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

Immunity 2023 Aug 08

filter terms:

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. Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

Hang Thi Thuy Gander-Bui, Joëlle Schläfli, Johanna Baumgartner, Sabrina Walthert, Vera Genitsch, Geert van Geest, José A Galván, Carmen Cardozo, Cristina Graham Martinez, Mona Grans, Sabine Muth, Rémy Bruggmann, Hans Christian Probst, Cem Gabay, Stefan Freigang. Targeted removal of macrophage-secreted interleukin-1 receptor antagonist protects against lethal Candida albicans sepsis. Immunity. 2023 Aug 08;56(8):1743-1760.e9