Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Institute for Immunology, Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University School of Medicine, Beijing, China.
Allergy. 2018 Aug;73(8):1642-1652. doi: 10.1111/all.13395. Epub 2018 Feb 5.
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.
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.
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.
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.
IL-37 作为一种抗炎细胞因子，特别是在先天炎症中，正在逐渐受到关注。然而，IL-37 在 Th2 介导的过敏性肺炎症中的作用仍不确定。我们试图确定 IL-37 在屋尘螨（HDM）诱导的小鼠哮喘模型发展中的作用及其潜在机制。
我们在吸入 HDM 诱导的 Th2 介导的过敏性哮喘的致敏或激发阶段检查了 IL-37 给药对其的影响。在暴露于 HDM 的肺中，确定了 CCL11 的细胞来源和 IL-37 受体、IL-18Rα 和 IL-1R8 的分布。最后，我们研究了 IL-37 对不同原代肺结构细胞类型在 IL-4/IL-13 刺激下 CCL11 产生和 STAT6 激活的影响。
IL-37 对 HDM 致敏没有影响，但在激发阶段给药时，显著减轻了肺部嗜酸性粒细胞浸润、CCL11 产生和气道高反应性（AHR）。有趣的是，IL-37 治疗对肺浸润 T 细胞和 Th2 细胞因子的产生没有显著影响。鼻内共给予 CCL11 逆转了 IL-37 对 HDM 诱导的肺部嗜酸性粒细胞浸润和 AHR 的抑制作用。此外，我们证明 CCL11 主要由成纤维细胞和气道平滑肌细胞（AMSC）表达，而 IL-37 受体则由气管支气管上皮细胞（TEC）表达。体外研究表明，IL-37 通过其对 TEC 的直接作用抑制了 IL-4/IL-13 诱导的成纤维细胞和 AMSC 中的 STAT6 激活和 CCL11 产生。此外，IL-37 处理的 TEC 之间的细胞接触是其抑制作用所必需的。
IL-37 可减轻 HDM 诱导的哮喘，可能是通过其直接作用于 TEC 抑制 IL-4/IL-13 诱导的成纤维细胞和 AMSC 中的 CCL11 产生。
