Assessment of ATP8B1 Deficiency in Pediatric Patients With Cholestasis Using Peripheral Blood Monocyte-Derived Macrophages

作者：Hayashi Hisamitsu^*; Naoi Sotaro; Togawa Takao; Hirose Yu; Kondou Hiroki; Hasegawa Yasuhiro; Abukawa Daiki; Sasaki Mika; Muroya Koji; Watanabe Satoshi; Nakano Satoshi; Minowa Kei; Inui Ayano; Fukuda Akinari; Kasahara Mureo; Nagasaka Hironori; Bessho Kazuhiko; Suzuki Mitsuyoshi; Kusuhara Hiroyuki

来源：EBioMedicine, 2018, 27: 187-199.

DOI：10.1016/j.ebiom.2017.10.007

• Pediatric liver disease
• Diagnosis
• Progressive familial intrahepatic cholestasis

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)-inducedM2c, 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.

• 出版日期2018-1