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Candida Albicans Triggers NADPH Oxidase-Independent Neutrophil Extracellular Traps Through dectin-2

Candida Albicans Triggers NADPH Oxidase-Independent Neutrophil Extracellular Traps Through dectin-2

Sheng-Yang Wu, Chia-Lin Weng, Min-Jhen Jheng, Hung-Wei Kan, Sung-Tsang Hsieh, Fu-Tong Liu, Betty A Wu-Hsieh

PLoS Pathog. 2019 Nov 6;15(11):e1008096.

PMID: 31693704

Abstract:

Candida albicans is one of the top leading causes of healthcare-associated bloodstream infection. Neutrophil extracellular traps (NET) are known to capture and kill pathogens. It is reported that opsonized C. albicans-triggered NETosis is NADPH oxidase-dependent. We discovered a NADPH oxidase-independent NETosis pathway in neutrophil response to unopsonized C. albicans. While CR3 engagement with opsonized C. albicans triggered NET, dectin-2 recognized unopsonized C. albicans and mediated NET formation. Engagement of dectin-2 activated the downstream Syk-Ca2+-PKCδ-protein arginine deiminase 4 (PAD4) signaling pathway which modulated nuclear translocation of neutrophil elastase (NE), histone citrullination and NETosis. In a C. albicans peritonitis model we observed Ki67+Ly6G+ NETotic cells in the peritoneal exudate and mesenteric tissues within 3 h of infection. Treatment with PAD4 inhibitor GSK484 or dectin-2 deficiency reduced % Ki67+Ly6G+ cells and the intensity of Ki67 in peritoneal neutrophils. Employing DNA digestion enzyme micrococcal nuclease, GSK484 as well as dectin-2-deficient mice, we further showed that dectin-2-mediated PAD4-dependent NET formation in vivo restrained the spread of C. albicans from the peritoneal cavity to kidney. Taken together, this study reveals that unopsonized C. albicans evokes NADPH oxidase-independent NETosis through dectin-2 and its downstream signaling pathway and dectin-2-mediated NET helps restrain fungal dissemination.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1652591815	GSK484		1652591-81-5	Price

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