Assessment of ATP8B1 Deficiency in Pediatric Patients With Cholestasis Using Peripheral Blood Monocyte-Derived Macrophages.
Assessment of ATP8B1 Deficiency in Pediatric Patients With Cholestasis Using Peripheral Blood Monocyte-Derived Macrophages.
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DOI：
10.1016/j.ebiom.2017.10.007
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发表时间：
2018-01
期刊：
影响因子：
11.1
通讯作者：
Kusuhara H
中科院分区：
文献类型：
--
作者：
Hayashi H;Naoi S;Togawa T;Hirose Y;Kondou H;Hasegawa Y;Abukawa D;Sasaki M;Muroya K;Watanabe S;Nakano S;Minowa K;Inui A;Fukuda A;Kasahara M;Nagasaka H;Bessho K;Suzuki M;Kusuhara H
进行性家族性肝内胆汁淤积1型（PFIC 1）是一种罕见的遗传性隐性疾病，由ATP 8B 1基因缺陷引起，可进展为肝功能衰竭。由于难以基于其临床和组织学特征以及基因组测序将PFIC 1与PFIC的其他亚型区分开，因此需要用于诊断PFIC 1的替代方法。在此，我们分析了人外周血单核细胞衍生的巨噬细胞（HMDM），并发现在白细胞介素-10（IL-10）诱导的M2 c中主要表达ATP 8B 1，M2 c是一种交替活化的巨噬细胞亚群。在IL-10处理的HMDM中，siRNA介导的ATP 8B 1消耗显著抑制了M2 c相关表面标志物的表达，并增加了M2 c的侧向散射（SSC），这可能是通过损害IL-10/STAT 3信号转导途径实现的。这些表型特征在IL-10治疗的HMDM中得到了证实，这些HMDM来自4名PFIC 1患者，两个等位基因都有致病突变，但在4名其他PFIC亚型患者中没有得到证实。该方法在一组未通过基因组测序诊断的PFIC患者中鉴定了三名PFIC 1患者，这与通过分析肝脏标本和体外诱变研究获得的诊断结果相同。总之，ATP 8B 1缺陷导致HMDM不完全极化为M2 c。M2 c的表型分析有助于识别在ATP 8B 1中没有明显致病突变的PFIC 1患者。ATP 8B 1是PFIC 1的致病基因，在IL-10诱导的M2 c中表达，M2 c是交替激活的巨噬细胞的子集。ATP 8B 1缺陷导致HMDM不完全极化为M2 c，可能是通过IL-10/STAT 3信号传导受损。M2 c的表型分析有助于区分PFIC 1与其他未通过基因组分析诊断的儿科肝病。PFIC 1是一种罕见的遗传性隐性疾病，由ATP 8B 1的遗传缺陷引起，进展为肝功能衰竭。PFIC 1与PFIC的其他亚型有许多共同的临床和组织学特征，但其治疗选择不同。由于临床诊断为PFIC的患者的基因组测序不能总是识别致病突变，因此需要一种用于诊断PFIC 1的替代方法。我们鉴定了ATP 8B 1在IL-10诱导的M2 c（巨噬细胞的一个子集）中的表达，并证明了其对M2 c正常表型表达的贡献。M2 c的表型分析有助于区分PFIC 1与其他未通过基因组分析诊断的儿科肝病。
Progressive familial intrahepatic cholestasis type 1 (PFIC1), a rare inherited recessive disease resulting from a genetic deficiency in ATP8B1, progresses to liver failure. Because of the difficulty of discriminating PFIC1 from other subtypes of PFIC based on its clinical and histological features and genome sequencing, an alternative method for diagnosing PFIC1 is desirable. Herein, we analyzed human peripheral blood monocyte-derived macrophages (HMDM) and found predominant expression of ATP8B1 in interleukin-10 (IL-10)-induced M2c, a subset of alternatively activated macrophages. SiRNA-mediated depletion of ATP8B1 in IL-10-treated HMDM markedly suppressed the expression of M2c-related surface markers and increased the side scatter (SSC) of M2c, likely via impairment of the IL-10/STAT3 signal transduction pathway. These phenotypic features were confirmed in IL-10-treated HMDM from four PFIC1 patients with disease-causing mutations in both alleles, but not in those from four patients with other subtypes of PFIC. This method identified three PFIC1 patients in a group of PFIC patients undiagnosed by genome sequencing, an identical diagnostic outcome to that achieved by analysis of liver specimens and in vitro mutagenesis studies. In conclusion, ATP8B1 deficiency caused incomplete polarization of HMDM into M2c. Phenotypic analysis of M2c helps to identify PFIC1 patients with no apparent disease-causing mutations in ATP8B1. ATP8B1, a causal gene of PFIC1, was expressed in IL-10-induced M2c, a subset of alternatively activated macrophages. ATP8B1 deficiency caused incomplete polarization of HMDM into M2c, likely via impairment of IL-10/STAT3 signaling. Phenotypic analysis of M2c helps to discriminate PFIC1 from other pediatric liver diseases undiagnosed by genomic analysis. PFIC1, a rare inherited recessive disease resulting from a genetic deficiency in ATP8B1, progresses to liver failure. PFIC1 shares many clinical and histological features with other subtypes of PFIC, but differs in its therapeutic options. Because genome sequencing in patients with a clinical diagnosis of PFIC cannot always identify disease-causing mutations, an alternative method for diagnosing PFIC1 is desirable. We identified expression of ATP8B1 in IL-10-induced M2c, a subset of macrophages, and demonstrated its contribution to normal phenotypic expression of M2c. The phenotypic analysis of M2c helps to discriminate PFIC1 from other pediatric liver diseases undiagnosed by genomic analysis.
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