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Altered expression of vacuole membrane protein 1 (VMP1) has recently been observed in the context of multiple sclerosis and Parkinson's disease (PD). However, how changes in VMP1 expression may impact pathogenesis has not been explored. Here, we report that genetic deletion of VMP1 from a monocytic cell line resulted in increased NLRP3 inflammasome activation and release of proinflammatory molecules. Examination of the VMP1 dependent changes in these cells revealed that VMP1 deficiency led to decreased SERCA activity and increased intracellular [Ca 2+ ]. We also observed calcium overload in mitochondria in VMP1 depleted cells, which was associated with mitochondrial dysfunction and release of mitochondrial DNA into the cytoplasm and the extracellular environment. Autophagic defects were also observed in VMP1 depleted macrophages. Collectively, these studies reveal VMP1 as a negative regulator of inflammatory responses, and we postulate that decreased expression of VMP1 can aggravate the inflammatory sequelae associated with neurodegenerative diseases like PD.