Monocyte-macrophage membrane expression of IL-1R2 is a severity biomarker in sepsis
Interleukin-1 (IL-1)/IL-1 receptor family consists of activators and inhibitors which play a key role in inflammation, emergency myelopoiesis, and myeloid cell activation. The latter includes the IL-1R2 decoy receptor. To investigate the expression and significance of IL-1R2 in sepsis, we conducted high-dimensional flow cytometry of circulating cells from patients stratified according to the Sequential Sepsis-Related Organ Failure Assessment (SOFA) score. Here we report that the IL-1 decoy receptor is selectively upregulated on the plasma membrane of leukocytes and, in particular, monocytes from septic patients, and downregulated in septic shock. Flow cytometry combined with transcriptomic analysis of publicly available datasets indicated that IL-1R2 is associated with the differentiation of monocytes to a population of circulating monocytic cells with macrophage features (Mono/Mφ). In vitro stimulation of monocytes from healthy donors with Colony Stimulating Factors (CSFs), in particular GM-CSF and Lipopolysaccharides (LPS), induced IL-1R2<sup>+</sup> Mono/Mφ, which recapitulated the characteristics of sepsis-associated monocytic cells, including low expression of HLA-DR, high levels of macrophage markers such as MS4A4A and CD63, immune checkpoints, immunosuppressive molecules and selected scavenger receptors. Membrane-associated IL-1R2 and MS4A4A correlated with immunological markers, cytokine storm, and clinical parameters (e.g., SOFA score, creatinine, survival), reflecting the infection severity in hospitalized patients.Thus, in sepsis IL-1R2 is expressed in a subset of circulating monocytes co-expressing mature macrophage and immune dysfunction features with clinical significance.
Authors
- Francesco Scavello (ORCID: https://orcid.org/0000-0002-0297-0946)
- Rita Silva-Gomes (ORCID: https://orcid.org/0000-0003-1529-3777)
- Stefanos Bonovas (ORCID: https://orcid.org/0000-0001-6102-6579)
- Antonio Desai (ORCID: https://orcid.org/0000-0003-4674-4905)
- Sarah N. Mapelli (ORCID: https://orcid.org/0000-0002-0129-2055)
- Cecília Garlanda (ORCID: https://orcid.org/0000-0002-1510-7703)
- Carlo Mario Fedeli (ORCID: https://orcid.org/0000-0003-2971-3154)
- Diletta Di Mitri (ORCID: https://orcid.org/0000-0002-9626-4259)
- Roberto Leone (ORCID: https://orcid.org/0000-0003-4978-7847)
- Alberto Mantovani (ORCID: https://orcid.org/0000-0001-5578-236X)
- Sonia Valentino (ORCID: https://orcid.org/0000-0001-8652-3168)
- Daniele Piovani (ORCID: https://orcid.org/0000-0002-1414-6639)
- Andrea Mariancini (ORCID: https://orcid.org/0000-0003-1980-4423)
- Federica Portale (ORCID: https://orcid.org/0000-0002-4730-5931)
- Silvia Carnevale (ORCID: https://orcid.org/0000-0002-9176-5636)
- Elena Magrini (ORCID: https://orcid.org/0000-0003-1507-2325)
- Rita Garuti (ORCID: https://orcid.org/0009-0008-8551-8832)
- Barbara Bottazzi (ORCID: https://orcid.org/0000-0002-1930-9257)
- Sadaf Davoudian (ORCID: https://orcid.org/0000-0002-5080-7836)
- Marina Sironi (ORCID: https://orcid.org/0000-0002-3342-1149)
- Domenico Supino (ORCID: https://orcid.org/0000-0001-9690-1791)
- D.P. Comina (ORCID: https://orcid.org/0000-0003-4474-3634)
- Antonio Voza
Institutions
- Humanitas University (IT)
- Queen Mary University of London (GB)
- William Harvey Research Institute (GB)
- IRCCS Humanitas Research Hospital (IT)
- University of Minho (PT)
Publication Details
- Journal
- Cell Death and Disease
- Published
- 2025-04-09
- DOI
- https://doi.org/10.1038/s41419-025-07597-x
- Citations
- 12
- Primary Topic
- Sepsis Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 16.25
Funders
- European Commission
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro
- Horizon 2020 Framework Programme
- Fundação para a Ciência e a Tecnologia