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Interleukin-33 is activated by allergen- and necrosis-associated proteolytic activities to regulate its alarmin activity during epithelial damage.

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.

SUBMITTER: Scott IC

PROVIDER: S-EPMC5820248 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Interleukin-33 is activated by allergen- and necrosis-associated proteolytic activities to regulate its alarmin activity during epithelial damage.

Scott Ian C IC Majithiya Jayesh B JB Sanden Caroline C Thornton Peter P Sanders Philip N PN Moore Tom T Guscott Molly M Corkill Dominic J DJ Erjefält Jonas S JS Cohen E Suzanne ES

Scientific reports 20180220 1

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 th ...[more]

PMID: 29463838

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Project description:Ischemia and reperfusion injury is an early inflammatory process during liver transplantation that impacts on graft function and clinical outcomes. Interleukin (IL)-33 is a danger-associated molecular pattern involved in kidney ischemia/reperfusion injury and several liver diseases. The aims were to assess whether IL-33 was released as an alarmin responsible for ischemia/reperfusion injury in a mouse model of warm hepatic ischemia, and whether this hypothesis could also apply in the setting of human liver transplantation. First, a model of warm hepatic ischemia/reperfusion was used in wild-type and IL-33-deficient mice. Severity of ischemia/reperfusion injury was assessed with ALT and histological analysis. Then, serum IL-33 was measured in a pilot cohort of 40 liver transplant patients. Hemodynamic postreperfusion syndrome, graft dysfunction (assessed by model for early allograft scoring >6), renal failure, and tissue lesions on time-zero biopsies were assessed. In the mouse model, IL-33 was constitutively expressed in the nucleus of endothelial cells, immediately released in response to hepatic pedicle clamping without neosynthesis, and participated in the recruitment of neutrophils and tissue injury on site. The kinetics of IL-33 in liver transplant patients strikingly matched the ones in the animal model, as attested by serum levels reaching a peak immediately after reperfusion, which correlated to clinical outcomes including postreperfusion syndrome, posttransplant renal failure, graft dysfunction, and histological lesions of ischemia/reperfusion injury. IL-33 was an independent factor of graft dysfunction with a cutoff of IL-33 at 73 pg/ml after reperfusion (73% sensitivity, area under the curve of 0.76). Taken together, these findings establish the immediate implication of IL-33 acting as an alarmin in liver I/R injury and provide evidence of its close association with cardinal features of early liver injury-associated disorders in LT patients.

Dataset Information

Interleukin-33 is activated by allergen- and necrosis-associated proteolytic activities to regulate its alarmin activity during epithelial damage.

Publications

Interleukin-33 is activated by allergen- and necrosis-associated proteolytic activities to regulate its alarmin activity during epithelial damage.

Similar Datasets

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