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

9 Citations (Scopus)

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

Fingerprint

Inflammasomes
Galectin 3
Liver
Cholangitis
Chemical activation
Macrophages
Wounds and Injuries
Interleukin-17
Interleukin-1
Caspase 1
Deoxycholic Acid
Macrophage Activation
Retinoids
Lectins
Liver Diseases
Proteins
Fibrosis
Association reactions
Tissue
Apoptosis

Keywords

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

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Galectin-3 regulates inflammasome activation in cholestatic liver injury. / Tian, Jijing; Yang, Guoxiang; Chen, Huan Yuan; Hsu, Daniel K.; Tomilov, Alexey; Olson, Kristin A; Dehnad, Ali; Fish, Sarah R.; Cortopassi, Gino A; Zhao, Bin; Liu, Fu-Tong; Gershwin, M. Eric; Torok, Natalia J; Jiang, Xiaosong.

In: FASEB Journal, Vol. 30, No. 12, 01.12.2016, p. 4202-4213.

Research output: Contribution to journalArticle

Tian, Jijing ; Yang, Guoxiang ; Chen, Huan Yuan ; Hsu, Daniel K. ; Tomilov, Alexey ; Olson, Kristin A ; Dehnad, Ali ; Fish, Sarah R. ; Cortopassi, Gino A ; Zhao, Bin ; Liu, Fu-Tong ; Gershwin, M. Eric ; Torok, Natalia J ; Jiang, Xiaosong. / Galectin-3 regulates inflammasome activation in cholestatic liver injury. In: FASEB Journal. 2016 ; Vol. 30, No. 12. pp. 4202-4213.
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AU - Olson, Kristin A

AU - Dehnad, Ali

AU - Fish, Sarah R.

AU - Cortopassi, Gino A

AU - Zhao, Bin

AU - Liu, Fu-Tong

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AU - Torok, Natalia J

AU - Jiang, Xiaosong

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