Interferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy

Abstract

Infantile-onset RNaseT2 deficient leukoencephalopathy is characterised by cystic brain lesions, multifocal white matter alterations, cerebral atrophy, and severe psychomotor impairment. The phenotype is similar to congenital cytomegalovirus brain infection and overlaps with type I interferonopathies, suggesting a role for innate immunity in its pathophysiology. To date, pathophysiological studies have been hindered by the lack of mouse models recapitulating the neuroinflammatory encephalopathy found in patients. In this study, we generated Rnaset2−/− mice using CRISPR/Cas9-mediated genome editing. Rnaset2−/− mice demonstrate upregulation of interferon-stimulated genes and concurrent IFNAR1-dependent neuroinflammation, with infiltration of CD8+ effector memory T cells and inflammatory monocytes into the grey and white matter. Single nuclei RNA sequencing reveals homeostatic dysfunctions in glial cells and neurons and provide important insights into the mechanisms of hippocampal-accentuated brain atrophy and cognitive impairment. The Rnaset2−/− mice may allow the study of CNS damage associated with RNaseT2 deficiency and may be used for the investigation of potential therapies.

Epigenetics and Neuroinflammation Associated With Neurodevelopmental Disorders: A Microglial Perspective

“…Loss of function mutations in ribonuclease T2 ( RNASET2 ) cause early onset leukoencephalopathy resembling congenital cytomegalovirus brain infection in humans ( Henneke et al, 2009 ). Homozygous knockout of RNASET2 homologs in mice and zebrafish causes abnormal activation of microglia and increased expression of interferon-stimulated genes in the brains ( Hamilton et al, 2020 ; Kettwig et al, 2021 ; Rutherford et al, 2021 ). These results warrant further examination to reveal the epigenetic mechanisms underlying leukoencephalopathies using zebrafish models.…”

Differentiating central nervous system demyelinating disorders: The role of clinical, laboratory, imaging characteristics and peripheral blood type I interferon activity

“…Moreover, ubiquitin-specific peptidase 18 (USP18) deletion in young adult mouse models [normally downregulating signal transducer and activator of transcription 1 (STAT1) signaling], led to increased activation of downstream type I IFN signaling in white matter microglial cells causing microgliopathy (Goldmann et al, 2015). Of interest, abrogation of type I IFN signaling in the Rnaset2 −/− mice characterized by AGS-resembling leukoencephalopathy syndrome, led to complete resolution of CNS features (Kettwig et al, 2021).…”

Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion

“…Recent studies in ovarian cancer models suggest that RNASET2 contributes to maintaining the balance of M1/M2 macrophages in the tumor environment and may impact upon T cell adaptive immune memory response ( 19 , 42 ). Likewise, Rnaset2 −/− mice develop not only neuroinflammatory encephalopathy but autoinflammatory organ disease and a disrupted hematopoiesis as well ( 43 ). In contrast, enhanced levels of RNASET2 is are detected in vitiligo patient specimens and can be induced in vitro in cultured primary human melanocytes and keratinocyte in response to stress ( 44 ).…”