Fatty acid activates NLRP3 inflammasomes in mouse Kupffer cells through mitochondrial DNA release.

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in many developed and developing countries worldwide. It has been well established that the chronic sterile inflammation caused by the NLRP3 inflammasome is closely related to NAFLD development. Kupffer cells (KCs) are involved in the pathogenesis of various liver diseases. We used methionine choline-deficient diets to establish a mouse nonalcoholic steatohepatitis (NASH) model. The expression and formation of the NLRP3 inflammasome in the KCs from the mouse and cell models were determined by Western blotting and co-immunoprecipitation. Evidence of mitochondrial DNA (mtDNA) release was determined by live cell labeling and imaging. KCs and the NLRP3 inflammasome exerted proinflammatory effects on the development and progression of NASH through secretion of the proinflammatory cytokine IL-1β. NLRP3, ASC and Caspase-1 protein expression levels in KCs from NASH mouse livers were significantly higher than those in KCs from NLRP3-/- mice, and the number of NLRP3 inflammasome protein complexes was significantly higher in KCs from NASH mouse livers, whereas these protein complexes could not be formed in NLRP3-/- mice. In in vitro experiments, palmitic acid (PA) decreased the mitochondrial membrane potential and subsequently induced mtDNA release from the mitochondria to the cytoplasm. NLRP3 inflammasome expression was substantially increased, and mtDNA-NLRP3 inflammasome complexes formed upon PA stimulation. Our data suggest that mtDNA released from mitochondria during PA stimulation causes NLRP3 inflammasome activation, providing a missing link between NLRP3 inflammasome activation and NASH development, via binding of cytosolic mtDNA to the NLRP3 inflammasome.

• Authors: Junjiang Pan, Zhibing Ou, Can Cai, Peizhi Li, Jianping Gong, Xiong Z Ruan, Kun He
• Journal: Cellular immunology (Cell Immunol) Vol. 332 Pg. 111-120 (10 2018) ISSN: 1090-2163 [Electronic] Netherlands
• PMID: 30103942 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• DNA, Mitochondrial
• Fatty Acids
• Inflammasomes
• Interleukin-1beta
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Caspase 1

Topics

• Animals
• Caspase 1 (metabolism)
• Cytoplasm (metabolism)
• DNA, Mitochondrial (metabolism)
• Disease Models, Animal
• Fatty Acids (metabolism)
• Inflammasomes (metabolism)
• Inflammation (metabolism)
• Interleukin-1beta (metabolism)
• Kupffer Cells (metabolism)
• Male
• Membrane Potential, Mitochondrial (physiology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mitochondria (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Non-alcoholic Fatty Liver Disease (metabolism)