Extracellular SQSTM1 as an inflammatory mediator.

Area of Science:

• Immunology
• Cell Biology
• Pathology

Background:

• Excessive inflammation is a major cause of sepsis-related mortality.
• Key mediators and mechanisms driving lethal inflammation in sepsis remain incompletely understood.

Purpose of the Study:

• To identify novel lethal inflammatory mediators in sepsis.
• To elucidate the mechanisms of SQSTM1/p62 (sequestosome 1) in sepsis pathogenesis.

Main Methods:

• Investigated SQSTM1/p62 release mechanisms (passive via pyroptosis, active via STING1/STING/TMEM173 and secretory lysosomes).
• Examined extracellular SQSTM1-INSR pathway activation, glycolysis, and NF-κB signaling.
• Utilized genetic deletion and pharmacological inhibition in experimental mouse sepsis models.
• Correlated pathway activation with sepsis severity in human patients.

Main Results:

• SQSTM1/p62 is identified as a lethal inflammatory mediator in sepsis and septic shock.
• Extracellular SQSTM1 binds INSR, activating glycolysis and promoting pro-inflammatory cytokine production via NF-κB.
• Inhibition of the SQSTM1-INSR pathway ameliorated sepsis-induced tissue damage, inflammation, organ failure, and mortality in mice.
• SQSTM1-INSR pathway activation correlated with sepsis severity in patients.

Conclusions:

• Extracellular SQSTM1/p62 plays a critical pathological role in sepsis.
• The SQSTM1-INSR pathway represents a novel therapeutic target for sepsis and related inflammatory conditions.