Bozza Silvia, Zelante Teresa, Moretti Silvia, Bonifazi Pierluigi, DeLuca Antonella, D'Angelo Carmen, Giovannini Gloria, Garlanda Cecilia, Boon Louis, Bistoni Francesco, Puccetti Paolo, Mantovani Alberto, Romani Luigina
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
J Immunol. 2008 Mar 15;180(6):4022-31. doi: 10.4049/jimmunol.180.6.4022.
TLRs contribute to the inflammatory response in fungal infections. Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases. In this study, we tested the hypothesis that Toll IL-1R8 (TIR8)/single Ig IL-1-related receptor, a member of the IL-1R family acting as a negative regulator of TLR/IL-1R signaling, affects TLR responses in fungal infections. Genetically engineered Tir8(-/-) mice were assessed for inflammatory and adaptive Th cell responses to Candida albicans and Aspergillus fumigatus. Inflammatory pathology and susceptibility to infection were higher in Tir8(-/-) mice and were causally linked to the activation of the Th17 pathway. IL-1R signaling was involved in Th17 cell activation by IL-6 and TGF-beta in that limited inflammatory pathology and relative absence of Th17 cell activation were observed in IL-1RI(-/-) mice. These data demonstrate that TIR8 is required for host resistance to fungal infections and that it functions to negatively regulate IL-1-dependent activation of inflammatory Th17 responses. TIR8 may contribute toward fine-tuning the balance between protective immunity and immunopathology in infection.
Toll样受体（TLRs）在真菌感染中参与炎症反应。尽管炎症是对真菌保护性反应的重要组成部分，但其失调可能会显著加重真菌疾病。在本研究中，我们检验了以下假设：Toll白细胞介素-1受体8（TIR8）/单免疫球蛋白白细胞介素-1相关受体，作为TLR/白细胞介素-1受体信号的负调节因子，是白细胞介素-1受体（IL-1R）家族的一员，会影响真菌感染中的TLR反应。我们评估了基因工程改造的Tir8基因敲除（-/-）小鼠对白色念珠菌和烟曲霉的炎症反应及适应性Th细胞反应。Tir8基因敲除（-/-）小鼠的炎症病理学表现及对感染的易感性更高，且与Th17通路的激活存在因果关系。IL-1受体信号通过白细胞介素-6和转化生长因子-β参与Th17细胞的激活，因为在IL-1RI基因敲除（-/-）小鼠中观察到有限的炎症病理学表现及相对缺乏Th17细胞激活。这些数据表明，TIR8是宿主抵抗真菌感染所必需的，并且它的功能是负向调节白细胞介素-1依赖的炎症性Th17反应的激活。TIR8可能有助于微调感染中保护性免疫和免疫病理学之间的平衡。
