Inflammatory cell death and monocyte dysfunction in VEXAS syndrome

Area of Science:

• Immunology
• Genetics
• Cell Biology

Background:

• VEXAS syndrome is a severe autoinflammatory disease driven by somatic UBA1 gene mutations.
• The exact mechanisms of myeloid cell dysfunction in VEXAS remain unclear.

Purpose of the Study:

• Investigate the functional consequences of the UBA1M41V mutation in monocytes.
• Elucidate the molecular pathways underlying VEXAS pathogenesis.

Main Methods:

• Utilized a genetically engineered THP-1 monocytic model.
• Performed ex vivo analyses on VEXAS patient blood and tissue samples.
• Analyzed cell death pathways (apoptosis, necroptosis) and immune signaling (NF-κB, TLR).

Main Results:

• UBA1-mutated monocytes undergo TNF-α-induced cell death via RIPK1, MLKL, and caspase-8.
• Patient-derived cells confirm aberrant apoptotic and necroptotic cell death.
• Defective NF-κB responses and reduced cFLIP(L) expression contribute to cell death.
• Mutated cells show blunted TLR responses and impaired efferocytosis due to lysosomal dysfunction.
• UBA1-mutated macrophages exhibit a pro-inflammatory profile.

Conclusions:

• UBA1 mutations link to RIPK1-mediated inflammatory cell death, impaired immunity, and defective resolution in VEXAS.
• Findings provide mechanistic insights into myeloid dysfunction in VEXAS.
• Supports targeting inflammatory cell death pathways for VEXAS therapy.