Neutrophil Elastase-mediated proteolysis activates the anti-inflammatory cytokine IL-36 Receptor antagonist

• DOI: 10.1038/srep24880
• Publication Date: 2016-04-22T09:24:59Z
• Authors: Tom Macleod; Rosella Doble; Dennis McGonagle; Christopher W. Wa...; Adewonuola Alase; Martin Stacey; Miriam Wittmann
• Keywords: CCL20; Neutrophil elastase; Proteolysis

The interleukin-36 receptor antagonist (IL-36Ra) which regulates IL-36α, -β and -γ is linked to psoriatic inflammation, especially loss-of-function mutations in pustular psoriasis subtypes. As observed with other IL-1 superfamily proteins, the IL-36 members require N-terminal cleavage for full biological activity but mechanisms of IL-36Ra activation remain poorly defined. Using different blood leukocyte skin resident cell preparations, recombinant we have identified that neutrophil elastase, not derived proteases, cleaves into its highly active antagonistic form. this processed form was confirmed human primary dermal fibroblasts keratinocytes equivalents. A significant dose dependent reduction IL-36γ induced IL-8 chemokine ligand 20 (CCL20) levels were detected following addition cleaved compared length IL-36Ra. By activating IL-36Ra, protease can inhibit production, including CCL20, reduce further inflammatory infiltration. These findings strongly indicate elastase be a key enzyme function neutrophils play regulatory role inflammation regard balancing pro-inflammatory IL-36.