Mitochondrial NLRP3 protein induces reactive oxygen species to promote Smad protein signaling and fibrosis independent from the inflammasome.

Abstract

Nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) is a pattern recognition receptor that is implicated in the pathogenesis of inflammation and chronic diseases. Although much is known regarding the NLRP3 inflammasome that regulates proinflammatory cytokine production in innate immune cells, the role of NLRP3 in non-professional immune cells is unclear. Here we report that NLRP3 is expressed in cardiac fibroblasts and increased during TGFβ stimulation. NLRP3-deficient cardiac fibroblasts displayed impaired differentiation and R-Smad activation in response to TGFβ. Only the central nucleotide binding domain of NLRP3 was required to augment R-Smad signaling because the N-terminal Pyrin or C-terminal leucine-rich repeat domains were dispensable. Interestingly, NLRP3 regulation of myofibroblast differentiation proceeded independently from the inflammasome, IL-1β/IL-18, or caspase 1. Instead, mitochondrially localized NLRP3 potentiated reactive oxygen species to augment R-Smad activation. In vivo, NLRP3-deficient mice were protected against angiotensin II-induced cardiac fibrosis with preserved cardiac architecture and reduced collagen 1. Together, these results support a distinct role for NLRP3 in non-professional immune cells independent from the inflammasome to regulate differential aspects of wound healing and chronic disease.

• Authors: Nathan A Bracey, Benjamin Gershkovich, Justin Chun, Akosua Vilaysane, H Christopher Meijndert, James R Wright Jr, Paul W Fedak, Paul L Beck, Daniel A Muruve, Henry J Duff
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 28 Pg. 19571-84 (Jul 11 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 24841199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Carrier Proteins
• Collagen Type I
• IL1B protein, mouse
• Inflammasomes
• Interleukin-18
• Interleukin-1beta
• Mitochondrial Proteins
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Reactive Oxygen Species
• Smad Proteins, Receptor-Regulated
• Transforming Growth Factor beta
• Vasoconstrictor Agents
• Angiotensin II

Topics

• Angiotensin II (adverse effects, pharmacology)
• Animals
• Carrier Proteins (genetics, metabolism)
• Collagen Type I (biosynthesis, genetics)
• Fibrosis
• Heart Diseases (chemically induced, genetics, metabolism, pathology)
• Inflammasomes
• Interleukin-18 (genetics, metabolism)
• Interleukin-1beta (genetics, metabolism)
• Mice
• Mice, Knockout
• Mitochondrial Proteins (genetics, metabolism)
• Myocardium (metabolism, pathology)
• Myofibroblasts (metabolism, pathology)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Reactive Oxygen Species (metabolism)
• Signal Transduction
• Smad Proteins, Receptor-Regulated (genetics, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)
• Vasoconstrictor Agents (adverse effects, pharmacology)