Ito Takashi, Hirose Koichi, Saku Aiko, Kono Kenta, Takatori Hiroaki, Tamachi Tomohiro, Goto Yoshiyuki, Renauld Jean-Christophe, Kiyono Hiroshi, Nakajima Hiroshi
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
J Exp Med. 2017 Oct 2;214(10):3037-3050. doi: 10.1084/jem.20162108. Epub 2017 Aug 15.
Previous studies have shown that IL-22, one of the Th17 cell-related cytokines, plays multiple roles in regulating allergic airway inflammation caused by antigen-specific Th2 cells; however, the underlying mechanism remains unclear. Here, we show that allergic airway inflammation and Th2 and Th17 cytokine production upon intratracheal administration of house dust mite (HDM) extract, a representative allergen, were exacerbated in IL-22-deficient mice. We also found that IL-22 induces Reg3γ production from lung epithelial cells through STAT3 activation and that neutralization of Reg3γ significantly exacerbates HDM-induced eosinophilic airway inflammation and Th2 cytokine induction. Moreover, exostatin-like 3 (EXTL3), a functional Reg3γ binding protein, is expressed in lung epithelial cells, and intratracheal administration of recombinant Reg3γ suppresses HDM-induced thymic stromal lymphopoietin and IL-33 expression and accumulation of type 2 innate lymphoid cells in the lung. Collectively, these results suggest that IL-22 induces Reg3γ production from lung epithelial cells and inhibits the development of HDM-induced allergic airway inflammation, possibly by inhibiting cytokine production from lung epithelial cells.
先前的研究表明，白细胞介素-22（IL-22）作为与辅助性T细胞17（Th17）相关的细胞因子之一，在调节由抗原特异性辅助性T细胞2（Th2）引起的过敏性气道炎症中发挥多种作用；然而，其潜在机制仍不清楚。在此，我们发现，在气管内给予代表性过敏原屋尘螨（HDM）提取物后，IL-22缺陷小鼠的过敏性气道炎症以及Th2和Th17细胞因子的产生会加剧。我们还发现，IL-22通过激活信号转导和转录激活因子3（STAT3）诱导肺上皮细胞产生再生胰岛衍生蛋白3γ（Reg3γ），并且中和Reg3γ会显著加剧HDM诱导的嗜酸性气道炎症和Th2细胞因子的诱导。此外，外抑素样3（EXTL3）作为一种功能性Reg3γ结合蛋白，在肺上皮细胞中表达，气管内给予重组Reg3γ可抑制HDM诱导的胸腺基质淋巴细胞生成素和白细胞介素-33的表达以及肺中2型固有淋巴细胞的积聚。总体而言，这些结果表明，IL-22诱导肺上皮细胞产生Reg3γ，并可能通过抑制肺上皮细胞产生细胞因子来抑制HDM诱导的过敏性气道炎症的发展。
