IL-37 requires IL18Rα and SIGIRR to ameliorate experimental allergic asthma in mice

Rationale: Recently, the new cytokine interleukin (IL) 37 has been described as a negative regulator of the innate immune system. It reduces activation of DCs and the production of pro-inflammatory mediators in TLR stimulated murine and human macrophage, monocyte and epithelial cell lines. Results from the CLARA study gave the first hint towards an implication of IL-37 in asthma pathogenesis. However, until yet it is unknown, whether IL-37 plays a role in asthma pathogenesis by providing anti-inflammatory effects on an adaptive immune response and through which receptor it exerts such effects.

Methods: Peripheral blood mononuclear cells were isolated from asthmatic and healthy children, cultured for 48h and restimulated. IL-37 concentrations in supernatants were determined by ELISA. Wildtype and knockout (IL18Rα, SIGIRR) mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol to induce experimental asthma. IL-37 was applied intra-nasally 24h before each OVA aerosol challenge. Airway hyperresponsiveness (AHR) was determined. CBA was utilized to assess cytokine levels in broncho-alveolar lavage (BAL) fluid. Expression of IL-18 receptor signaling components was analyzed by qRT-PCR. Epithelial mucus was quantified by design-based stereology using PAS stained lung sections.

Results: IL-37 production of human PBMCs following anti-CD3/CD28-stimulation was significantly lower in allergic asthmatics versus healthy controls. Intra-nasal application of recombinant IL-37 dampened allergic airway inflammation induced by OVA in wildtype mice: levels of pro-inflammatory cytokines, mucus production, AHR, and eosinophilic infiltration were significantly reduced. All these beneficial effects of IL-37 applied locally during the challenge phase 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. Furthermore, our data suggest a mode of action of IL-37 that involves binding to IL18Rα and subsequent heterodimerization with or activation of SIGIRR.