新型细胞因子白细胞介素-38在过敏性哮喘中的抗炎作用
2019/11/12
摘要
我们阐明了IL-38在过敏性哮喘中的抗炎作用机制。人类支气管上皮细胞在病毒RLR配位聚(I:C) / LyoVec或感染相关性细胞因子TNF-α诱导细胞因子/趋化因子/粘附分子的表达的刺激下与嗜酸性粒细胞共培养。通过构建屋尘螨(HDM)致变应性哮喘和人源性变应性哮喘NOD/SCID小鼠模型来评价其体内抗炎机制。在共培养体系中IL-38显著抑制诱导促炎的IL- 6、IL-1β、CCL5,CXCL10生产和抗病毒β干扰素和细胞间粘附分子1的表达。大规模血细胞计数和RNA测序分析显示,IL-38可以中和细胞内STAT1的激活,STAT3, p38 MAPK, ERK1/2, NF-κB通路,同时上调宿主防御相关基因POU2AF1和抗过敏反应基因RGS13的表达。向屋尘螨诱导的过敏性哮喘小鼠腹腔注射IL-38可通过减少肺内嗜酸性粒细胞的积累，抑制支气管肺泡灌洗液(BALF)和肺匀浆中与Th2相关的细胞因子IL-4、IL-5和IL-13的表达，改善气道高反应性。组织学检查提示肺炎症减轻，细胞浸润减少，杯状细胞增生减少，Th2、Th17、固有淋巴样2型细胞数量减少，调节性T细胞在肺、脾、淋巴结的比例增加。IL-38可抑制小鼠气道高反应性及哮喘相关IL-4和IL-5的表达，并可显著降低BALF和肺部的CCR3+嗜酸性粒细胞数量，降低人类CD4+CRTH2+ Th2细胞在肺和纵隔淋巴结的百分比。总之，我们的结果证明了IL-38的抗炎机制，并为开发基于调节细胞因子的过敏性哮喘治疗提供了基础。
Sun X, Hou T, Cheung E, Iu TN, Tam VW, Chu IM, Tsang MS, Chan PK, Lam CW, Wong CK.
Abstract
We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma. Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly (I:C)/LyoVec or infection-related cytokine TNF-α to induce expression of cytokines/chemokines/adhesion molecules. House dust mite (HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo. IL-38 significantly inhibited induced proinflammatory IL-6, IL-1β, CCL5, and CXCL10 production, and antiviral interferon-β and intercellular adhesion molecule-1 expression in the coculture system. Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1, STAT3, p38 MAPK, ERK1/2, and NF-κB pathways, and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13. Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) and lung homogenates. Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia, together with reduced Th2, Th17, and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs, spleen, and lymph nodes. IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice, together with significantly decreased CCR3+ eosinophil numbers in the BALF and lungs, and a reduced percentage of human CD4+CRTH2+ Th2 cells in the lungs and mediastinal lymph nodes. Together, our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.
我们阐明了IL-38在过敏性哮喘中的抗炎作用机制。人类支气管上皮细胞在病毒RLR配位聚(I:C) / LyoVec或感染相关性细胞因子TNF-α诱导细胞因子/趋化因子/粘附分子的表达的刺激下与嗜酸性粒细胞共培养。通过构建屋尘螨(HDM)致变应性哮喘和人源性变应性哮喘NOD/SCID小鼠模型来评价其体内抗炎机制。在共培养体系中IL-38显著抑制诱导促炎的IL- 6、IL-1β、CCL5,CXCL10生产和抗病毒β干扰素和细胞间粘附分子1的表达。大规模血细胞计数和RNA测序分析显示,IL-38可以中和细胞内STAT1的激活,STAT3, p38 MAPK, ERK1/2, NF-κB通路,同时上调宿主防御相关基因POU2AF1和抗过敏反应基因RGS13的表达。向屋尘螨诱导的过敏性哮喘小鼠腹腔注射IL-38可通过减少肺内嗜酸性粒细胞的积累，抑制支气管肺泡灌洗液(BALF)和肺匀浆中与Th2相关的细胞因子IL-4、IL-5和IL-13的表达，改善气道高反应性。组织学检查提示肺炎症减轻，细胞浸润减少，杯状细胞增生减少，Th2、Th17、固有淋巴样2型细胞数量减少，调节性T细胞在肺、脾、淋巴结的比例增加。IL-38可抑制小鼠气道高反应性及哮喘相关IL-4和IL-5的表达，并可显著降低BALF和肺部的CCR3+嗜酸性粒细胞数量，降低人类CD4+CRTH2+ Th2细胞在肺和纵隔淋巴结的百分比。总之，我们的结果证明了IL-38的抗炎机制，并为开发基于调节细胞因子的过敏性哮喘治疗提供了基础。
(中日友好医院呼吸与危重症医学科 张清 摘译 林江涛 审校)
(Cell Mol Immunol. 2019 Oct 23. doi: 10.1038/s41423-019-0300-7)
(Cell Mol Immunol. 2019 Oct 23. doi: 10.1038/s41423-019-0300-7)
Anti-inflammatory mechanisms of the novel cytokine interleukin-38 in allergic asthma.
Sun X, Hou T, Cheung E, Iu TN, Tam VW, Chu IM, Tsang MS, Chan PK, Lam CW, Wong CK.
Abstract
We elucidated the anti-inflammatory mechanisms of IL-38 in allergic asthma. Human bronchial epithelial cells and eosinophils were cocultured upon stimulation with the viral RLR ligand poly (I:C)/LyoVec or infection-related cytokine TNF-α to induce expression of cytokines/chemokines/adhesion molecules. House dust mite (HDM)-induced allergic asthma and humanized allergic asthma NOD/SCID murine models were established to assess anti-inflammatory mechanisms in vivo. IL-38 significantly inhibited induced proinflammatory IL-6, IL-1β, CCL5, and CXCL10 production, and antiviral interferon-β and intercellular adhesion molecule-1 expression in the coculture system. Mass cytometry and RNA-sequencing analysis revealed that IL-38 could antagonize the activation of the intracellular STAT1, STAT3, p38 MAPK, ERK1/2, and NF-κB pathways, and upregulate the expression of the host defense-related gene POU2AF1 and anti-allergic response gene RGS13. Intraperitoneal injection of IL-38 into HDM-induced allergic asthma mice could ameliorate airway hyperreactivity by decreasing the accumulation of eosinophils in the lungs and inhibiting the expression of the Th2-related cytokines IL-4, IL-5, and IL-13 in the bronchoalveolar lavage fluid (BALF) and lung homogenates. Histological examination indicated lung inflammation was alleviated by reductions in cell infiltration and goblet cell hyperplasia, together with reduced Th2, Th17, and innate lymphoid type 2 cell numbers but increased proportions of regulatory T cells in the lungs, spleen, and lymph nodes. IL-38 administration suppressed airway hyperreactivity and asthma-related IL-4 and IL-5 expression in humanized mice, together with significantly decreased CCR3+ eosinophil numbers in the BALF and lungs, and a reduced percentage of human CD4+CRTH2+ Th2 cells in the lungs and mediastinal lymph nodes. Together, our results demonstrated the anti-inflammatory mechanisms of IL-38 and provided a basis for the development of a regulatory cytokine-based treatment for allergic asthma.
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在哮喘模型中PM2.5可以通过Got1 and HIF-1α扰乱Th17和Treg的平衡
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经局部调节的CXCR4hi中性粒细胞通过释放中性粒细胞胞外杀菌网络触发环境驱动的过敏性哮喘
