Abstract Rationale Interleukin-37 (IL-37) is an anti-inflammatory cytokine of the IL-1 family that suppresses innate and adaptive immune responses. Previous studies have shown that recombinant IL-37 attenuates airway inflammation in experimental asthma. However, its therapeutic efficacy remains limited by rapid degradation and suboptimal receptor interaction. We hypothesized that a modified IL-37 variant with enhanced stability and receptor affinity would provide superior protection against allergen-induced airway inflammation compared with wild-type IL-37. Methods Two established murine models of allergic asthma were employed: a house dust mite (HDM) model (local sensitization by intranasal allergen exposure) and an ovalbumin (OVA) model (systemic sensitization and local challenge). Female C57BL/6 mice (n = 16 per group) were randomized to receive intranasal vehicle, recombinant human IL-37, or a modified IL-37 variant during the final five consecutive days of allergen exposure. Airway inflammation was assessed by bronchoalveolar lavage (BAL) cytology and lung histopathology. Mucus production was quantified by periodic acid-Schiff (PAS) staining, and airway resistance was measured via invasive plethysmography following methacholine challenge. Results Both IL-37 and modified IL-37 significantly reduced airway inflammation compared with vehicle controls in the HDM and OVA models, as evidenced by decreased BAL total cell counts and eosinophilia. Treatment also diminished peribronchial and perivascular inflammatory infiltrates and lowered expression of Th2 cytokines in lung homogenates. In a second approach single applications only showed reduced airway inflammation by modified IL-37 but not of natural IL-37. Conclusions Intranasal administration of a genetically modified IL-37 variant provides enhanced suppression of allergic airway inflammation and improved functional outcomes compared with recombinant IL-37 in murine asthma models. These findings support further investigation of engineered IL-37 derivatives as potential biologic therapies for allergic asthma. This abstract is funded by: None
Lunding et al. (Fri,) studied this question.