Inflammasome-mediated regulation of hepatic stellate cells
- 1 June 2009
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Gastrointestinal and Liver Physiology
- Vol. 296 (6), G1248-G1257
- https://doi.org/10.1152/ajpgi.90223.2008
Abstract
The inflammasome is a cytoplasmic multiprotein complex that has recently been identified in immune cells as an important sensor of signals released by cellular injury and death. Analogous to immune cells, hepatic stellate cells (HSC) also respond to cellular injury and death. Our aim was to establish whether inflammasome components were present in HSC and could regulate HSC functionality. Monosodium urate (MSU) crystals (100 μg/ml) were used to experimentally induce inflammasome activation in LX-2 and primary mouse HSC. Twenty-four hours later primary mouse HSC were stained with α-smooth muscle actin and visualized by confocal microscopy, and TGF-β and collagen1 mRNA expression was quantified. LX-2 cells were further cultured with or without MSU crystals for 24 h in a transwell chemotaxis assay with PDGF as the chemoattractant. We also examined inhibition of calcium (Ca2+) signaling in LX-2 cells treated with or without MSU crystals using caged inositol 1,4,5-triphosphate (IP3). Finally, we confirmed an important role of the inflammasome in experimental liver fibrosis by the injection of carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild-type mice and mice lacking components of the inflammasome. Components of the inflammasome are expressed in LX-2 cells and primary HSC. MSU crystals induced upregulation of TGF-β and collagen1 mRNA and actin reorganization in HSCs from wild-type mice but not mice lacking inflammasome components. MSU crystals inhibited the release of Ca2+ via IP3 in LX-2 cells and also inhibited PDGF-induced chemotaxis. Mice lacking the inflammasome-sensing and adaptor molecules, NLRP3 and apoptosis-associated speck-like protein containing CARD, had reduced CCl4 and TAA-induced liver fibrosis. We concluded that inflammasome components are present in HSC, can regulate a variety of HSC functions, and are required for the development of liver fibrosis.Keywords
This publication has 25 references indexed in Scilit:
- Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9Hepatology, 2007
- Mammalian NLR proteins; discriminating foe from friendImmunology & Cell Biology, 2007
- Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cellsAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2007
- Structural insights into the regulatory mechanism of IP3 receptorBiochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2004
- Inositol 1,4,5‐trisphosphate receptor (type 1) phosphorylation and modulation by Cdc2Journal of Cellular Biochemistry, 2003
- Molecular identification of a danger signal that alerts the immune system to dying cellsNature, 2003
- Smads 2 and 3 Are Differentially Activated by Transforming Growth Factor-β (TGF-β) in Quiescent and Activated Hepatic Stellate CellsPublished by Elsevier BV ,2003
- Monocyte chemotactic protein-1 as a chemoattractant for human hepatic stellate cellsHepatology, 1999
- Calcium signalling: How do IP3 receptors work?Current Biology, 1997
- Angiotensin II-induced Down-regulation of Inositol Trisphosphate Receptors in WB Rat Liver Epithelial CellsPublished by Elsevier BV ,1997