UBA1-depleted neutrophils disrupt immune homeostasis and induce VEXAS-like autoinflammatory disease in mice.

ABSTRACT: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a hemato-rheumatoid disease caused by somatic UBA1 mutations in hematopoietic stem cells (HSCs). The pathogenic cell type(s) responsible for the syndrome are unknown, and murine models recapitulating the disease are lacking. We report that loss of Uba1 in various mouse hematopoietic cell types resulted in pleiotropic consequences and demonstrate that an approximate 70% loss of Uba1 in neutrophils (NEs) of murine mutants induced nonlethal VEXAS-like symptoms. Depletion of Uba1 in HSCs induced extensive hematopoietic cell loss, whereas depletion of Uba1 in B cells, T cells, or megakaryocytes induced corresponding cell death, but these mutant mice appeared normal. Depletion of Uba1 in monocytes and NEs failed to indu

SUBMITTER: Dong G 

PROVIDER: S-EPMC12578396 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature