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

Abstract

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.

IL-36, IL-37, and IL-38 Cytokines in Skin and Joint Inflammation: A Comprehensive Review of Their Therapeutic Potential

“…In the attempt to develop additional strategies to target the activation of the IL-36 cytokines, small molecules inhibiting the elastase have been generated. Since their efficacy to reduce IL-36 activation has been proven [80], they might represent a novel approach to inhibit IL-36-driven inflammation in psoriasis and other IL-36-dependent inflammatory diseases [81].…”

<p>Cathepsin G cleaves and activates IL-36&gamma; and promotes the inflammation of psoriasis</p>

“…As an IL-36R agonist, IL-36γ is now considered to be a valuable biomarker in psoriatic patients, which correlates closely with disease activity 8. Similar to IL-36α and IL-36β, IL-36γ is expressed as an inactive precursor, which needs to be proteolytically processed and activated, and neutrophil-derived proteases seemed to be potent activating enzymes of IL-36γ 9. Henry et al reported neutrophil elastase (NE) could cleave recombinant full-length (FL)-IL-36γ and activate the protein;10 however, Johnston et al found cathepsin G (CG) but not NE had the ability to activate IL-36γ in vitro, and NE could cleave FL-IL-36α 2…”

Cathepsin-sensitive nanoscale drug delivery systems for cancer therapy and other diseases

“…Interestingly, peptide-based pseudosubstrates for Cathepsin G and elastase were developed. These substrates can decrease the activated interleukin-36 (IL-36) family cytokines especially in case of inflammatory diseases(e.g., psoriasis, arthritis)because such cytokines are proteolytically processed in the presence of Cathepsin G and other proteases [191]. In another study, it was proven that amodiaquine, an antimalarial drug, inhibited host Cathepsin B to protect host cells against infection with multiple toxins or viruses [192].…”