B cell-mediated maintenance of CD169+ cells is critical for liver regeneration

K Vogel; Y Zhuang; X Haifeng; B Sundaram; J Huang; M Reich; AV Tumanov; R Polz; J Scheller; CF Ware; K Pfeffer; V Keitel; D Häussinger; AA Pandyra; KS Lang; PA Lang

doi:10.1055/s-0038-1677107

Zeitschrift für Gastroenterologie, Table of Contents

Z Gastroenterol 2019; 57(01): e26
DOI: 10.1055/s-0038-1677107

1. Basic Hepatology (Fibrogenesis, NPC, Transport)

Georg Thieme Verlag KG Stuttgart · New York

B cell-mediated maintenance of CD169+ cells is critical for liver regeneration

K Vogel

¹Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany

,

Y Zhuang

¹Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany

,

X Haifeng

¹Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany

,

B Sundaram

¹Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany

,

J Huang

¹Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany

,

M Reich

²Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany

,

AV Tumanov

³Department of Microbiology, Immunology & Molecular Genetics, University of Texas Health Science Center, San Antonio, TX 78229,

,

R Polz

⁴Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany,

,

J Scheller

⁴Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany,

,

CF Ware

⁵Infectious and Inflammatory Diseases Research Center, Sanford Burnham Prebys Medical Discovery Research Institute, La Jolla, CA 92037,

,

K Pfeffer

⁶Institute of Medical Microbiology and Hospital Hygiene, University Hospital, Heinrich-Heine-University, Düsseldorf, Germany,

,

V Keitel

²Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany

,

D Häussinger

²Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany

,

AA Pandyra

¹Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany

,

KS Lang

⁷Institute of Immunology, Medical Faculty, University of Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany.

,

PA Lang

¹Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitätsstr. 1, 40225 Düsseldorf, Germany

› Author Affiliations

Abstract

Full Text

Introduction:

The liver has an extraordinary capacity to regenerate via activation of key molecular pathways. Loss of at least 30% of liver mass, leads to synchronized proliferation of mature hepatocytes and rapid restoration of liver mass via compensatory hyperplasia. However, central regulators controlling liver regeneration such as the contribution of B cells and CD169+ cells during liver regeneration remain insufficiently studied.

Methods:

To analyze the dynamic processes during liver regeneration, we performed Partial Hepatectomy (PHx) and Splenectomy (Sx) in different Knockout-mice without and after antibody treatment or IL-6/IL-6R injection. Using kinetics we examined the gene expression profile of liver and spleen tissue after PHx. H/E-staining of liver sections and cytokine ELISAs were performed and serum protein levels were analyzed.

Results:

Here we show that B cell-deficient animals failed to induce sufficient liver regeneration after partial hepatectomy (PHx). Consistently, adoptive transfer of B cells could rescue defective liver regeneration. B cell mediated lymphotoxin beta production promoted recovery from PHx. Absence of B cells coincided with loss of splenic CD169+ macrophages. Moreover, depletion of CD169+ cells resulted in defective liver regeneration and decreased survival, which was associated with reduced hepatocyte proliferation. Mechanistically, CD169+ cells contributed to liver regeneration by inducing hepatic IL-6 production. Accordingly, treatment of CD169+ cell depleted animals with IL-6/Il-6R rescued severe pathology following PHx.

In conclusion, we identified CD169+ cells to be a central trigger for liver regeneration, by inducing several key signaling pathways important for liver regeneration.