Abstract
Interleukin (IL)-33 is an IL-1 family alarmin released from damaged epithelial and endothelial barriers to elicit immune responses and allergic inflammation via its receptor ST2. Serine proteases released from neutrophils, mast cells and cytotoxic lymphocytes have been proposed to process the N-terminus of IL-33 to enhance its activity. Here we report that processing of full length IL-33 can occur in mice deficient in these immune cell protease activities. We sought alternative mechanisms for the proteolytic activation of IL-33 and discovered that exogenous allergen proteases and endogenous calpains, from damaged airway epithelial cells, can process full length IL-33 and increase its alarmin activity up to ~60-fold. Processed forms of IL-33 of apparent molecular weights ~18, 20, 22 and 23 kDa, were detected in human lungs consistent with some, but not all, proposed processing sites. Furthermore, allergen proteases degraded processed forms of IL-33 after cysteine residue oxidation. We suggest that IL-33 can sense the proteolytic and oxidative microenvironment during tissue injury that facilitate its rapid activation and inactivation to regulate the duration of its alarmin function.
Highlights
Interleukin (IL)-33 is a constitutively expressed IL-1 family cytokine alarmin predominantly localised in the nucleus of epithelial cells in barrier tissues and in endothelial cells in blood vessels
To investigate the role of DPP-1-activated immune cell proteases in IL-33 processing in vivo we challenged the lungs of Ctsc−/− and wild type (WT) mice with the Alternaria alternata (ALT) extract to induce IL-33 release and processing
Given the strong interest in IL-33 function and efforts to target it therapeutically, the mechanisms regulating IL-33 activity have remained controversial in comparison to other IL-1 family cytokines[13,30]
Summary
Interleukin (IL)-33 is a constitutively expressed IL-1 family cytokine alarmin predominantly localised in the nucleus of epithelial cells in barrier tissues and in endothelial cells in blood vessels. Of IL-33 can be rapidly inactivated by disulphide bonding (DSB) of critical cysteine residues[17] Despite these observations, a greater understanding of the mechanisms of proteolytic activation and inactivation of IL-33 in vivo and how this interacts with its release and oxidation is required. Serine proteases from neutrophils (cathepsin G (CG), neutrophil elastase (NE) and proteinase-3 (PR-3)), mast cells (chymase and tryptase), and cytotoxic lymphocytes (granzyme B (gzmB)) are proposed to N-terminal process IL-33 into mature forms with up to 30-fold more potent activity[13,14,15]. In this study we utilised dipeptidyl peptidase I (DPP-1, Cathepsin C) deficient mice (Ctsc−/−), which lack NE, CG, PR-3, gzmB and chymase activities and have a 75% reduction in tryptase activity[19,20,21], to investigate potential roles of DPP-1 activated immune cell proteases in IL-33 processing in vivo
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