Aspergillus fumigatus Stimulates the NLRP3 Inflammasome through a Pathway Requiring ROS Production and the Syk Tyrosine Kinase

被引:224
作者
Said-Sadier, Najwane [1 ,2 ,3 ]
Padilla, Eduardo [1 ,2 ]
Langsley, Gordon [3 ,4 ]
Ojcius, David M. [1 ,2 ]
机构
[1] Univ Calif Merced, Hlth Sci Res Inst, Merced, CA USA
[2] Univ Calif Merced, Sch Nat Sci, Merced, CA USA
[3] Univ Paris Diderot, Grad Grp Biochim Biotherapies Biol Mol & Infectio, Paris, France
[4] Univ Paris 05, CNRS, UMR 8104, Inst Cochin,INSERM,U1016, Paris, France
来源
PLOS ONE | 2010年 / 5卷 / 03期
关键词
INNATE IMMUNE RECOGNITION; INVASIVE ASPERGILLOSIS; HOST-DEFENSE; CASPASE-1; ACTIVATION; FUNGAL-INFECTIONS; CANDIDA-ALBICANS; RECEPTORS; DECTIN-1; PROTEIN; CELLS;
D O I
10.1371/journal.pone.0010008
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Invasive aspergillosis (IA) is a life-threatening disease that occurs in immunodepressed patients when infected with Aspergillus fumigatus. This fungus is the second most-common causative agent of fungal disease after Candida albicans. Nevertheless, much remains to be learned about the mechanisms by which A. fulmigatus activates the innate immune system. We investigated the inflammatory response to conidia and hyphae of A. fumigatus and specifically, their capacity to trigger activation of an inflammasome. Our results show that in contrast to conidia, hyphal fragments induce NLRP3 inflammasome assembly, caspase-1 activation and IL-1 beta release from a human monocyte cell line. The ability of Aspergillus hyphae to activate the NLRP3 inflammasome in the monocytes requires K+ efflux and ROS production. In addition, our data show that NLRP3 inflammasome activation as well as pro-IL-1 beta expression relies on the Syk tyrosine kinase, which is downstream from the pathogen recognition receptor Dectin-1, reinforcing the importance of Dectin-1 in the innate immune response against fungal infection. Furthermore, we show that treatment of monocytes with corticosteroids inhibits transcription of the gene encoding IL-1 beta. Thus, our data demonstrate that the innate immune response against A. fumigatus infection involves a two step activation process, with a first signal promoting expression and synthesis of pro-IL-1 beta; and a second signal, involving Syk-induced activation of the NLRP3 inflammasome and caspase-1, allowing processing and secretion of the mature cytokine.
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页数:10
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