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Updated: Jul 22, 2025
Assessing Anti-fungal Activity of Isolated Alveolar Macrophages by Confocal Microscopy
Published on: July 9, 2014
Targeted removal of macrophage-secreted interleukin-1 receptor antagonist protects against lethal Candida albicans
Hang Thi Thuy Gander-Bui1, Joëlle Schläfli2, Johanna Baumgartner1
1Division 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.
Abstract:
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.
Insights
Interleukin-1 receptor antagonist (IL-1Ra) from macrophages worsens invasive fungal infections. Neutralizing IL-1Ra restores immune function and cures lethal candidiasis, revealing a new therapeutic target.
Area of Science:
- Immunology
- Infectious Diseases
- Microbiology
Background:
- Invasive fungal infections, particularly candidiasis, have high mortality rates.
- Current treatment options are limited, highlighting the need to understand disease mechanisms.
Purpose of the Study:
- To investigate the role of interleukin-1 receptor antagonist (IL-1Ra) in disseminated Candida albicans infection.
- To explore IL-1Ra as a potential therapeutic target for invasive fungal infections.
Main Methods:
- Investigated the role of macrophage-secreted IL-1Ra in a mouse model of disseminated candidiasis.
- Analyzed the impact of IL-1Ra neutralization on neutrophil function and inflammation.
- Examined the effect of type I interferon on IL-1Ra secretion and disease severity.
Main Results:
- Macrophage-derived IL-1Ra is secreted in two distinct waves, hindering early neutrophil recruitment and pathogen containment.
- Therapeutic neutralization of IL-1Ra restored neutrophil function, resolved hyper-inflammation, and eradicated lethal infections.
- Type I interferon-induced augmentation of IL-1Ra secretion exacerbated disease mortality.
Conclusions:
- Macrophage-secreted IL-1Ra is a key mechanism underlying susceptibility to invasive candidiasis.
- IL-1Ra represents a potential biomarker and therapeutic target for severe systemic candidiasis.
- Interferon-stimulated IL-1Ra secretion may worsen fungal dissemination in human patients.
