Galectin-3 regulates inflammasome activation in cholestatic liver injury

Jijing Tian, Guoxiang Yang, Huan Yuan Chen, Daniel K. Hsu, Alexey Tomilov, Kristin A Olson, Ali Dehnad, Sarah R. Fish, Gino A Cortopassi, Bin Zhao, Fu-Tong Liu, M. Eric Gershwin, Natalia J Torok, Xiaosong Jiang

Research output: Contribution to journalArticle

14 Scopus citations

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-bRII 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 CmRNA, 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-bRII/galectin-3-/- (dn/Gal3-/-) mice, which showed impaired inflammasome activation alongwith 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.

Original languageEnglish (US)
Pages (from-to)4202-4213
Number of pages12
JournalFASEB Journal
Volume30
Issue number12
DOIs
StatePublished - Dec 1 2016

Keywords

  • Galectin-3
  • IL-17
  • NLRP3
  • Primary biliary cholangitis

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Fingerprint Dive into the research topics of 'Galectin-3 regulates inflammasome activation in cholestatic liver injury'. Together they form a unique fingerprint.

  • Cite this