Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands.
VIB Center for Inflammation Research, VIB, Ghent, Belgium.
Clin Exp Allergy. 2018 Dec;48(12):1705-1714. doi: 10.1111/cea.13262. Epub 2018 Sep 27.
Asthma is a heterogeneous disease of the airways that involves several types of granulocytic inflammation. Recently, we have shown that the activation status of myeloid cells regulated by TNFAIP3/A20 is a crucial determinant of eosinophilic or neutrophilic airway inflammation. However, whether neutrophilic inflammation observed in this model is dependent on IL-17 remains unknown.
In this study, we investigated whether IL-17RA-signalling is essential for eosinophilic or neutrophilic inflammation in house dust mite (HDM)-driven airway inflammation.
Tnfaip3 xLyz2 (Tnfaip3 ) mice were crossed to Il17ra mice, generating Tnfaip3 Il17ra mice and subjected to an HDM-driven airway inflammation model.
Both eosinophilic and neutrophilic inflammation observed in HDM-exposed WT and Tnfaip3 mice respectively were unaltered in the absence of IL-17RA. Production of IL-5, IL-13 and IFN-γ by CD4 T cells was similar between WT, Tnfaip3 and Il17ra mice, whereas mucus-producing cells in Tnfaip3 Il17ra mice were reduced compared to controls. Strikingly, spontaneous accumulation of pulmonary Th1, Th17 and γδ-17 T cells was observed in Tnfaip3 Il17ra mice, but not in the other genotypes. Th17 cell-associated cytokines such as GM-CSF and IL-22 were increased in the lungs of HDM-exposed Tnfaip3 Il17ra mice, compared to IL-17RA-sufficient controls. Moreover, neutrophilic chemo-attractants CXCL1, CXCL2, CXCL12 and Th17-promoting cytokines IL-1β and IL-6 were unaltered between Tnfaip3 and Tnfaip3 Il17ra mice.
These findings show that neutrophilic airway inflammation induced by activated TNFAIP3/A20-deficient myeloid cells can develop in the absence of IL-17RA-signalling. Neutrophilic inflammation is likely maintained by similar quantities of pro-inflammatory cytokines IL-1β and IL-6 that can, independently of IL-17-signalling, induce the expression of neutrophil chemo-attractants.
哮喘是一种气道的异质性疾病，涉及多种粒细胞炎症。最近，我们发现，受 TNFAIP3/A20 调节的髓样细胞的激活状态是嗜酸性粒细胞或中性粒细胞气道炎症的关键决定因素。然而，该模型中观察到的中性粒细胞炎症是否依赖于 IL-17 尚不清楚。
在这项研究中，我们研究了在屋尘螨（HDM）驱动的气道炎症中，IL-17RA 信号是否对嗜酸性粒细胞或中性粒细胞炎症至关重要。
将 Tnfaip3 xLyz2（Tnfaip3）小鼠与 Il17ra 小鼠杂交，生成 Tnfaip3 Il17ra 小鼠，并使其暴露于 HDM 驱动的气道炎症模型中。
在缺乏 IL-17RA 的情况下，WT 和 Tnfaip3 小鼠分别暴露于 HDM 时观察到的嗜酸性粒细胞和中性粒细胞炎症均未改变。WT、Tnfaip3 和 Il17ra 小鼠的 CD4 T 细胞产生的 IL-5、IL-13 和 IFN-γ 相似，而 Tnfaip3 Il17ra 小鼠中的黏液产生细胞则减少。值得注意的是，在 Tnfaip3 Il17ra 小鼠中观察到自发积累的肺部 Th1、Th17 和 γδ-17 T 细胞，但在其他基因型中没有观察到。与 IL-17RA 充足的对照相比，HDM 暴露的 Tnfaip3 Il17ra 小鼠肺部的 Th17 细胞相关细胞因子（如 GM-CSF 和 IL-22）增加。此外，在 Tnfaip3 和 Tnfaip3 Il17ra 小鼠之间，中性粒细胞趋化因子 CXCL1、CXCL2、CXCL12 和促进 Th17 分化的细胞因子 IL-1β 和 IL-6 没有改变。
这些发现表明，在缺乏 IL-17RA 信号的情况下，由激活的 TNFAIP3/A20 缺陷髓样细胞诱导的中性粒细胞气道炎症可以发展。中性粒细胞炎症可能由相似数量的促炎细胞因子 IL-1β 和 IL-6 维持，这些细胞因子可独立于 IL-17 信号诱导中性粒细胞趋化因子的表达。
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