Glycosphingolipids Mediate Pneumocystis Cell Wall β-Glucan Activation of the IL-23/IL-17 Axis in Human Dendritic Cells

被引:31
作者
Carmona, Eva M. [1 ,2 ]
Kottom, Theodore J. [1 ,2 ]
Hebrink, Deanne M. [1 ,2 ]
Moua, Teng [1 ,2 ]
Singh, Raman-Deep [1 ,2 ]
Pagano, Richard E. [1 ,2 ]
Limper, Andrew H. [1 ,2 ]
机构
[1] Mayo Clin & Mayo Fdn, Div Pulm Crit Care & Internal Med, Dept Med, Rochester, MN 55905 USA
[2] Mayo Clin & Mayo Fdn, Thorac Dis Res Unit, Rochester, MN 55905 USA
基金
美国国家卫生研究院;
关键词
Pneumocystis; beta-glucan; dendritic cells; IL-23; IL-17; ALVEOLAR EPITHELIAL-CELLS; FACTOR-KAPPA-B; CARINII-PNEUMONIA; LIPID RAFTS; TRANSCRIPTION FACTOR; SYNTHESIS INHIBITOR; RECEPTOR; DIFFERENTIATION; ARTHRITIS; DECTIN-1;
D O I
10.1165/rcmb.2011-0159OC
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Pneumocystis species are opportunistic fungal organisms that cause severe pneumonia in immune-compromised hosts, with resultant high morbidity and mortality. Recent work indicates that IL-17 responses are important components of host defense against fungal pathogens. In the present study, we demonstrate that cell-surface beta-glucan components of Pneumocystis (PCBG) stimulate human dendritic cells (DCs) to secrete IL-23 and IL-6. These cytokines are well established to stimulate a T helper-17 (Th17) phenotype. Accordingly, we further observe that PCBG-stimulated human DCs interact with lymphocytes to drive the secretion of IL-17 and IL-22, both Th17-produced cytokines. The activation of DCs was shown to involve the dectin-1 receptor with a downstream activation of the Syk kinase and subsequent translocation of both the canonical and noncanonical components of the NF-kappa B transcription factor family. Finally, we demonstrate that glycosphingolipid-rich microdomains of the plasma membrane participate in the activation of DCs by PCBG through the accumulation of lactosylceramide at the cell surface during stimulation with PCBG. These data strongly support the idea that the beta-glucan surface components of Pneumocystis drive the activation of the IL-23/IL-17 axis during this infection, through a glycosphingolipid-initiated mechanism.
引用
收藏
页码:50 / 59
页数:10
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