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Pharmacological Inhibition of the NLRP3 Inflammasome: Structure, Molecular Activation, and Inhibitor-NLRP3 Interaction

Public Domain


Details

  • Personal Author:
    Ma, Qiang
  • Description:
    The nucleotide-binding, oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multi-protein complex that combines sensing, regulation, and effector functions to regulate inflammation in health and disease. NLRP3 is activated by a diverse range of inflammation-instigating signals known as pathogen associated molecular patterns and danger associated molecular patterns. Upon activation, NLRP3 oligomerizes and recruits partner proteins to form a supramolecular platform to process the maturation and release of interleukin (IL)-1β, IL-18, and gasdermin D, major mediators of inflammation and inflammatory cell death termed pyroptosis. The NLRP3 inflammasome has been implicated in the pathogenesis of a wide range of disease conditions, including chronic inflammatory disease that are associated with lifestyle and dietary changes, aging, and environmental exposures and have become the leading cause of death worldwide. Pharmacological targeting of NLRP3 and signaling demonstrated promising efficacy in ameliorating a list of disease conditions in animal models. These findings underscore the potential and importance of NLRP3 as a druggable target for treating a range of diseases. In this review, recent progress in understanding the structure and mechanism of action of the NLRP3 inflammasome is discussed with focus on pharmacological inhibition of NLRP3 by small molecule inhibitors. New structural and mechanistic insights into NLRP3 activation and inhibitor-NLRP3 interactions would aid in the rational design and pharmacological evaluation of NLRP3 inhibitors for treatment of human disease. [Description provided by NIOSH]
  • Subjects:
  • Keywords:
  • ISSN:
    0031-6997
  • Document Type:
    Text
  • Genre:
    Journal Article
  • Place as Subject:
  • CIO:
    National Institute for Occupational Safety and Health (NIOSH)
  • Division:
    HELD - Health Effects Laboratory Division
  • Topic:
    Workplace Safety & Health
  • Location:
    North America
  • Pages in Document:
    34 pdf pages
  • Volume:
    75
  • NIOSHTIC Number:
    nn:20066841
  • Citation:
    Pharmacol Rev 2023 May; 75(3):487-520
  • Contact Point Address:
    Qiang Ma, Toxicology & Molecular Pharmacology Branch, TMBB/HELD/NIOSH/CDC, United States
  • Email:
    qam1@cdc.gov
  • Federal Fiscal Year:
    2023
  • NORA Priority Area:
    Construction
  • Peer Reviewed:
    True
  • Source Full Name:
    Pharmacological Reviews
  • Collection(s):
  • Main Document Checksum:
    urn:sha-512:4d7a0a8e1dafde4ea3561b3fd2177ef1ab157c22552f09096f79ac1e48ab95916dda6d8a2a15e34014efb559f38ce224b408b7b3169228772c31993ee5d6ec68
  • Download URL:
  • File Type:
    Filetype[PDF - 3.46 MB ]
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