Defects in mitochondrial clearance predispose human monocytes to interleukin-1β hypersecretion

Area of Science:

• Immunology
• Cell Biology
• Genetics

Background:

• Hereditary periodic fever syndromes often involve dysregulated interleukin-1 beta (IL-1β) secretion.
• Mevalonate kinase deficiency (MKD) causes periodic fevers due to impaired isoprenoid biosynthesis, but its autoinflammation mechanisms are unclear.

Purpose of the Study:

• To investigate the mechanisms of autoinflammation in mevalonate kinase deficiency.
• To identify the role of autophagy defects in IL-1β generation and inflammasome activation.

Main Methods:

• Studied the effects of isoprenoid shortage on IL-1β production.
• Utilized ATG7 knockdown to model defective autophagy.
• Analyzed reactive oxygen species (ROS) and redox status in monocytes and lymphocytes.
• Assessed mitochondrial stability and autophagosomal degradation.

Main Results:

• Defective autophagy leads to increased reactive oxygen species and an oxidized monocyte redox status, driving IL-1β and IL-18 hypersecretion.
• Impaired autophagy causes mitochondrial instability and reduced degradation of cytosolic mitochondrial content.
• ATG7 knockdown resulted in prolonged cytosolic retention of damaged mitochondria and elevated IL-1β secretion.
• Autophagy activation reduced IL-1β secretion in healthy cells but not in MKD patient cells.

Conclusions:

• Defective autophagy is a novel inflammasome activation signal in mevalonate kinase deficiency.
• Autophagy dysfunction primes monocytes for NLRP3 inflammasome activation via damaged mitochondria.
• This mechanism contributes to IL-1β hypersecretion in mevalonate kinase deficiency, offering potential therapeutic targets.