Department of Biological Sciences, Virginia Tech, 149 Life Science 1 Bldg, Blacksburg, VA, 24061-0910, USA.
Inflamm Res. 2023 Aug;72(8):1733-1744. doi: 10.1007/s00011-023-01779-z. Epub 2023 Aug 10.
Proper inflammation resolution is crucial to prevent runaway inflammation during sepsis and reduce sepsis-related mortality/morbidity. Previous studies suggest that deleting TRAM, a key TLR4 signaling adaptor, can reprogram the first inflammatory responder cell-neutrophil from an inflammatory state to a resolving state. In this study, we aim to examine the therapeutic potential of TRAM-deficient neutrophils in vivo with recipient mice undergoing experimental sepsis.
Wild-type or Tram mice were intraperitoneally injected with cecal slurry to induce either severe or mild sepsis. Phenotypic examinations of sepsis and neutrophil characteristics were examined in vivo and ex vivo. The propagations of resolution from donor neutrophils to recipient cells such as monocytes, T cells, and endothelial cells were examined through co-culture assays in vitro. The efficacies of Tram neutrophils in reducing inflammation were studied by transfusing either wild-type or Tram neutrophils into septic recipient mice.
Tram septic mice had improved survival and attenuated injuries within the lung and kidney tissues as compared to wild-type septic mice. Wild-type septic mice transfused with Tram resolving neutrophils exhibited reduced multi-organ damages and improved cellular homeostasis. In vitro co-culture studies revealed that donor Tram neutrophils can effectively propagate cellular homeostasis to co-cultured neighboring monocytes, neutrophils, T cells as well as endothelial cells.
Neutrophils with TRAM deletion render effective reprogramming into a resolving state beneficial for ameliorating experimental sepsis, with therapeutic potential in propagating cellular and tissue homeostasis as well as treating sepsis.
适当的炎症反应解决对于预防脓毒症中失控性炎症和降低脓毒症相关死亡率/发病率至关重要。先前的研究表明，删除 TLR4 信号转导的关键适配器 TRAM 可以将最初的炎症反应细胞-中性粒细胞从炎症状态重新编程为解决状态。在这项研究中，我们旨在使用接受实验性脓毒症的受体小鼠来检验 TRAM 缺陷中性粒细胞的治疗潜力。
野生型或 Tram 小鼠经腹腔注射盲肠内容物以诱导严重或轻度脓毒症。体内和体外检查脓毒症和中性粒细胞特征的表型检查。通过体外共培养实验研究供体中性粒细胞向受体细胞（如单核细胞、T 细胞和内皮细胞）传播解决的情况。通过将野生型或 Tram 中性粒细胞输注到脓毒症受体小鼠中，研究 Tram 中性粒细胞在减轻炎症中的功效。
与野生型脓毒症小鼠相比，Tram 脓毒症小鼠的存活率提高，肺和肾脏组织的损伤减轻。输注 Tram 解决中性粒细胞的野生型脓毒症小鼠表现出减少的多器官损伤和改善的细胞内稳态。体外共培养研究表明，供体 Tram 中性粒细胞可以有效地将细胞内稳态传播到共培养的邻近单核细胞、中性粒细胞、T 细胞和内皮细胞。
具有 TRAM 缺失的中性粒细胞有效地重新编程为解决状态，有利于改善实验性脓毒症，具有传播细胞和组织内稳态以及治疗脓毒症的治疗潜力。
