title: Galectin-3 regulates inflammasome activation in cholestatic liver injury.
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.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA.|State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jijing
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis Medical Center, Sacramento, California, USA.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA.|Institute of Biomedical Sciences, Academia Sinica, Taipei City, Taiwan.
authors.forename: Huan-Yuan
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Hsu
authors.affiliation: Department of Molecular Biosciences, University of California Davis, Sacramento, California, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Tomilov
authors.affiliation: Department of Pathology, University of California Davis Medical Center, Sacramento, California, USA; and.
authors.forename: Kristin A
authors.initials: KA
authors.lastname: Olson
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Dehnad
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Fish
authors.affiliation: Department of Molecular Biosciences, University of California Davis, Sacramento, California, USA.
authors.forename: Gino
authors.initials: G
authors.lastname: Cortopassi
authors.affiliation: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA.|Institute of Biomedical Sciences, Academia Sinica, Taipei City, Taiwan.
authors.forename: Fu-Tong
authors.initials: FT
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Division of Rheumatology, Allergy, and Clinical Immunology, University of California Davis Medical Center, Sacramento, California, USA.
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA.|Veterans Administration Northern California Medical Center, Mather, California, USA.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Török
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of California Davis Medical Center, Sacramento, California, USA; joyjiang@ucdavis.edu.
authors.forename: Joy X
authors.initials: JX
authors.lastname: Jiang
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D008099:Liver / Q000293:injuries / Q000378:metabolism*; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D008822:Mice, Transgenic; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D037502:Galectin 3; D058847:Inflammasomes; D020381:Interleukin-17; D053759:Interleukin-23; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D020170:Caspase 1
keywords: IL-17; NLRP3; galectin-3; primary biliary cholangitis