The inhibition of mevalonate pathway induces up-regulation of NALP3 expression: new insight in the pathogenesis of mevalonate kinase deficiency.
Résumé
Mevalonate Kinase Deficiency (MKD) is a rare hereditary auto-inflammatory syndrome due to mutations in mevalonate kinase, the second enzyme of mevalonate pathway of cholesterol and non sterol-isoprenoids biosynthesis. The shortage of mevalonate-derived intermediates, and in particular of geranylgeranyl pyrophosphate (GGPP), has been linked to the activation of caspase-1 and thereby to the production of IL-1β, but the true concatenation of these two events has not been clarified yet. We hypothesized that inflammasomes could mediate the activation of caspase-1 due to the shortage of GGPP. We monitored the expression of the principal proteins (NALP1, NALP3, IPAF) of the three known inflammasomes, first in a cellular model of MKD, then in two MKD patients, after bacterial lipopolysaccharide (LPS) stimulation. In healthy subjects, alendronate alone induced the expression of NALP1 and NALP3, when together with LPS it induced a dramatic increase in NALP3 expression. In MKD patients, NALP3 expression was higher than in untreated healthy controls. Our results, even though preliminary, demonstrated that the inhibition of the mevalonate pathway lead to a hyper-expression of NALP3, suggesting a possible involvement of NALP3-inflammasome in the activation of caspase-1 consequent to GGPP decrement. This is the first time that the involvement of the inflammasome complexes was demonstrated in MKD pathogenesis.
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