Inflammatory cell death and monocyte dysfunction in VEXAS syndrome - PubMed
5 hours ago
- #inflammatory cell death
- #VEXAS syndrome
- #UBA1 mutation
- VEXAS syndrome is a severe adult-onset autoinflammatory disease caused by somatic mutations in the UBA1 gene.
- UBA1 mutations disrupt myeloid cell function, leading to TNF-α-induced cell death via RIPK1 phosphorylation, MLKL, and caspase-8 pathways.
- Defective NF-κB responses and reduced cFLIP(L) expression contribute to aberrant apoptotic and necroptotic cell death in UBA1-mutated monocytes.
- UBA1-mutated monocytes show blunted cytokine responses to TLR agonists despite preserved TLR expression.
- UBA1M41V-derived macrophages exhibit a pro-inflammatory profile, increased chemokine secretion, and impaired efferocytosis due to lysosomal dysfunction.
- The study highlights a pathogenic axis linking UBA1 loss of function to inflammatory cell death, impaired signaling, and defective resolution mechanisms in VEXAS syndrome.