HSP70 is a chaperone for IL-33 secretion and function in chronic airway disease
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{Delta}34 that escapes nuclear sequestration to be tonically secreted by recruitment to unconventional protein secretory pathways by HSP70. IL-33{Delta}34 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{Delta}34 by inhibiting oxidation/degradation thereby enhancing IL-33{Delta}34-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{Delta}34 secretion and activity that may be amenable for therapeutic targeting in airway diseases such as asthma and COPD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/635799v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@b01ea9org.highwire.dtl.DTLVardef@ad18c9org.highwire.dtl.DTLVardef@364c0forg.highwire.dtl.DTLVardef@bba135_HPS_FORMAT_FIGEXP M_FIG C_FIG