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Factor XII-driven coagulation traps bacterial infections

Nickel, Katrin F ; Jämsä, Anne ; Konrath, Sandra ; Papareddy, Praveen LU orcid ; Butler, Lynn M ; Stavrou, Evi X ; Frye, Maike ; Gelderblom, Mathias ; Nieswandt, Bernhard and Hammerschmidt, Sven , et al. (2025) In The Journal of experimental medicine 222(7).
Abstract

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... (More)

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.

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publishing date
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Contribution to journal
publication status
published
subject
keywords
Animals, Factor XII/metabolism, Blood Coagulation, Mice, Humans, Staphylococcus aureus/immunology, Mice, Inbred C57BL, Staphylococcal Infections/immunology, Mice, Knockout, Streptococcus pneumoniae/immunology, Bacterial Infections/immunology, Immunity, Innate, Pneumococcal Infections/immunology, Fibrin/metabolism
in
The Journal of experimental medicine
volume
222
issue
7
article number
e20250049
publisher
Rockefeller University Press
external identifiers
  • pmid:40261297
ISSN
1540-9538
DOI
10.1084/jem.20250049
language
English
LU publication?
yes
additional info
© 2025 Nickel et al.
id
078bd70e-66cd-446e-abed-94a126ade58e
date added to LUP
2025-05-01 14:41:06
date last changed
2025-05-06 15:45:41
@article{078bd70e-66cd-446e-abed-94a126ade58e,
  abstract     = {{<p>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.</p>}},
  author       = {{Nickel, Katrin F and Jämsä, Anne and Konrath, Sandra and Papareddy, Praveen and Butler, Lynn M and Stavrou, Evi X and Frye, Maike and Gelderblom, Mathias and Nieswandt, Bernhard and Hammerschmidt, Sven and Herwald, Heiko and Renné, Thomas}},
  issn         = {{1540-9538}},
  keywords     = {{Animals; Factor XII/metabolism; Blood Coagulation; Mice; Humans; Staphylococcus aureus/immunology; Mice, Inbred C57BL; Staphylococcal Infections/immunology; Mice, Knockout; Streptococcus pneumoniae/immunology; Bacterial Infections/immunology; Immunity, Innate; Pneumococcal Infections/immunology; Fibrin/metabolism}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{7}},
  publisher    = {{Rockefeller University Press}},
  series       = {{The Journal of experimental medicine}},
  title        = {{Factor XII-driven coagulation traps bacterial infections}},
  url          = {{http://dx.doi.org/10.1084/jem.20250049}},
  doi          = {{10.1084/jem.20250049}},
  volume       = {{222}},
  year         = {{2025}},
}