Targeted removal of macrophage-secreted interleukin-1 receptor antagonist protects against lethal Candida albicans sepsis
Open accessAbstract
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.
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Macrophages but not neutrophils are known to produce IL-1Ra during C. albicans systemic infection.
“macrophages but not neutrophils are known to produce IL-1Ra during C. albicans systemic infection [35]”
C. albicans and C. auris infection induces IL-1Ra in macrophages and decreases the killing activity of neutrophils to different host niches, including the kidney and skin, respectively.
“Our results, along with others [35], suggest that C. albicans and C. auris infection induces IL-1Ra in macrophages and decreases the killing activity of neutrophils to different host niches, including the kidney and skin, respectively”
A recent study on C. albicans using a systemic mouse model of infection revealed the role of secreted IL-1Ra by splenic macrophages limits neutrophil activity in kidneys, contributing to immune evasion of fungi.
“A recent study on C. albicans using a systemic mouse model of infection revealed the role of secreted IL-1Ra by splenic macrophages limits the neutrophil activity in kidneys, contributing to the immune evasion of fungi [35]”
IL-1Ra is produced predominantly by macrophages in response to C. auris and inhibits IL-1α and IL-1β signaling by competitively binding to IL-1R.
“IL-1Ra is produced predominantly by macrophages in response to C. auris and inhibits IL-1α and IL-1β signaling by competitively binding to IL-1R [88,89].”
From Host–Candida auris interactions in the skin (2026) · cites this paper as [89]
Cites
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Balakumar, A., Das, D., Datta, A., Mishra, A., Bryak, G., Ganesh, S. M., Netea, M. G., Kumar, V., Lionakis, M. S., Arora, D., et al. (2024) · PLOS Pathogens · doi:10.1371/journal.ppat.1012699 · Cited by 25 · see citing works
Host–Candida auris interactions in the skin
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- Authors
- Gander-Bui, H. T. T., Schläfli, J., Baumgartner, J., Walthert, S., Genitsch, V., van Geest, G., Galván, J. A., Cardozo, C., Graham Martinez, C., Grans, M., Muth, S., Bruggmann, R., Probst, H. C., Gabay, C., & Freigang, S.
- Affiliations
- University of Bern (CH)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- University Hospital of Geneva (CH)
- Corresponding author
- Freigang, Stefan
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2023-08
- Volume
- 56
- Issue
- 8
- Pages
- 1743-1760.e9
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W4384938359
- Cited by
- 47
- References
- 5
- Citations by year
- 2026: 22 · 2025: 11 · 2024: 9 · 2023: 5
- FWCI
- 9.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Immunity (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
- Open Access CRIS of the University of Bern
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- interleukin-1 receptor antagonist, Candida albicans, invasive candidiasis, sepsis, macrophages, neutrophil recruitment, type I interferon, hyperinflammation, fungal dispersal, candidemia, immune regulation, therapeutic target, biomarkers
- MeSH terms
- Candida albicans, Candidiasis, Humans, Macrophages, Receptors, Interleukin-1, Sepsis, Interleukin 1 Receptor Antagonist Protein
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