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

• Published in: Cell death & disease Vol. 9; no. 3; pp. 378 - 15
• Main Authors: Sullivan, Graeme P, Henry, Conor M, Clancy, Danielle M, Mametnabiev, Tazhir, Belotcerkovskaya, Ekaterina, Davidovich, Pavel, Sura-Trueba, Sylvia, Garabadzhiu, Alexander V, Martin, Seamus J
• Format: Journal Article
• Language: English
• Published: England Springer Nature B.V 07.03.2018; Nature Publishing Group UK
• Subjects: Antagonists; Antiinflammatory agents; Cathepsin G; Cell activation; Cytokines; Elastase; Inflammation; Interleukin 1; Neutrophils; Peptides; Plaques; Proteolysis; Psoriasis; Skin
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-0385-4

Sterile inflammation is initiated by molecules released from necrotic cells, called damage-associated molecular patterns (DAMPs). Members of the extended IL-1 cytokine family are important DAMPs, are typically only released through necrosis, and require limited proteolytic processing for activation. The IL-1 family cytokines, IL-36α, IL-36β, and IL-36γ, are expressed as inactive precursors and have been implicated as key initiators of psoriatic-type skin inflammation. We have recently found that IL-36 family cytokines are proteolytically processed and activated by the neutrophil granule-derived proteases, elastase, and cathepsin G. Inhibitors of IL-36 processing may therefore have utility as anti-inflammatory agents through suppressing activation of the latter cytokines. We have identified peptide-based pseudosubstrates for cathepsin G and elastase, based on optimal substrate cleavage motifs, which can antagonize activation of all three IL-36 family cytokines by the latter proteases. Human psoriatic skin plaques displayed elevated IL-36β processing activity that could be antagonized by peptide pseudosubstrates specific for cathepsin G. Thus, antagonists of neutrophil-derived proteases may have therapeutic potential for blocking activation of IL-36 family cytokines in inflammatory conditions such as psoriasis.