Neutrophils take center stage in VEXAS syndrome pathogenesis.

Abstract

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an adult-onset inflammatory disorder caused by somatic UBA1 mutations in hematopoietic stem cells. UBA1 encodes a key enzyme that catalyzes protein ubiquitination. Clinically, VEXAS is characterized by systemic inflammation and hematologic abnormalities. Patient studies have hinted that the transition of UBA1-mutated stem cells into proinflammatory myeloid precursors may propagate the manifestations of VEXAS syndrome. In this issue of the JCI, Dong and colleagues developed nine unique conditional knockout mouse strains and found that only neutrophil-specific Uba1 deletion reproduced VEXAS syndrome-like findings. The observed phenotype was at least in part due to inflammatory reprogramming and longer survival of the mutant neutrophils. In addition to deepening our mechanistic understanding of VEXAS syndrome pathogenesis, this work should provide a platform to pursue more targeted approaches to treatment.