Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.

Invasive fungal infections by Candida albicans (Ca) are a frequent cause of lethal sepsis in intensive care unit patients. While a contribution of type I interferons (IFNs-I) in fungal sepsis remains unknown, these immunostimulatory cytokines mediate the lethal effects of endotoxemia and bacterial s...

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Autores principales:	Olivia Majer, Christelle Bourgeois, Florian Zwolanek, Caroline Lassnig, Dontscho Kerjaschki, Matthias Mack, Mathias Müller, Karl Kuchler
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/6324bc6ddc8248498c30959bdbb51009
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spelling	oai:doaj.org-article:6324bc6ddc8248498c30959bdbb510092021-11-18T06:04:10ZType I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.1553-73661553-737410.1371/journal.ppat.1002811https://doaj.org/article/6324bc6ddc8248498c30959bdbb510092012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22911155/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Invasive fungal infections by Candida albicans (Ca) are a frequent cause of lethal sepsis in intensive care unit patients. While a contribution of type I interferons (IFNs-I) in fungal sepsis remains unknown, these immunostimulatory cytokines mediate the lethal effects of endotoxemia and bacterial sepsis. Using a mouse model lacking a functional IFN-I receptor (Ifnar1⁻/⁻), we demonstrate a remarkable protection against invasive Ca infections. We discover a mechanism whereby IFN-I signaling controls the recruitment of inflammatory myeloid cells, including Ly6C(hi) monocytes and neutrophils, to infected kidneys by driving expression of the chemokines CCL2 and KC. Within kidneys, monocytes differentiate into inflammatory DCs but fail to functionally mature in Ifnar1⁻/⁻ mice, as demonstrated by the impaired upregulation of the key activation markers PDCA1 and iNOS. The increased activity of inflammatory monocytes and neutrophils results in hyper-inflammation and lethal kidney pathology. Pharmacological diminution of monocytes and neutrophils by treating mice with pioglitazone, a synthetic agonist of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ), strongly reduces renal immunopathology during Ca infection and improves mouse survival. Taken together, our data connect for the first time the sepsis-promoting functions of IFNs-I to the CCL2-mediated recruitment and the activation of inflammatory monocytes/DCs with high host-destructing potency. Moreover, our data demonstrate a therapeutic relevance of PPAR-γ agonists for microbial infectious diseases where inflammatory myeloid cells may contribute to fatal tissue damage.Olivia MajerChristelle BourgeoisFlorian ZwolanekCaroline LassnigDontscho KerjaschkiMatthias MackMathias MüllerKarl KuchlerPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 7, p e1002811 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Olivia Majer Christelle Bourgeois Florian Zwolanek Caroline Lassnig Dontscho Kerjaschki Matthias Mack Mathias Müller Karl Kuchler Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.
description	Invasive fungal infections by Candida albicans (Ca) are a frequent cause of lethal sepsis in intensive care unit patients. While a contribution of type I interferons (IFNs-I) in fungal sepsis remains unknown, these immunostimulatory cytokines mediate the lethal effects of endotoxemia and bacterial sepsis. Using a mouse model lacking a functional IFN-I receptor (Ifnar1⁻/⁻), we demonstrate a remarkable protection against invasive Ca infections. We discover a mechanism whereby IFN-I signaling controls the recruitment of inflammatory myeloid cells, including Ly6C(hi) monocytes and neutrophils, to infected kidneys by driving expression of the chemokines CCL2 and KC. Within kidneys, monocytes differentiate into inflammatory DCs but fail to functionally mature in Ifnar1⁻/⁻ mice, as demonstrated by the impaired upregulation of the key activation markers PDCA1 and iNOS. The increased activity of inflammatory monocytes and neutrophils results in hyper-inflammation and lethal kidney pathology. Pharmacological diminution of monocytes and neutrophils by treating mice with pioglitazone, a synthetic agonist of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ), strongly reduces renal immunopathology during Ca infection and improves mouse survival. Taken together, our data connect for the first time the sepsis-promoting functions of IFNs-I to the CCL2-mediated recruitment and the activation of inflammatory monocytes/DCs with high host-destructing potency. Moreover, our data demonstrate a therapeutic relevance of PPAR-γ agonists for microbial infectious diseases where inflammatory myeloid cells may contribute to fatal tissue damage.
format	article
author	Olivia Majer Christelle Bourgeois Florian Zwolanek Caroline Lassnig Dontscho Kerjaschki Matthias Mack Mathias Müller Karl Kuchler
author_facet	Olivia Majer Christelle Bourgeois Florian Zwolanek Caroline Lassnig Dontscho Kerjaschki Matthias Mack Mathias Müller Karl Kuchler
author_sort	Olivia Majer
title	Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.
title_short	Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.
title_full	Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.
title_fullStr	Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.
title_full_unstemmed	Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.
title_sort	type i interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during candida infections.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/6324bc6ddc8248498c30959bdbb51009
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Type I interferons promote fatal immunopathology by regulating inflammatory monocytes and neutrophils during Candida infections.

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