Targeted removal of macrophage-secreted interleukin-1 receptor antagonist protects against lethal Candida albicans sepsis.

Autor:	Gander-Bui HTT; Division of Experimental Pathology, Institute of Tissue Medicine and Pathology, University of Bern, 3008 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland., Schläfli J; Division of Experimental Pathology, Institute of Tissue Medicine and Pathology, University of Bern, 3008 Bern, Switzerland., Baumgartner J; Division of Experimental Pathology, Institute of Tissue Medicine and Pathology, University of Bern, 3008 Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland., Walthert S; Division of Experimental Pathology, Institute of Tissue Medicine and Pathology, University of Bern, 3008 Bern, Switzerland., Genitsch V; Institute of Tissue Medicine and Pathology, University of Bern, 3008 Bern, Switzerland., van Geest G; Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, 3012 Bern, Switzerland., Galván JA; Institute of Tissue Medicine and Pathology, University of Bern, 3008 Bern, Switzerland., Cardozo C; Institute of Tissue Medicine and Pathology, University of Bern, 3008 Bern, Switzerland., Graham Martinez C; Institute of Tissue Medicine and Pathology, University of Bern, 3008 Bern, Switzerland., Grans M; Institute for Immunology, University Medical Center Mainz, 55131 Mainz, Germany., Muth S; Institute for Immunology, University Medical Center Mainz, 55131 Mainz, Germany., Bruggmann R; Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Bern, 3012 Bern, Switzerland., Probst HC; Institute for Immunology, University Medical Center Mainz, 55131 Mainz, Germany., Gabay C; Division of Rheumatology, Department of Medicine, University Hospital of Geneva, 1211 Geneva, Switzerland., Freigang S; Division of Experimental Pathology, Institute of Tissue Medicine and Pathology, University of Bern, 3008 Bern, Switzerland. Electronic address: stefan.freigang@unibe.ch.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2023 Aug 08; Vol. 56 (8), pp. 1743-1760.e9. Date of Electronic Publication: 2023 Jul 20.
DOI:	10.1016/j.immuni.2023.06.023
Abstrakt:	Invasive fungal infections are associated with high mortality rates, and the lack of efficient treatment options emphasizes an urgency to identify underlying disease mechanisms. We report that disseminated Candida albicans infection is facilitated by interleukin-1 receptor antagonist (IL-1Ra) secreted from macrophages in two temporally and spatially distinct waves. Splenic CD169 + macrophages release IL-1Ra into the bloodstream, impeding early neutrophil recruitment. IL-1Ra secreted by monocyte-derived tissue macrophages further impairs pathogen containment. Therapeutic IL-1Ra neutralization restored the functional competence of neutrophils, corrected maladapted hyper-inflammation, and eradicated the otherwise lethal infection. Conversely, augmentation of macrophage-secreted IL-1Ra by type I interferon severely aggravated disease mortality. Our study uncovers how a fundamental immunoregulatory mechanism mediates the high disease susceptibility to invasive candidiasis. Furthermore, interferon-stimulated IL-1Ra secretion may exacerbate fungal dissemination in human patients with secondary candidemia. Macrophage-secreted IL-1Ra should be considered as an additional biomarker and potential therapeutic target in severe systemic candidiasis. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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