Publication:
4-octyl itaconate reduces NLRP3 inflammasome constitutive activation with cryopyrin-associated periodic syndrome p.R262W, p.D305N and p.T350M variants

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Date
2025-05-23
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Authors
Molina-López, Cristina ; Hurtado-Navarro, Laura ; O'Neill, Luke A.J. ; Pelegrin, Pablo
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Publisher
Springer, Birkhäuser Verlag
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Bioquímica y Biología Molecular B e Inmunología
Description
Abstract
Cryopyrin-associated periodic syndrome (CAPS) is a condition characterized by dominant genetic variants in the NLRP3 gene, leading to the formation of constitutively active inflammasomes. These inflammasomes play a crucial role in the inflammatory episodes experienced by CAPS patients, primarily driven by the production of interleukin (IL)-1. Although treatment with IL-1 blockers is effective for CAPS, some patients develop refractory responses and adverse reactions to these therapies. Consequently, there is a need for novel treatments for CAPS patients. Promising candidates are the derivatives of itaconate, which have been shown to impair NLRP3 inflammasome activation and IL-1 release in blood mononuclear cells from CAPS patients. In this study, we provide insight into the inhibitory mechanisms of the itaconate derivative 4-octyl itaconate (4-OI) on NLRP3 with different (p.R262W, p.D305N and p.T350M) gain-of-function mutations associated with CAPS. Notably, 4-OI effectively blocks the basal auto-activation of the inflammasome formed by NLRP3 p.R262W, p.D305N and p.T350M variants, resulting in reduced caspase-1 activation, gasdermin D processing, and IL-18 release. Furthermore, after lipopolysaccharide priming of macrophages, 4-OI also decreases IL-1 gene expression and release. Overall, 4-OI impairs CAPS p.D305N-associated inflammasome function at multiple levels, and therapeutic agents based on itaconate could be a promising therapeutic approach to managing inflammatory episodes in CAPS patients carrying p.R262W, p.D305N or p.T350M variants.
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Itaconate , Autoinflammatory disease , CAPS , NLRP3 , Inflammasome
Citation
Cellular and Molecular Life Sciences Vol. 82, 209, (2025)
URI
http://hdl.handle.net/10201/158084
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