Zelante Teresa, De Luca Antonella, Bonifazi Pierluigi, Montagnoli Claudia, Bozza Silvia, Moretti Silvia, Belladonna Maria L, Vacca Carmine, Conte Carmela, Mosci Paolo, Bistoni Francesco, Puccetti Paolo, Kastelein Robert A, Kopf Manfred, Romani Luigina
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Eur J Immunol. 2007 Oct;37(10):2695-706. doi: 10.1002/eji.200737409.
Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases. We found here that the IL-23/IL-17 developmental pathway acted as a negative regulator of the Th1-mediated immune resistance to fungi and played an inflammatory role previously attributed to uncontrolled Th1 cell responses. Both inflammation and infection were exacerbated by a heightened Th17 response against Candida albicans and Aspergillus fumigatus, two major human fungal pathogens. IL-23 acted as a molecular connection between uncontrolled fungal growth and inflammation, being produced by dendritic cells in response to a high fungal burden and counter-regulating IL-12p70 production. Both IL-23 and IL-17 subverted the inflammatory program of neutrophils, which resulted in severe tissue inflammatory pathology associated with infection. Our data are the first demonstrating that the IL-23/IL-17 pathway promotes inflammation and susceptibility in an infectious disease model. As IL-23-driven inflammation promotes infection and impairs antifungal resistance, modulation of the inflammatory response represents a potential strategy to stimulate protective immune responses to fungi.
尽管炎症是对真菌的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。我们在此发现，IL-23/IL-17发育途径作为Th1介导的抗真菌免疫抵抗的负调节因子，并发挥了先前归因于不受控制的Th1细胞反应的炎症作用。针对两种主要的人类真菌病原体白色念珠菌和烟曲霉的Th17反应增强，加剧了炎症和感染。IL-23作为不受控制的真菌生长与炎症之间的分子联系，由树突状细胞响应高真菌负荷而产生，并反调节IL-12p70的产生。IL-23和IL-17都破坏了中性粒细胞的炎症程序，这导致了与感染相关的严重组织炎症病理。我们的数据首次证明，IL-23/IL-17途径在传染病模型中促进炎症和易感性。由于IL-23驱动的炎症促进感染并损害抗真菌抵抗力，调节炎症反应代表了一种刺激对真菌的保护性免疫反应的潜在策略。
