Type I interferon (IFN-I) is a pivotal cytokine of the innate immune response, playing a significant role in the pathophysiology of inflammation-induced damage in the central nervous system (CNS). Enhanced, constitutive IFN-I signaling is a defining feature of a number of Mendelian inborn errors of immunity, which are coined type I interferonopathies. However, understanding the pathophysiology of these disorders is hindered by the inability of numerous animal models to replicate the neurological phenotype essential for these diseases. Fortunately, we have recently generated and characterized the Rnaset2-/- mouse model, which shows IFN-I signaling in the CNS and the periphery. Furthermore, neuroinflammation and hippocampal-accentuated brain atrophy became evident at the age of 20 weeks and were IFNAR-dependent. Here, we investigated cell death pathways in Rnaset2-/- mouse brains to better understand the characteristic hippocampal-accentuated brain atrophy in these animals. We report significant alterations in key pyroptotic markers such as apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1 (CASP1), and gasdermin D (GSDMD) at both mRNA and protein levels. Immunofluorescence labeling of ASC further confirmed positive staining in ionized calcium binding adaptor molecule 1 (IBA1) positive microglia cells, indicating that pyroptosis might occur in microglia. In addition, we found an upregulation of microglia-associated chemokine C-C motif ligand 5 (CCL5) and C-X-C motif ligand 13 (CXCL13). Our results suggest that a microglia pyroptosis-induced inflammatory response could contribute to the neurodegenerative phenotype in Rnaset2-/- mice.