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

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2017 Nov 7

PMID 29104077

Citations 9

Authors

Hisamitsu Hayashi

Sotaro Naoi

Takao Togawa

Yu Hirose

Hiroki Kondou

Yasuhiro Hasegawa

Daiki Abukawa

Mika Sasaki

Koji Muroya

Satoshi Watanabe

Satoshi Nakano

Kei Minowa

Ayano Inui

Akinari Fukuda

Mureo Kasahara

Hironori Nagasaka

Kazuhiko Bessho

Mitsuyoshi Suzuki

Hiroyuki Kusuhara

Affiliations

Soon will be listed here.

Abstract

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.

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