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FASEB J. 2016 Dec;30(12):4202-4213. Epub 2016 Sep 14.

Galectin-3 regulates inflammasome activation in cholestatic liver injury.

Author information

1
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA.
2
State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
3
Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis Medical Center, Sacramento, California, USA.
4
Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA.
5
Institute of Biomedical Sciences, Academia Sinica, Taipei City, Taiwan.
6
Department of Molecular Biosciences, University of California Davis, Sacramento, California, USA.
7
Department of Pathology, University of California Davis Medical Center, Sacramento, California, USA; and.
8
Veterans Administration Northern California Medical Center, Mather, California, USA.
9
Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA; joyjiang@ucdavis.edu.

Abstract

Macrophage activation is an important feature of primary biliary cholangitis (PBC) pathogenesis and other cholestatic liver diseases. Galectin-3 (Gal3), a pleiotropic lectin, is produced by monocytic cells and macrophages. However, its role in PBC has not been addressed. We hypothesized that Gal3 is a key to induce NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in macrophages and in turn to propagate proinflammatory IL-17 signaling. In liver tissues from patients with PBC and dnTGF-βRII mice, a model of autoimmune cholangitis, the expression of Gal3, NLRP3, and the adaptor protein adaptor apoptosis-associated speck-like protein was induced, with the downstream activation of caspase-1 and IL-1β. In wild-type hepatic macrophages, deoxycholic acid induced the association of Gal3 and NLRP3 with direct activation of the inflammasome, resulting in an increase in IL-1β. Downstream retinoid-related orphan receptor C mRNA, IL-17A, and IL-17F were induced. In Gal3-/- macrophages, no inflammasome activation was detected. To confirm the key role of Gal3 in the pathogenesis of cholestatic liver injury, we generated dnTGF-βRII/galectin-3-/- (dn/Gal3-/-) mice, which showed impaired inflammasome activation along with significantly improved inflammation and fibrosis. Taken together, our data point to a novel role of Gal3 as an initiator of inflammatory signaling in autoimmune cholangitis, mediating the activation of NLRP3 inflammasome and inducing IL-17 proinflammatory cascades. These studies provide a rationale to target Gal3 in autoimmune cholangitis and potentially other cholestatic diseases.-Tian, J., Yang, G., Chen, H.-Y., Hsu, D. K., Tomilov, A., Olson, K. A., Dehnad, A., Fish, S. R., Cortopassi, G., Zhao, B., Liu, F.-T., Gershwin, M. E., Török, N. J., Jiang, J. X. Galectin-3 regulates inflammasome activation in cholestatic liver injury.

KEYWORDS:

IL-17; NLRP3; galectin-3; primary biliary cholangitis

PMID:
27630169
PMCID:
PMC5102125
DOI:
10.1096/fj.201600392RR
[Indexed for MEDLINE]
Free PMC Article

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