The Role of Neonatal Gr-1+ Myeloid Cells in a Murine Model of Rhesus-Rotavirus-Induced Biliary Atresia

Am J Pathol. 2018 Nov;188(11):2617-2628. doi: 10.1016/j.ajpath.2018.07.024. Epub 2018 Sep 8.

Abstract

Activation of innate immunity together with cholangiocyte damage occurs in biliary atresia (BA). However, detailed information on the inflammatory cells involved is lacking. This study investigates both the pathophysiology of CD11b+Gr-1+ cells in a mouse model of BA and their presence in BA patients. CD11b+Gr-1+ cells were targeted by an anti-Ly6G antibody in murine BA induced by inoculation with rhesus rotavirus. Expression of the Ly6G homolog CD177+ was examined in biopsies from BA patients. The symptoms of BA were ameliorated, and survival was prolonged in those mice receiving 5 to 10 μg of antibody per mouse every 3 days for four times compared with the mice treated with virus alone. However, the mice later developed chronic BA with persistent low body weight and jaundice. Hepatic inflammatory cells were reduced compared with acute BA. Blockade of extrahepatic bile ducts occurred, whereas intrahepatic ductules were partially preserved, and a progressive increase in liver fibrosis was observed. High levels of CD11b+Gr-1+ cells were present in these mice. The administration of an anti-Ly6G antibody again in those chronic BA mice reduced jaundice and restored body weight. In BA patients CD177+ cells were highly expressed in the liver. Our data suggest that the chronic mouse BA model shares key characteristics with clinical BA and indicates the importance of CD11b+Gr-1+ cells in the initiation and progression of BA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Antibodies, Monoclonal / pharmacology
  • Antigens, Ly / metabolism*
  • Biliary Atresia / drug therapy
  • Biliary Atresia / etiology*
  • Biliary Atresia / metabolism
  • Biliary Atresia / pathology
  • Disease Models, Animal*
  • GPI-Linked Proteins / immunology
  • GPI-Linked Proteins / metabolism
  • Humans
  • Infant
  • Isoantigens / immunology*
  • Isoantigens / metabolism
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / etiology*
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Mice
  • Mice, Inbred BALB C
  • Myeloid Cells / drug effects
  • Myeloid Cells / immunology*
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Receptors, Cell Surface / immunology*
  • Receptors, Cell Surface / metabolism
  • Rotavirus / pathogenicity*
  • Rotavirus Infections / complications
  • Rotavirus Infections / immunology*

Substances

  • Antibodies, Monoclonal
  • Antigens, Ly
  • CD177 protein, human
  • GPI-Linked Proteins
  • Isoantigens
  • Ly6G antigen, mouse
  • Receptors, Cell Surface