SERPINB1-mediated checkpoint of inflammatory caspase activation

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• Inflammatory caspases (caspase-1, -4, -5, -11) are crucial for host defense against microbes, processing cytokines and inducing pyroptosis.
• Tight regulation is necessary to prevent aberrant inflammatory caspase activation.

Purpose of the Study:

• To investigate the role of serpin family B member 1 (SERPINB1) in regulating inflammatory caspase activity.
• To elucidate the mechanisms by which SERPINB1 controls caspase activation and subsequent inflammatory responses.

Main Methods:

• Investigated SERPINB1's interaction with inflammatory caspases using biochemical assays.
• Utilized knockdown and gene deletion models of SERPINB1 in mice.
• Assessed caspase activation, cytokine release (IL-1β), pyroptosis, and inflammatory phenotypes.

Main Results:

• SERPINB1 suppresses inflammatory caspase activation by inhibiting CARD oligomerization.
• SERPINB1 possesses distinct domains for inhibiting neutrophil serine proteases and inflammatory caspases.
• SERPINB1 deficiency resulted in spontaneous caspase-1/-4/-5/-11 activation, IL-1β release, and pyroptosis.
• SERPINB1-deficient mice exhibited increased inflammation and susceptibility to endotoxemia.

Conclusions:

• SERPINB1 acts as a critical gatekeeper of inflammation by restraining both neutrophil serine proteases and inflammatory caspases.
• SERPINB1's regulatory functions are genetically and functionally separable.
• SERPINB1 is essential for maintaining immune homeostasis and preventing excessive inflammation.