Macrophage Depletion Attenuates Extracellular Matrix Deposition and Ductular Reaction in a Mouse Model of Chronic Cholangiopathies.
Chronic cholangiopathies, such as primary and secondary sclerosing cholangitis, are progressive disease entities, associated with periportal accumulation of inflammatory cells, encompassing monocytes and macrophages, peribiliary extracellular matrix (ECM) deposition and ductular reaction (DR). This study aimed to elucidate the relevance of macrophages in the progression of chronic cholangiopathies through macrophage depletion in a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) mouse model. One group of mice received a single i.p. injection of Clodronate encapsulated liposomes (CLOLipo) at day 7 of a 14 day DDC treatment, while control animals were co-treated with PBSLipo instead. Mice were sacrificed after 7 or respectively 14 days of treatment for immunohistochemical assessment of macrophage recruitment (F4/80), ECM deposition (Sirius Red, Laminin) and DR (CK19). Macrophage depletion during a 14 day DDC treatment resulted in a significant inhibition of ECM deposition. Porto-lobular migration patterns of laminin-rich ECM and ductular structures were significantly attenuated and a progression of DR was effectively inhibited by macrophage depletion. CLOLipo co-treatment resulted in a confined DR to portal regions without amorphous cell clusters. This study suggests that therapeutic options selectively directed towards macrophages might represent a feasible treatment for chronic cholestatic liver diseases.
Liver Cell Biology Laboratory, Department of Basic Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussel, Belgium.|Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
Jan
J
Best
Liver Cell Biology Laboratory, Department of Basic Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussel, Belgium.
Stefaan
S
Verhulst
Foundation for Liver Research, The Institute of Hepatology, London, United Kingdom.|Division of Gastroenterology and Hepatology, Medical University of South Carolina, Charleston, South Carolina, United States of America.|Section of Gastroenterology, Ralph H Johnson Veteran Affairs Medical Center, Charleston, South Carolina, United States of America.
Wing-Kin
WK
Syn
Liver Cell Biology Laboratory, Department of Basic Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussel, Belgium.
Kimberly
K
Lagaisse
Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussel, Belgium.
Noemi
N
van Hul
Department of Hepatology & Gastroenterology, Ghent University, Ghent, Belgium.
Femke
F
Heindryckx
Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
Jan-Peter
JP
Sowa
Liver Cell Biology Laboratory, Department of Basic Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussel, Belgium.
Liesbeth
L
Peeters
Department of Hepatology & Gastroenterology, Ghent University, Ghent, Belgium.
Hans
H
Van Vlierberghe
Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCL), Brussel, Belgium.
Isabelle A
IA
Leclercq
Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
Ali
A
Canbay
Liver Cell Biology Laboratory, Department of Basic Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussel, Belgium.
Laurent
L
Dollé
Liver Cell Biology Laboratory, Department of Basic Biomedical Sciences, Vrije Universiteit Brussel (VUB), Brussel, Belgium.
Leo A
http://orcid.org/0000-0002-0990-7034
LA
van Grunsven
D000818:Animals; D001649:Bile Duct Diseases / Q000378:metabolism / Q000473:pathology*; D001652:Bile Ducts / Q000473:pathology*; D049109:Cell Proliferation; D002908:Chronic Disease; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D008264:Macrophages / Q000473:pathology*; D051379:Mice