Reviewing the importance of TLR‐NLRP3‐pyroptosis pathway and mechanism of experimental NLRP3 inflammasome inhibitors

• Published in: Scandinavian journal of immunology Vol. 95; no. 2; pp. e13124 - n/a
• Main Authors: Kinra, Manas, Nampoothiri, Madhavan, Arora, Devinder, Mudgal, Jayesh
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.02.2022
• Subjects: Alarmins - metabolism; Caspase; Caspase 1 - immunology; Cell death; Cell Membrane - metabolism; Cell membranes; Enzyme Inhibitors - pharmacology; Humans; Immunity, Innate - immunology; inflammasome inhibitors; Inflammasomes; Inflammation; Innate immunity; Interleukin-18 - metabolism; Interleukin-1beta - metabolism; Intracellular Signaling Peptides and Proteins - immunology; Intracellular signalling; NLR Family, Pyrin Domain-Containing 3 Protein - antagonists & inhibitors; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflammasome; Pathogen-Associated Molecular Pattern Molecules - metabolism; Phosphate-Binding Proteins - immunology; Proteolysis; Pyroptosis; Pyroptosis - immunology; Signal transduction; Signal Transduction - immunology; Toll-Like Receptors - metabolism; NLRP3 inflammasome; Pyroptosis; inflammasome inhibitors
• DOI: 10.1111/sji.13124
• ISSN: 0300-9475; 1365-3083

Cells encounter continuous challenges due to tissue insult caused by endogenous and/or exogenous stimuli. Among the mechanisms set in place to counterbalance the tissue insult, innate immunity is always at the forefront. Cells of innate immunity efficiently recognize the ‘danger signals’ via a specialized set of membrane‐bound receptors known as Toll‐like receptors. Once this interaction is established, toll‐like receptor passes on the responsibility to cytosolic NOD‐like receptors through a cascade of signalling pathways. Subsequently, NOD‐like receptors assemble to a specialized multiprotein intracellular complex, that is inflammasome. Inflammasome activates Caspase‐1 and Gasdermin‐D which initiate pyroptotic cell death in the affected tissue by two simultaneous mechanisms. Being a protease, caspase‐1 cleaves and activates pro‐inflammatory cytokines IL‐1β and IL‐18. On the other hand, Gasdermin‐D causes proteolytic cleavage which forms a pore in the cell membrane. This review highlights the molecular events ranging from recognition of stimuli to pyroptosis. The review is also an attempt to discuss the mechanisms of the most specific experimental NLRP3 inhibitors.