title: Neutrophil-Derived Proteases Escalate Inflammation through Activation of IL-36 Family Cytokines.
abstract: Recent evidence has strongly implicated the IL-1 family cytokines IL-36α, IL-36β, and IL-36γ as key initiators of skin inflammation. Similar to the other members of the IL-1 family, IL-36 cytokines are expressed as inactive precursors and require proteolytic processing for activation; however, the responsible proteases are unknown. Here, we show that IL-36α, IL-36β, and IL-36γ are activated differentially by the neutrophil granule-derived proteases cathepsin G, elastase, and proteinase-3, increasing their biological activity ~500-fold. Active IL-36 promoted a strong pro-inflammatory signature in primary keratinocytes and was sufficient to perturb skin differentiation in a reconstituted 3D human skin model, producing features resembling psoriasis. Furthermore, skin eluates from psoriasis patients displayed significantly elevated cathepsin G-like activity that was sufficient to activate IL-36β. These data identify neutrophil granule proteases as potent IL-36-activating enzymes, adding to our understanding of how neutrophils escalate inflammatory reactions. Inhibition of neutrophil-derived proteases may therefore have therapeutic benefits in psoriasis.
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Conor M
authors.initials: CM
authors.lastname: Henry
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Graeme P
authors.initials: GP
authors.lastname: Sullivan
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Clancy
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.
authors.forename: Inna S
authors.initials: IS
authors.lastname: Afonina
authors.affiliation: Experimental Dermatology, Department of Dermatology, Dresden University of Technology, 01307 Dresden, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kulms
authors.affiliation: Molecular Cell Biology Laboratory, Department of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland. Electronic address: martinsj@tcd.ie.
authors.forename: Seamus J
authors.initials: SJ
authors.lastname: Martin
mesh_terms: D002403:Cathepsins / Q000378:metabolism*; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology*; D011565:Psoriasis / Q000276:immunology*
chemical_list: D007375:Interleukin-1; C572887:interleukin 36, human; D002403:Cathepsins
keywords: IL-1 family; IL-17; IL-36; cathepsin G; elastase; inflammation; neutrophil; protease; psoriasis