Factor XII–driven coagulation traps bacterial infections
Blood coagulation is essential for stopping bleeding but also drives thromboembolic disorders. Factor XII (FXII)-triggered coagulation promotes thrombosis while being dispensable for hemostasis, making it a potential anticoagulant target. However, its physiological role remains unclear. Here, we demonstrate that FXII-driven coagulation enhances innate immunity by trapping pathogens and restricting bacterial infection in mice. Streptococcus pneumoniae infection was more severe in FXII-deficient (F12-/-) mice, with increased pulmonary bacterial burden, systemic spread, and mortality. Similarly, Staphylococcus aureus skin infections and systemic dissemination were exacerbated in F12-/- mice. Reconstitution with human FXII restored bacterial containment. Plasma kallikrein amplifies FXII activation, and its deficiency aggravated S. aureus skin infections, similarly to F12-/- mice. FXII deficiency impaired fibrin deposition in abscess walls, leading to leaky capsules and bacterial escape. Bacterial long-chain polyphosphate activated FXII, triggering fibrin formation. Deficiency in FXII substrate factor XI or FXII/factor XI co-deficiency similarly exacerbated S. aureus infection. The data reveal a protective role for FXII-driven coagulation in host defense, urging caution in developing therapeutic strategies targeting this pathway.
Authors
- Bernhard Nieswandt (ORCID: https://orcid.org/0000-0003-1454-7413)
- Lynn M. Butler (ORCID: https://orcid.org/0000-0002-2352-8217)
- Maike Frye (ORCID: https://orcid.org/0000-0002-6257-7636)
- Evi X. Stavrou (ORCID: https://orcid.org/0000-0002-6075-7609)
- Thomas Renné (ORCID: https://orcid.org/0000-0003-4594-5975)
- Sandra Konrath (ORCID: https://orcid.org/0009-0007-2336-8982)
- Sven Hammerschmidt (ORCID: https://orcid.org/0000-0002-6382-6681)
- Mathias Gelderblom (ORCID: https://orcid.org/0000-0002-4254-3439)
- Praveen Papareddy (ORCID: https://orcid.org/0000-0002-3872-478X)
- Anne Jämsä
- Heiko Herwald (ORCID: https://orcid.org/0000-0002-8111-2842)
- Katrin F. Nickel (ORCID: https://orcid.org/0000-0003-1287-6766)
Institutions
- Karolinska University Hospital (SE)
- Royal College of Surgeons in Ireland (IE)
- Universität Hamburg (DE)
- Lund University (SE)
- Johannes Gutenberg University Mainz (DE)
- University of Würzburg (DE)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Universität Greifswald (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- University Medical Center Hamburg-Eppendorf (DE)
- Louis Stokes Cleveland VA Medical Center (US)
- Universitätsklinikum Würzburg (DE)
- German Centre for Cardiovascular Research (DE)
- University School (US)
- Case Western Reserve University (US)
- UiT The Arctic University of Norway (NO)
- KTH Royal Institute of Technology (SE)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-04-22
- DOI
- https://doi.org/10.1084/jem.20250049
- Citations
- 8
- Primary Topic
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Type
- article
- Field-Weighted Citation Impact
- 13.00
Funders
- Case Western Reserve University
- Deutsche Forschungsgemeinschaft
- Vetenskapsrådet
- Gesellschaft für Thrombose- und Hämostaseforschung
- National Institutes of Health
- H2020 European Research Council