Nickel Katrin F, Jämsä Anne, Konrath Sandra, Papareddy Praveen, Butler Lynn M, Stavrou Evi X, Frye Maike, Gelderblom Mathias, Nieswandt Bernhard, Hammerschmidt Sven, Herwald Heiko, Renné Thomas
Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Clinical Chemistry, Department of Molecular Medicine and Surgery, and Center of Molecular Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden.
J Exp Med. 2025 Jul 7;222(7). doi: 10.1084/jem.20250049. Epub 2025 Apr 22.
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.
血液凝固对于止血至关重要，但也会引发血栓栓塞性疾病。因子 XII（FXII）触发的凝血促进血栓形成，而对于止血并非必需，这使其成为潜在的抗凝靶点。然而，其生理作用仍不清楚。在此，我们证明 FXII 驱动的凝血通过捕获病原体和限制小鼠的细菌感染来增强先天免疫。肺炎链球菌感染在 FXII 缺陷（F12 - / -）小鼠中更为严重，肺部细菌负荷增加、全身扩散以及死亡率升高。同样，金黄色葡萄球菌皮肤感染和全身播散在 F12 - / - 小鼠中也加剧。用人 FXII 重建可恢复对细菌的控制。血浆激肽释放酶放大 FXII 激活，其缺乏与 F12 - / - 小鼠类似，加重了金黄色葡萄球菌皮肤感染。FXII 缺乏损害脓肿壁中的纤维蛋白沉积，导致包膜渗漏和细菌逃逸。细菌长链多聚磷酸盐激活 FXII，触发纤维蛋白形成。FXII 底物因子 XI 缺乏或 FXII/因子 XI 共同缺乏同样加剧了金黄色葡萄球菌感染。这些数据揭示了 FXII 驱动的凝血在宿主防御中的保护作用，这促使在开发针对该途径的治疗策略时要谨慎。
