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 lowering of the threshold for pyrin inflammasome activation.

To establish a cellular model of MKD and discover novel inflammatory pathways contributing to disease pathogenesis, with a focus on IL-18 and interferon-gamma (IFNγ) signaling.

Using CRISPR/Cas9 gene editing, we generated a THP1 monocyte cell line harbouring homozygous MVK I268T mutations, a pathogenic variant observed in patients with MKD. Functional assays were conducted to assess inflammasome activation and cytokine responses following stimulation with the pyrin agonist etiocholanolone. Experiments using MKD patient-derived PBMCs were performed to validate in vitro findings.

MVKI268T/I268T THP1 cells exhibited impaired isoprenoid biosynthesis, consistent with the metabolic defect observed in MKD. Activation of the pyrin inflammasome in MVKI268T/I268T THP1 cells induced robust secretion of IL-1β and IL-18, which was attenuated by supplementation with geranylgeranyl pyrophosphate. MKD PBMCs hypersecreted IL-18 in response to pyrin inflammasome activation, reflected by elevated IL-18 levels in plasma of MKD patients. Specifically, MKD T and NK cells were characterized by enhanced IL-18-driven IFNγ production. Elevated IFNγ and IL-18BP levels in MKD plasma, and transcriptomic data of MKD PBMCs, further confirmed the presence of an IFNγ signature in MKD.

Our findings identify a pyrin-inflammasome driven IL-18/IFNγ axis as a key signaling module of MKD-associated inflammation. This pathway may represent a novel target for therapeutic intervention in MKD.