IL‐37 inhibits IL‐4/IL‐13‐induced CCL11 production and lung eosinophilia in murine allergic asthma

Background IL‐37 is emerging as an anti‐inflammatory cytokine, particularly in innate inflammation. However, the role of IL‐37 in Th2‐mediated allergic lung inflammation remains uncertain. We sought to determine the role and the underlying mechanisms of IL‐37 in the development of house dust mites (HDM)‐induced murine asthma model. Methods We examined the effect of IL‐37 administration during the sensitization or challenge phase on Th2‐mediated allergic asthma induced by inhaled HDM. Cellular source of CCL11 and distribution of IL‐37 receptors, IL‐18Rα and IL‐1R8, were determined in HDM‐exposed lungs. Finally, we examined the effect of IL‐37 on CCL11 production and STAT6 activation in different primary lung structural cell types upon IL‐4/IL‐13 stimulation. Results IL‐37 had no effect on HDM sensitization, but when administrated during the challenge phase, significantly attenuated pulmonary eosinophilia, CCL11 production, and airway hyper‐reactivity (AHR). Interestingly, IL‐37 treatment had no significant effects on lung infiltrating T cells and Th2 cytokine production. Intranasal co‐administration of CCL11 reversed the inhibiting effect of IL‐37 on HDM‐induced pulmonary eosinophilia and AHR. Furthermore, we demonstrated that CCL11 was primarily expressed by fibroblasts and airway smooth muscle cells (AMSC), while IL‐37 receptors by tracheobronchial epithelial cells (TEC). In vitro study showed that IL‐37 inhibited IL‐4/IL‐13‐induced STAT6 activation and CCL11 production by fibroblasts and AMSC, which was dependent on its direct action on TEC. Moreover, cell contact was required for the inhibitory effect of IL‐37‐treated TEC. Conclusions IL‐37 attenuates HDM‐induced asthma, possibly by inhibiting IL‐4/IL‐13‐induced CCL11 production by fibroblasts and AMSC via its direct act on TEC.