Suppressing IL-36-driven inflammation using peptide pseudosubstrates for neutrophil proteases

Area of Science:

• Immunology
• Dermatology
• Biochemistry

Background:

• Sterile inflammation involves damage-associated molecular patterns (DAMPs) from necrotic cells.
• Interleukin-36 (IL-36) cytokines, part of the IL-1 family, are key DAMPs initiating psoriatic skin inflammation.
• IL-36 cytokines require proteolytic processing for activation, typically occurring after release from necrotic cells.

Purpose of the Study:

• To investigate the role of neutrophil granule-derived proteases in activating IL-36 cytokines.
• To identify potential therapeutic strategies by developing inhibitors of IL-36 activation.
• To explore the therapeutic potential of targeting neutrophil proteases for inflammatory skin diseases.

Main Methods:

• Identified peptide-based pseudosubstrates for neutrophil elastase and cathepsin G.
• Assessed the ability of these pseudosubstrates to inhibit IL-36 cytokine activation.
• Measured IL-36β processing activity in human psoriatic skin plaques.

Main Results:

• Neutrophil proteases, elastase and cathepsin G, were found to process and activate IL-36α, IL-36β, and IL-36γ.
• Peptide pseudosubstrates effectively antagonized IL-36 activation by these proteases.
• Psoriatic skin plaques exhibited increased IL-36β processing activity, which was inhibited by cathepsin G-specific pseudosubstrates.

Conclusions:

• Neutrophil proteases are crucial for IL-36 cytokine activation in sterile inflammation.
• Inhibitors of neutrophil proteases represent a promising therapeutic approach for psoriasis and related inflammatory conditions.
• Targeting IL-36 activation pathways offers a novel strategy for managing inflammatory skin diseases.