Abstract
SUMMARY IL-33 is a key driver of type 2 inflammation relevant to airway epithelial biology. However, the mechanisms for IL-33 secretion and regulation in the context of chronic airway disease is poorly understood. Here we report a disease-associated isoform IL-33 Δ34 that escapes nuclear sequestration to be tonically secreted by recruitment to unconventional protein secretory pathways by HSP70. IL-33 Δ34 interacts with HSP70 within cells to be targeted to secretory organelles through coordinated binding to phosphatidylserine (PS). Once secreted, this HSP70/cytokine complex stabilizes IL-33 Δ34 by inhibiting oxidation/degradation thereby enhancing IL-33 Δ34 -receptor binding and activity. We find evidence for IL-33, HSP70 and chaperonin TCP-1 are dysregulated in human chronic airway disease. This phenomenon is reflected in differential proteomics of diseased bronchial wash extracellular vesicles. This study confirms proteostasis intermediates, chiefly HSP70, as a chaperone for non-canonical IL-33 Δ34 secretion and activity that may be amenable for therapeutic targeting in airway diseases such as asthma and COPD. GRAPHICAL ABSTRACT
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SUMMARY
IL-33 is a key driver of type 2 inflammation relevant to airway epithelial biology. However, the mechanisms for IL-33 secretion and regulation in the context of chronic airway disease is poorly understood. Here we report a disease-associated isoform IL-33Δ34 that escapes nuclear sequestration to be tonically secreted by recruitment to unconventional protein secretory pathways by HSP70. IL-33Δ34 interacts with HSP70 within cells to be targeted to secretory organelles through coordinated binding to phosphatidylserine (PS). Once secreted, this HSP70/cytokine complex stabilizes IL-33Δ34 by inhibiting oxidation/degradation thereby enhancing IL-33Δ34-receptor binding and activity. We find evidence for IL-33, HSP70 and chaperonin TCP-1 are dysregulated in human chronic airway disease. This phenomenon is reflected in differential proteomics of diseased bronchial wash extracellular vesicles. This study confirms proteostasis intermediates, chiefly HSP70, as a chaperone for non-canonical IL-33Δ34 secretion and activity that may be amenable for therapeutic targeting in airway diseases such as asthma and COPD.
Competing Interest Statement
JAB is a site principal investigator for the Astra Zeneca TILIA clinical trial.
Footnotes
Manuscript was updated from original form to include additional data
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