[Inflammasome and interleukin 1].
The innate immune system, which corresponds to the first line of defense against microorganisms, brings into play cell surface and intracellular sensors that detect pathogen ligands and danger signals. Among them, NOD-like receptors (NLRs) are intracellular proteins involved in inflammatory signaling pathways. NLRs are part of multiprotein complexes, called inflammasomes, which usually bring into play a NLR, an adaptor protein called ASC, and the pro-inflammatory caspase 1 protein. The activation of inflammasome by different stimuli triggers the proteolytic cleavage of pro-caspase 1 into active caspase 1, which, in turn, converts pro-interleukin 1β (pro-IL1β) into the mature IL1β. IL1β plays a crucial role in systemic inflammation due to its ability to induce the expression of a large panel of pro-inflammatory genes and to act on various target organs. Mutations in NLR genes are responsible for several autoinflammatory and/or autoimmune disorders. For example, mutations in NLRP3, which are responsible for three Mendelian autoinflammatory disorders called cryopyrinopathies, lead to inflammasome autoactivation. Peripheral blood mononuclear cells from patients carrying NLRP3 mutations secrete high levels of IL1β; in many patients presenting with autoinflammatory disorders, blocking IL1 activity by anti-IL1 therapy significantly improves their manifestations. The mechanisms leading to IL1β hypersecretion in other autoinflammatory disorders remain to be identified, as is the case for the role of each inflammasome in vivo. Better knowledge in this field should also contribute to the development of new anti-inflammatory treatments.
Jéru
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Inserm, U933, hôpital Armand-Trousseau, 26, avenue du Dr. Arnold-Netter, 75571 Paris cedex 12, France. isabelle.jeru@trs.aphp.fr
Amselem
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D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D020170:Caspase 1 / Q000276:immunology; D056587:Cryopyrin-Associated Periodic Syndromes / Q000235:genetics / Q000276:immunology; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007375:Interleukin-1 / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D015398:Signal Transduction / Q000276:immunology
D015415:Biomarkers; D002352:Carrier Proteins; D058847:Inflammasomes; D007375:Interleukin-1; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D020170:Caspase 1