Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase.
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-1beta 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-1beta 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-1beta. 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-1beta; and a second signal, involving Syk-induced activation of the NLRP3 inflammasome and caspase-1, allowing processing and secretion of the mature cytokine.
Saïd-Sadier
Najwane
N
Health Sciences Research Institute and School of Natural Sciences, University of California Merced, Merced, California, USA.
Padilla
Eduardo
E
Langsley
Gordon
G
Ojcius
David M
DM
D001232:Aspergillus fumigatus / Q000276:immunology*; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D054884:Host-Pathogen Interactions; D006801:Humans; D025301:Hyphae; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D009000:Monocytes; D011188:Potassium / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D013172:Spores, Fungal; D000072377:Syk Kinase
D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D020170:Caspase 1; D011188:Potassium