IL-37 requires IL18Rα and SIGIRR to diminish experimental allergic airway inflammation in mice

Abstract

Background: The cytokine interleukin 37 has been described as negative regulator of innate immunity. It reduces activation of DCs and the production of pro-inflammatory mediators in TLR stimulated murine and human cell lines. Results from the childhood asthma study CLARA gave first hints towards an implication of IL-37 in asthma pathogenesis. Aims: To examine whether IL-37 plays a role in asthma pathogenesis by providing anti-inflammatory effects on the adaptive immune response and through which receptor IL-37 exerts its effects. Methods: PBMCs were isolated from asthmatic and healthy children, cultured for 48h following stimulation. IL-37 levels in supernatants were determined. Wildtype and knockout (IL18Rα, SIGIRR) mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol to induce experimental asthma. IL-37 was applied locally before each challenge. Airway hyperresponsiveness was determined. Cytokines in broncho-alveolar lavage were assessed. Results: IL-37 production of human PBMCs was significantly lower in allergic asthmatics versus healthy children. Intra-nasal application of IL-37 dampened allergic airway inflammation in wildtype mice: levels of pro-inflammatory cytokines, mucus production, AHR, and eosinophilic infiltration were significantly reduced. All beneficial effects of IL-37 were completely abolished in mice lacking either IL18Rα or SIGIRR. Conclusion: This study demonstrates that IL-37 is able to diminish TH2 cell directed allergic airway inflammation and, thus, could be implemented in asthma pathogenesis. Our data suggest a mode of action that involves binding to IL18Rα and subsequent heterodimerization with or activation of SIGIRR.