Pyrin inflammasome activation triggers an IL-18-driven IFN-γ response in mevalonate kinase deficiency.

Abstract

Mevalonate kinase deficiency (MKD) is a rare monogenic autoinflammatory disorder characterized by recurrent fever episodes driven by dysregulated IL-1β secretion. Mutations in the MVK gene cause enzymatic defects resulting in a shortage of geranylgeranyl pyrophosphate, leading to a lowering of the threshold for pyrin inflammasome activation. A cellular model of MKD was established to discover novel inflammatory pathways contributing to disease pathogenesis, with a focus on IL-18 and IFN-γ signaling. Using CRISPR/Cas9 gene editing, we generated a THP1 monocyte cell line harboring homozygous MVK I268T mutations, a pathogenic variant observed in patients with MKD. Functional assays were conducted to assess inflammasome activation and cytokine responses after stimulation with the pyrin agonist etiocholanolone. Experiments using MKD patient-derived peripheral blood mononuclear cells were performed to validate in vitro findings. MVK^I268T/I268T THP1 cells exhibited impaired isoprenoid biosynthesis, consistent with the metabolic defect observed in MKD. Activation of the pyrin inflammasome in MVK^I268T/I268T THP1 cells induced robust secretion of IL-1β and IL-18, which was attenuated by supplementation with geranylgeranyl pyrophosphate. MKD peripheral blood mononuclear cells hypersecreted IL-18 in response to pyrin inflammasome activation, reflected by elevated IL-18 levels in plasma of MKD patients. Specifically, MKD T and natural killer cells were characterized by enhanced IL-18-driven IFN-γ production. Elevated IFN-γ and IL-18 binding protein levels in MKD plasma as well as transcriptomic data of MKD peripheral blood mononuclear cells further confirmed the presence of an IFN-γ signature in MKD. A pyrin inflammasome-driven IL-18/IFN-γ axis is a key signaling module of MKD-associated inflammation. This pathway may represent a novel target for therapeutic intervention in MKD.