DataSheet_1_Susceptibility to Infections During Acute Liver Injury Depends on Transient Disruption of Liver Macrophage Niche.docx

Kupffer cells are the primary liver resident immune cell responsible for the liver firewall function, including clearance of bacterial infection from the circulation, as they are strategically positioned inside the liver sinusoid with intimate contact with the blood. Disruption in the tissue-resident macrophage niche, such as in Kupffer cells, can lead to a window of susceptibility to systemic infections, which represents a significant cause of mortality in patients with acetaminophen (APAP) overdose-induced acute liver injury (ALI). However, how Kupffer cell niche disruption increases susceptibility to systemic infections in ALI is not fully understood. Using a mouse model of ALI induced by APAP overdose, we found that Kupffer cells upregulated the apoptotic cell death program and were markedly reduced in the necrotic areas during the early stages of ALI, opening the niche for the infiltration of neutrophils and monocyte subsets. In addition, during the resolution phase of ALI, the remaining tissue macrophages with a Kupffer cell morphology were observed forming replicating cell clusters closer to necrotic areas devoid of Kupffer cells. Interestingly, mice with APAP-induced liver injury were still susceptible to infections despite the dual cellular input of circulating monocytes and proliferation of remaining Kupffer cells in the damaged liver. Therapy with bone marrow-derived macrophages (BMDM) was shown to be effective in occupying the niche devoid of Kupffer cells following APAP-induced ALI. The rapid BMDM migration to the liver and their positioning within necrotic areas enhanced the healing of the tissue and restored the liver firewall function after BMDM therapy. Therefore, we showed that disruption in the Kupffer cell niche and its impaired function during acute liver injury are key factors for the susceptibility to systemic bacterial infections. In addition, modulation of the liver macrophage niche was shown to be a promising therapeutic strategy for liver injuries that reduce the Kupffer cell number and compromise the organ function.

库普弗细胞（Kupffer cells）是肝脏主要的驻留免疫细胞，负责行使肝脏免疫屏障功能（liver firewall function），包括清除循环中的细菌感染病原体——因其精准定位于肝血窦（liver sinusoid）内，可与血液直接紧密接触。组织驻留巨噬细胞微环境（tissue-resident macrophage niche）的破坏（如库普弗细胞微环境受损）会引发一段全身感染易感期，这是对乙酰氨基酚（acetaminophen，APAP）过量诱导的急性肝损伤（acute liver injury，ALI）患者死亡的重要诱因之一。然而，急性肝损伤状态下库普弗细胞微环境破坏如何增加全身感染易感性的机制尚未完全阐明。本研究采用对乙酰氨基酚过量诱导的急性肝损伤小鼠模型，发现急性肝损伤早期阶段，库普弗细胞会上调细胞凋亡程序，并在坏死区域显著减少，从而为中性粒细胞与单核细胞亚群的浸润腾出了微环境空位。此外，在急性肝损伤的消退期，可观察到残留的具有库普弗细胞形态的组织巨噬细胞形成增殖细胞簇，聚集于缺乏库普弗细胞的坏死区域附近。有趣的是，尽管受损肝脏内存在循环单核细胞的浸润补充以及残留库普弗细胞的增殖双重细胞来源，对乙酰氨基酚诱导肝损伤的小鼠仍对感染易感。研究显示，骨髓源性巨噬细胞（bone marrow-derived macrophages，BMDM）疗法可有效占据对乙酰氨基酚诱导急性肝损伤后库普弗细胞缺失的微环境空位。骨髓源性巨噬细胞快速迁移至肝脏并定位于坏死区域，可增强组织修复并在治疗后恢复肝脏免疫屏障功能。综上，本研究证实急性肝损伤期间库普弗细胞微环境的破坏及其功能受损是引发全身细菌感染易感的关键因素。此外，调节肝脏巨噬细胞微环境有望成为针对库普弗细胞数量减少、器官功能受损的肝损伤的潜在治疗策略。