Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.
Hepatobiliary Center, Key Laboratory of Liver Transplantation of Chinese Academy of Medical Sciences, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Hepatology. 2021 Oct;74(4):2118-2132. doi: 10.1002/hep.31906. Epub 2021 Aug 10.
BACKGROUND AND AIMS: Liver ischemia reperfusion injury (IRI) remains an unresolved clinical problem. This study dissected roles of liver-resident macrophage Kupffer cells (KCs), with a functional focus on efferocytosis receptor T-cell immunoglobulin and mucin domain-containing protein-4 (TIM-4), in both the activation and resolution of IRI in a murine liver partial warm ischemia model. APPROACH AND RESULTS: Fluorescence-activated cell sorting results showed that TIM-4 was expressed exclusively by KCs, but not infiltrating macrophages (iMФs), in IR livers. Anti-TIM-4 antibody depleted TIM-4 macrophages in vivo, resulting in either alleviation or deterioration of liver IRI, which was determined by the repopulation kinetics of the KC niche with CD11b macrophages. To determine the KC-specific function of TIM-4, we reconstituted clodronate-liposome-treated mice with exogenous wild-type or TIM-4-deficient KCs at either 0 hour or 24 hours postreperfusion. TIM-4 deficiency in KCs resulted in not only increases in the severity of liver IRI (at 6 hours postreperfusion), but also impairment of the inflammation resolution (at 7 days postreperfusion). In vitro analysis revealed that TIM-4 promoted KC efferocytosis to regulate their Toll-like receptor response by up-regulating IL-10 and down-regulating TNF-α productions. CONCLUSIONS: TIM-4 is critical for KC homeostatic function in both the activation and resolution of liver IRI by efferocytosis.
背景与目的：肝缺血再灌注损伤（IRI）仍然是一个未解决的临床问题。本研究在小鼠肝脏部分热缺血模型中，剖析了肝固有巨噬细胞库普弗细胞（KCs）的作用，其功能重点是吞噬作用受体 T 细胞免疫球蛋白和粘蛋白结构域蛋白 4（TIM-4），在IRI 的激活和解决中。 方法和结果：荧光激活细胞分选结果表明，TIM-4仅在 IR 肝脏中的 KCs 中表达，而不在浸润巨噬细胞（iMФs）中表达。抗 TIM-4 抗体在体内耗尽 TIM-4 巨噬细胞，导致肝 IRI 缓解或恶化，这取决于 KC 龛位中 CD11b 巨噬细胞的再填充动力学。为了确定 TIM-4 对 KC 的特异性功能，我们在用氯膦酸盐脂质体处理的小鼠中，在再灌注后 0 小时或 24 小时，用外源性野生型或 TIM-4 缺陷型 KCs 进行重建。KCs 中的 TIM-4 缺陷不仅导致肝 IRI 的严重程度增加（再灌注后 6 小时），而且还损害炎症的解决（再灌注后 7 天）。体外分析表明，TIM-4 通过上调 IL-10 和下调 TNF-α 的产生，促进 KC 吞噬作用，调节其 Toll 样受体反应。 结论：TIM-4 对通过吞噬作用调节肝 IRI 的激活和解决中 KC 的稳态功能至关重要。
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