| Objective The fungus Aspergillus fumigatus is the main pathogenic agent responsible for more than 90%of invasive aspergillosis cases,one of the most important invasive fungal infections of global concern.The increased level of drug resistance observed in Aspergillus clinical isolates further highlights the urgent need for the development of new therapies.A better understanding of host immunity against A.fumigatus will facilitate the identification of potential new strategies to improve host defense against invasive aspergillosis in at-risk patient groups.Interleukin-27?IL-27?is a pleiotropic cytokine composed of EBI3 and IL-27p28subunits,which signals through a heterodimeric receptor complex consisting of T-cell cytokine receptor?TCCR?/WSX-1?also known as IL-27R?and glycoprotein 130?gp130?,the former confers ligand specificity and the latter is shared by other IL-6 family cytokines.IL-27is principally produced by antigen-presenting cells?APC?such as dendrtic cells?DC?and monocytes/macrophages,and IL-27 has been shown to display complex immune-regulatory functions,which may result in either pro-/anti-activity depending on the biological context.It is unknown whether IL-27/IL-27R signaling influences susceptibility to aspergillosis.Therefore,the present study aimed to investigate the role of IL-27 in the immunopathology of invasive aspergillosis.Therefore,this study aims to study the immune function and mechanism of IL-27 in invasive pulmonary aspergillosis,and to provide new ideas for the study of the pathogenic mechanism and treatment strategy of pulmonary aspergillosis.Methods A bronchial injection of Aspergillus fumigatus spores?infection in the airways?was used to construct a mouse lung aspergillosis model,and the expression of IL-27 in blood and lungs of the mice was measured by ELISA.Animal experiments were performed on wild-type?WT?C57BL/6 mice and C57BL/6 background IL-27 receptor-deficient(IL-27R-/-)mice,from survival rate,fungal load,and HE staining,etc.to clear that IL-27 plays a detrimental role in pulmonary aspergillosis.The important role of IL-27 in pulmonary aspergillosis was further clarified by using flow cytometry,ELISA to detect related inflammatory cytokines,and in vivo and in vitro experiments by giving corresponding neutralizing antibodies.Results The expression of IL-27 in mice with pulmonary aspergillosis model was significantly increased,and it was involved in the immune process of the disease.Compared with WT mice,the survival rate of IL-27R-/-mice was significantly improved when Aspergillus fumigatus spores were attacked?p<0.05?,and their lung fungal load was significantly reduced?p<0.05?.In the alveolar lavage fluid of the two groups of mice,the albumin detection level and the number of white blood cells of the IL-27R-/-mice were significantly reduced?p<0.05?.It was found by ELISA that the expression levels of IL-6 and CCL-2 in the lungs of WT mice were significantly higher than those in defective mice?p<0.05?,which was consistent with the inflammation in the lungs of mice.Defects in IL-27R caused a significant increase in IFN-?production in the lungs after Aspergillus fumigatus infection?p<0.05?,and neutralizing IFN-?eliminated the resistance of IL-27R-/-mice to invasive Aspergillus pneumoniae infection.In vitro experiments show that IFN-?can enhance the conidiocidal activity of macrophages,but has no obvious effect on neutrophils.More importantly,neutralizing IL-27 can improve the bacterial clearance of mice with severe pneumonia,thereby significantly increasing their survival rate.Conclusion In a mouse model of invasive pulmonary aspergillosis,the expression of IL-27 is significantly increased,which can aggravate the development of Aspergillus fumigatus pneumonia by inhibiting the expression of the inflammatory factor IFN-?,and neutralizing IL-27 can significantly improve the survival rate of mice.This study suggests that IL-27 may be a potential target for controlling Aspergillus infection. |
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