Toll-like receptor 6 drives interleukin-17A expression during experimental hypersensitivity pneumonitis
Toll-like receptor 6 drives interleukin-17A expression during experimental hypersensitivity pneumonitis
复制标题
DOI：
10.1111/j.1365-2567.2009.03219.x
复制
发表时间：
2010-05-01
期刊：
影响因子：
6.4
通讯作者：
Joshi, Amrita D.
中科院分区：
文献类型：
--
作者：
Fong, Daniel J.;Hogaboam, Cory M.;Joshi, Amrita D.
P>；过敏性肺炎(HP)是一种T细胞驱动的疾病，其组织学特征是肺内弥漫性单核细胞浸润和疏松形成的肉芽肿。我们曾报道白介素17A(IL-17A)参与实验性幽门螺杆菌的发生，模式识别受体Toll样受体6(TLR6)可能是启动这一反应的一个因素。利用已建立的直立型糖多孢菌诱导幽门螺杆菌的小鼠模型，我们研究了TLR6在该病免疫发病机制中的作用。在没有TLR6信号的情况下，接受整形沙门氏菌抗原(SR-Ag)多次攻击的小鼠，与同样受到SR-Ag攻击的C57BL/6小鼠(野生型；WT)相比，肺部炎症显著减少。对SR-Ag攻击小鼠全肺样本的流式细胞仪分析显示，与WT小鼠相比，TLR6-/-小鼠的CD4+/CD8+T细胞比率降低。在最后一次SR-Ag攻击后不同天的细胞因子分析显示，TLR6-/-小鼠的全肺含有的IL-17A显著低于WT Hp感染小鼠的肺。IL-17A驱动的细胞因子IL-21和IL-23在SR-Ag攻击的TLR6-/-小鼠中的表达水平也低于SR-Ag攻击的WT小鼠。其他促炎细胞因子，即干扰素-γ和RANTES，也被发现受到TLR6信号的调节。抗TLR6中和抗体处理分散的肺细胞可显著抑制SR-Ag诱导的IL-17A和IL-6的产生。综上所述，这些结果表明TLR6通过其在IL-17A产生中的作用，在幽门螺杆菌的发展和严重程度中起着关键作用。
P>Hypersensitivity pneumonitis (HP) is a T-cell-driven disease that is histologically characterized by diffuse mononuclear cell infiltrates and loosely formed granulomas in the lungs. We have previously reported that interleukin-17A (IL-17A) contributes to the development of experimental HP, and that the pattern recognition receptor Toll-like receptor 6 (TLR6) might be a factor in the initiation of this response. Using a well-established murine model of Saccharopolyspora rectivirgula-induced HP, we investigated the role of TLR6 in the immunopathogenesis of this disease. In the absence of TLR6 signalling, mice that received multiple challenges with S. rectivirgula-antigen (SR-Ag) had significantly less lung inflammation compared with C57BL/6 mice (wild-type; WT) similarly challenged with SR-Ag. Flow cytometric analysis of whole lung samples from SR-Ag-challenged mice showed that TLR6-/- mice had a decreased CD4+ : CD8+ T-cell ratio compared with WT mice. Cytokine analysis at various days after the final SR-Ag challenge revealed that whole lungs from TLR6-/- mice contained significantly less IL-17A than lungs from WT mice with HP. The IL-17A-driving cytokines IL-21 and IL-23 were also expressed at lower levels in SR-Ag-challenged TLR6-/- mice, when compared with SR-Ag-challenged WT mice. Other pro-inflammatory cytokines, namely interferon-gamma and RANTES, were also found to be regulated by TLR6 signalling. Anti-TLR6 neutralizing antibody treatment of dispersed lung cells significantly impaired SR-Ag-induced IL-17A and IL-6 generation. Together, these results indicate that TLR6 plays a pivotal role in the development and severity of HP via its role in IL-17A production.