Anakinra prevents high glucose-mediated potentiation of IL-1β-induced NLRP3 inflammasome activation, small extracellular vesicle release and vascular inflammation
Abstract
Cardiometabolic diseases, including diabetes mellitus, are complicated by vascular disease, a major driver of morbidity and mortality. Although hyperglycaemia contributes to vascular dysfunction, it does not fully explain the vascular complications observed in patients. Chronic low-grade inflammation and persistent release of pro-inflammatory cytokines as interleukin-1β (IL-1β) are increasingly recognized as central mediators of diabetic vasculopathy. However, the mechanisms by which elevated glucose amplifies inflammatory signalling and vascular dysfunction, and their pharmacological modulation, remain incompletely understood. We investigated the interplay between IL-1β and high glucose in human aortic smooth muscle cells (HASMC) and its impact on NLRP3 inflammasome activation, cellular metabolism and small extracellular vesicles (sEV)-mediated intercellular communication. IL-1β induced NLRP3 inflammasome activation and a metabolic reprogramming characterized not only by a glycolytic shift, but also by activation of the pentose phosphate pathway and NADPH oxidase. IL-1β promoted the release of sEV enriched in inflammasome components, particularly pro-caspase-1, which propagated inflammation and senescence in recipient vascular cells. High glucose alone had no effect but potentiated IL-1β-induced responses. Pharmacologically, blockade of IL-1R with anakinra prevented inflammasome activation, metabolic reprogramming and sEV release. Moreover, both anakinra and the NLRP3 inhibitor MCC950 impeded, at different levels, the potentiating effect of high glucose on IL-1β–driven responses, reinforcing the relevance of targeting the IL-1β–NLRP3 autoinflammatory axis. These findings reveal that high glucose potentiates IL-1β-driven vascular inflammation by altering bioenergetic flexibility and sEV signalling in human vascular cells, providing novel mechanistic insight into how IL-1β-targeted therapies may mitigate vascular complications in cardiometabolic disorders as diabetes
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BibTeX
@article{valencia2026anakinra,
title = {{Anakinra prevents high glucose-mediated potentiation of IL-1β-induced NLRP3 inflammasome activation, small extracellular vesicle release and vascular inflammation}},
author = {Inés Valencia and Xavier Vidal-Gómez and Álvaro San Hipólito-Luengo and Alicia Villacampa and Licia Shamoon and Ana Cuadrado-Gómez and Diego Berlanas-Vicente and Fernando de la Cuesta and Salvador Moncada and Jorge Gomez-Cerezo and Carlos Sánchez-Ferrer and M.Carmen Martínez and Ramaroson Andriantsitohaina and Concepción Peiró},
journal = {Biochemical Pharmacology},
year = {2026},
month = oct,
doi = {10.1016/j.bcp.2026.118180},
url = {https://hal.science/hal-05663658v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Anakinra prevents high glucose-mediated potentiation of IL-1β-induced NLRP3 inflammasome activation, small extracellular vesicle release and vascular inflammation
AU - Inés Valencia
AU - Xavier Vidal-Gómez
AU - Álvaro San Hipólito-Luengo
AU - Alicia Villacampa
AU - Licia Shamoon
AU - Ana Cuadrado-Gómez
AU - Diego Berlanas-Vicente
AU - Fernando de la Cuesta
AU - Salvador Moncada
AU - Jorge Gomez-Cerezo
AU - Carlos Sánchez-Ferrer
AU - M.Carmen Martínez
AU - Ramaroson Andriantsitohaina
AU - Concepción Peiró
PY - 2026
DA - 2026/10/09
JO - Biochemical Pharmacology
DO - 10.1016/j.bcp.2026.118180
UR - https://hal.science/hal-05663658v1
AB - Cardiometabolic diseases, including diabetes mellitus, are complicated by vascular disease, a major driver of morbidity and mortality. Although hyperglycaemia contributes to vascular dysfunction, it does not fully explain the vascular complications observed in patients. Chronic low-grade inflammation and persistent release of pro-inflammatory cytokines as interleukin-1β (IL-1β) are increasingly recognized as central mediators of diabetic vasculopathy. However, the mechanisms by which elevated glucose amplifies inflammatory signalling and vascular dysfunction, and their pharmacological modulation, remain incompletely understood. We investigated the interplay between IL-1β and high glucose in human aortic smooth muscle cells (HASMC) and its impact on NLRP3 inflammasome activation, cellular metabolism and small extracellular vesicles (sEV)-mediated intercellular communication. IL-1β induced NLRP3 inflammasome activation and a metabolic reprogramming characterized not only by a glycolytic shift, but also by activation of the pentose phosphate pathway and NADPH oxidase. IL-1β promoted the release of sEV enriched in inflammasome components, particularly pro-caspase-1, which propagated inflammation and senescence in recipient vascular cells. High glucose alone had no effect but potentiated IL-1β-induced responses. Pharmacologically, blockade of IL-1R with anakinra prevented inflammasome activation, metabolic reprogramming and sEV release. Moreover, both anakinra and the NLRP3 inhibitor MCC950 impeded, at different levels, the potentiating effect of high glucose on IL-1β–driven responses, reinforcing the relevance of targeting the IL-1β–NLRP3 autoinflammatory axis. These findings reveal that high glucose potentiates IL-1β-driven vascular inflammation by altering bioenergetic flexibility and sEV signalling in human vascular cells, providing novel mechanistic insight into how IL-1β-targeted therapies may mitigate vascular complications in cardiometabolic disorders as diabetes
SN - 0006-2952
SN - 1873-2968
ER -