Background & Aim Following acetaminophen (APAP) overdose, acute liver injury (ALI) can occur in patients that present too late for N-acetylcysteine treatment, potentially leading to acute liver failure, systemic inflammation, and death. Macrophages influence the progression and resolution of ALI due to their innate immunological function and paracrine activity. Syngeneic primary bone marrow-derived macrophages (BMDMs) were tested as a cell-based therapy in a mouse model of APAP-induced ALI (APAP-ALI). Methods Several phenotypically distinct BMDM populations were delivered intravenously to APAP-ALI mice when hepatic necrosis was established, and then evaluated based on their effects on injury, inflammation, immunity, and regeneration. In vivo phagocytosis assays were used to interrogate the phenotype and function of alternatively activated BMDMs (AAMs) post-injection. Finally, primary human AAMs sourced from healthy volunteers were evaluated in immunocompetent APAP-ALI mice. Results BMDMs rapidly localised to the liver and spleen within 4 h of administration. Injection of AAMs specifically reduced hepatocellular necrosis, HMGB1 translocation, and infiltrating neutrophils following APAP-ALI. AAM delivery also stimulated proliferation in hepatocytes and endothelium, and reduced levels of several circulating proinflammatory cytokines within 24 h. AAMs displayed a high phagocytic activity both in vitro and in injured liver tissue post-injection. Crosstalk with the host innate immune system was demonstrated by reduced infiltrating host Ly6Chi macrophages in AAM-treated mice. Importantly, therapeutic efficacy was partially recapitulated using clinical-grade primary human AAMs in immunocompetent APAP-ALI mice, underscoring the translational potential of these findings. Conclusion We identify that AAMs have value as a cell-based therapy in an experimental model of APAP-ALI. Human AAMs warrant further evaluation as a potential cell-based therapy for APAP overdose patients with established liver injury. Lay summary After an overdose of acetaminophen (paracetamol), some patients present to hospital too late for the current antidote (N-acetylcysteine) to be effective. We tested whether macrophages, an injury-responsive leukocyte that can scavenge dead/dying cells, could serve as a cell-based therapy in an experimental model of acetaminophen overdose. Injection of alternatively activated macrophages rapidly reduced liver injury and reduced several mediators of inflammation. Macrophages show promise to serve as a potential cell-based therapy for acute liver injury.

中文翻译：

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选择性活化的巨噬细胞促进急性肝损伤后坏死的消退

背景与目的 对乙酰氨基酚 (APAP) 过量服用后，对 N-乙酰半胱氨酸治疗太晚的患者可能发生急性肝损伤 (ALI)，可能导致急性肝功能衰竭、全身炎症和死亡。由于其先天免疫功能和旁分泌活性，巨噬细胞影响 ALI 的进展和消退。在 APAP 诱导的 ALI (APAP-ALI) 小鼠模型中，同基因原代骨髓衍生巨噬细胞 (BMDM) 作为基于细胞的疗法进行了测试。方法 当肝坏死建立时，将几种表型不同的 BMDM 群体静脉注射给 APAP-ALI 小鼠，然后根据它们对损伤、炎症、免疫和再生的影响进行评估。体内吞噬作用测定用于询问注射后交替激活的 BMDM (AAM) 的表型和功能。最后，在免疫活性 APAP-ALI 小鼠中评估了来自健康志愿者的原代人类 AAM。结果 BMDMs 在给药后 4 小时内迅速定位于肝脏和脾脏。注射 AAMs 特别减少了 APAP-ALI 后的肝细胞坏死、HMGB1 易位和浸润的中性粒细胞。AAM 递送还刺激了肝细胞和内皮细胞的增殖，并在 24 小时内降低了几种循环促炎细胞因子的水平。AAMs 在体外和注射后损伤的肝组织中均显示出高吞噬活性。与宿主先天免疫系统的串扰通过 AAM 处理的小鼠中浸润宿主 Ly6Chi 巨噬细胞的减少来证明。重要的是，在免疫活性 APAP-ALI 小鼠中使用临床级原代人类 AAM 部分地概括了治疗功效，强调了这些发现的转化潜力。结论 我们确定 AAM 在 APAP-ALI 实验模型中作为基于细胞的疗法具有价值。人类 AAM 值得进一步评估，作为一种潜在的基于细胞的疗法，用于治疗已确定肝损伤的 APAP 过量患者。小结 在过量服用对乙酰氨基酚（扑热息痛）后，一些患者到医院太晚，目前的解毒剂（N-乙酰半胱氨酸）无法发挥作用。我们在对乙酰氨基酚过量的实验模型中测试了巨噬细胞（一种可以清除死亡/垂死细胞的损伤反应性白细胞）是否可以作为基于细胞的疗法。注射交替活化的巨噬细胞可迅速减少肝损伤并减少多种炎症介质。巨噬细胞有望作为一种潜在的基于细胞的急性肝损伤疗法。