2 even in a therapeutic setting lessens pulmonary inflammation in models of both steroid sensitive and steroid refractory asthma, treatment efficacy in those models was mirrored by diminished cell influx ( 27 ). Notably, intranasal administration of another antimicrobial peptide, mCRAMP (murine orthologue of LL-37), triggered asthma exacerbation in an allergic asthma mouse model ( 53 ), hence suggesting a unique role of hBD-2 in this setting.…”

“…To completely rule out this possibility, an additional control group, treated with a peptide of similar but random amino acid composition like hBD-2, could be included in future experiments. While intranasal administration of hBD-2 even in a therapeutic setting lessens pulmonary inflammation in models of both steroid sensitive and steroid refractory asthma, treatment efficacy in those models was mirrored by diminished cell influx (27). Notably, intranasal administration of another antimicrobial peptide, mCRAMP (murine orthologue of LL-37), A B FIGURE 5 | Total and differential cell counts (eosinophils, neutrophils, macrophages, and lymphocytes) in bronchoalveolar lavage fluid (A) and concentration of inflammatory cytokines (TNFa, IL-4, IL-5, IL-6, IL-9, IL-13, and IL-33) in lung homogenates of the 3 treatment groups (n=12 per group) (B).…”

“…A further obstacle in defensin research has been the technical difficulty to produce purified defensin for experimental studies. As hBD-2 protein only became available in sufficient quantities recently, only a handful of studies have investigated the role and potential of the molecule so far ( 17 , 27 , 31 , 32 ).…”

“…Human b-defensin 2 (hBD-2), which is almost non-existent in the unprovoked airways and gut but profoundly abundant in inflamed epithelial tissues in response to environmental stimuli (23)(24)(25)(26), may be of particular interest. Indeed, hBD-2 has recently been shown to ameliorate asthma and IBD in animal models (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”