Wagdi Almishri1, Julie Deans2, Mark G Swain3. 1. Gastrointestinal Research Groups, Snyder Institute, Canada. 2. Immunology and Snyder Institute, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Alberta, Canada. 3. Immunology and Snyder Institute, Canada; Gastrointestinal Research Groups, Snyder Institute, Canada; Liver Unit, Division of Gastroenterology, Department of Medicine, University of Calgary, Alberta, Canada. Electronic address: swain@ucalgary.ca.
Abstract
BACKGROUND & AIMS: Invariant natural killer T (iNKT) cells are present within the liver and have been implicated in the development of many liver diseases. Upon activation by glycolipid ligands (including α-galactosylceramide; αGalCer), hepatic iNKT cells produce numerous cytokines and recruit both pro-inflammatory and regulatory immune cells. However, the involvement of B cells in this process is poorly defined. METHODS: Wild-type (male, C57BL/6), B cell deficient, or B cell depleted mice were injected with αGalCer or vehicle, hepatic B cell phenotype and liver injury was subsequently determined. RESULTS: iNKT cell activation resulted in liver injury and the rapid activation and hepatic recruitment of B cells (mainly innate-like B1 and MZ-like B cells) from the spleen and peritoneal cavity. B cells recruited to the liver produce IL-10 and TGFβ, and express cell surface CD73 (ectoenzyme which generates adenosine). B cell deficient mice developed augmented αGalCer-induced hepatitis, enhanced neutrophil recruitment and striking alterations in the hepatic cytokine milieu. αGalCer-induced hepatitis was unaltered in IL-10(-/-) mice, or after TGFβ neutralization, but was significantly worsened in mice treated with a CD73 inhibitor. CONCLUSIONS: iNKT cell stimulation recruits innate-like regulatory B cells to the liver which suppress hepatic inflammation through IL-10 and TGFβ1 independent mechanisms, but involve CD73 activity. These findings highlight an important inflammation suppressing role for B cells at early time points during the development of an innate immune response within the liver, and represent a potential therapeutic target for the treatment of liver disease.
BACKGROUND & AIMS: Invariant natural killer T (iNKT) cells are present within the liver and have been implicated in the development of many liver diseases. Upon activation by glycolipid ligands (including α-galactosylceramide; αGalCer), hepatic iNKT cells produce numerous cytokines and recruit both pro-inflammatory and regulatory immune cells. However, the involvement of B cells in this process is poorly defined. METHODS: Wild-type (male, C57BL/6), B cell deficient, or B cell depleted mice were injected with αGalCer or vehicle, hepatic B cell phenotype and liver injury was subsequently determined. RESULTS: iNKT cell activation resulted in liver injury and the rapid activation and hepatic recruitment of B cells (mainly innate-like B1 and MZ-like B cells) from the spleen and peritoneal cavity. B cells recruited to the liver produce IL-10 and TGFβ, and express cell surface CD73 (ectoenzyme which generates adenosine). B cell deficient mice developed augmented αGalCer-induced hepatitis, enhanced neutrophil recruitment and striking alterations in the hepatic cytokine milieu. αGalCer-induced hepatitis was unaltered in IL-10(-/-) mice, or after TGFβ neutralization, but was significantly worsened in mice treated with a CD73 inhibitor. CONCLUSIONS: iNKT cell stimulation recruits innate-like regulatory B cells to the liver which suppress hepatic inflammation through IL-10 and TGFβ1 independent mechanisms, but involve CD73 activity. These findings highlight an important inflammation suppressing role for B cells at early time points during the development of an innate immune response within the liver, and represent a potential therapeutic target for the treatment of liver disease.
Authors: Wagdi Almishri; Rachelle P Davis; Abdel-Aziz Shaheen; Mohammed O Altonsy; Craig N Jenne; Mark G Swain Journal: Front Immunol Date: 2021-03-25 Impact factor: 7.561
Authors: Daniel S Smyk; Athanasios Mavropoulos; Giorgina Mieli-Vergani; Diego Vergani; Marco Lenzi; Dimitrios P Bogdanos Journal: Can J Gastroenterol Hepatol Date: 2018-06-26