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

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 induce cell death, and the mutant mice were viable. Among the tested models, only depletion of Uba1 in NEs induced autoinflammatory symptoms including increased counts and percentages of NEs, increased proinflammatory cytokines, presence of vacuoles in myeloid cells, splenomegaly, and dermatitis. Residual Uba1 was approximately 30% in the mutant NEs, which disrupted cellular hemostasis. Finally, genetic loss of the myeloid prosurvival regulator Morrbid partially mitigated the VEXAS-like symptoms. The established VEXAS-like murine model will further our understanding and treatment of the newly identified autoinflammatory syndrome prevalent among aged men.