Perez-Toledo Marisol, Beristain-Covarrubias Nonantzin, Pillaye Jamie, Persaud Ruby R, Marcial-Juarez Edith, Jossi Sian E, Hitchcock Jessica R, Alshayea Areej, Channell William M, Wiersma Niek T J, Lamerton Rachel E, Kavanagh Dean P, Carestia Agostina, Horsnell William G, Henderson Ian R, Mackman Nigel, Clark Andrew R, Jenne Craig N, Rayes Julie, Watson Steve P, Cunningham Adam F
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK.
Nat Commun. 2025 Mar 10;16(1):2356. doi: 10.1038/s41467-025-57466-6.
Inflammation-induced thrombosis is a common consequence of bacterial infections, such as those caused by Salmonella Typhimurium (STm). The presentation of multi-organ thrombosis post-infection that develops and resolves with organ-specific kinetics raises significant challenges for its therapeutic control. Here, we identify specific inflammatory events driving thrombosis in the spleens and livers of STm-infected mice. IFN-γ or platelet expression of C-type lectin-like receptor CLEC-2, key drivers of thrombosis in liver, are dispensable for thrombosis in the spleen. Platelets, monocytes, and neutrophils are identified as core constituents of thrombi in both organs. Depleting either neutrophils or monocytic cells abrogates thrombus formation. Neutrophils and monocytes secrete TNF and blocking TNF diminishes both thrombosis and inflammation, which correlates with reduced endothelial expression of E-selectin and leukocyte infiltration. Moreover, inhibiting tissue factor and P-selectin glycoprotein ligand-1 pathways impairs thrombosis in both spleen and liver. Therefore, we identify organ-specific, and shared mechanisms driving thrombosis within a single infection. This may inform on tailoring treatments towards infection-induced inflammation, and single- or multi-organ thrombosis, based on the clinical need.
炎症诱导的血栓形成是细菌感染的常见后果，例如由鼠伤寒沙门氏菌（STm）引起的感染。感染后多器官血栓形成的表现及其随着器官特异性动力学的发展和消退，对其治疗控制提出了重大挑战。在此，我们确定了驱动STm感染小鼠脾脏和肝脏血栓形成的特定炎症事件。肝脏血栓形成的关键驱动因素——干扰素-γ或C型凝集素样受体CLEC-2的血小板表达，对于脾脏血栓形成并非必需。血小板、单核细胞和中性粒细胞被确定为两个器官中血栓的核心成分。耗尽中性粒细胞或单核细胞可消除血栓形成。中性粒细胞和单核细胞分泌肿瘤坏死因子（TNF），阻断TNF可减少血栓形成和炎症，这与内皮细胞E-选择素表达降低和白细胞浸润减少相关。此外，抑制组织因子和P-选择素糖蛋白配体-1途径会损害脾脏和肝脏中的血栓形成。因此，我们确定了单一感染中驱动血栓形成的器官特异性和共同机制。这可能有助于根据临床需求针对感染诱导的炎症以及单器官或多器官血栓形成制定个性化治疗方案。
