Mitochondrial NLRP3 Induces Reactive Oxygen Species to Promote Smad Signalling and Fibrosis Independent from the Inflammasome [Molecular Bases of Disease]

May 19th, 2014 by Bracey, N. A., Gershkovich, B., Chun, J., Vilaysane, A., Meijndert, H. C., Wright, J. R., Fedak, P. W., Beck, P. L., Muruve, D. A., Duff, H. J.

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. While much is known regarding the NLRP3 inflammasome that regulates pro-inflammatory 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 signalling, as the N-terminal Pyrin or C-terminal leucine-rich repeats domains were dispensable. Interestingly, NLRP3 regulation of myofibroblast differentiation proceeded independently from the inflammasome, IL-1β/IL-18 or caspase-1. Instead, mitochondrial-localized NLRP3 potentiated reactive oxygen species (ROS) 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.
  • Posted in Journal of Biological Chemistry, Publications
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