Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Inflammasomes: Molecular Regulation and Implications for Metabolic and Cognitive Diseases

  • Choi, Alexander J.S. (Center for Sleep Medicine, Department of Pulmonary, Critical Care, and Sleep Medicine, Tufts University School of Medicine) ;
  • Ryter, Stefan W. (Joan and Sanford I. Weill Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College)
  • Received : 2014.04.28
  • Accepted : 2014.05.01
  • Published : 2014.06.30
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Abstract

Inflammasomes are specialized signaling platforms critical for the regulation of innate immune and inflammatory responses. Various NLR family members (i.e., NLRP1, NLRP3, and IPAF) as well as the PYHIN family member AIM2 can form inflammasome complexes. These multiprotein complexes activate inflammatory caspases (i.e., caspase-1) which in turn catalyze the maturation of select pro-inflammatory cytokines, including interleukin (IL)-$1{\beta}$ and IL-18. Activation of the NLRP3 inflammasome typically requires two initiating signals. Toll-like receptor (TLR) and NOD-like receptor (NLR) agonists activate the transcription of pro-inflammatory cytokine genes through an NF-${\kappa}B$-dependent priming signal. Following exposure to extracellular ATP, stimulation of the P2X purinoreceptor-7 ($P2X_7R$), which results in $K^+$ efflux, is required as a second signal for NLRP3 inflammasome formation. Alternative models for NLRP3 activation involve lysosomal destabilization and phagocytic NADPH oxidase and /or mitochondria-dependent reactive oxygen species (ROS) production. In this review we examine regulatory mechanisms that activate the NLRP3 inflammasome pathway. Furthermore, we discuss the potential roles of NLRP3 in metabolic and cognitive diseases, including obesity, type 2 diabetes mellitus, Alzheimer's disease, and major depressive disorder. Novel therapeutics involving inflammasome activation may result in possible clinical applications in the near future.

Keywords

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