Abstract
IL-33 is a key mediator of chronic airway disease driven by type 2 immune pathways, yet the nonclassical secretory mechanism for this cytokine remains undefined. We performed a comprehensive analysis in human airway epithelial cells, which revealed that tonic IL-33 secretion is dependent on the ceramide biosynthetic enzyme neutral sphingomyelinase 2 (nSMase2). IL-33 is cosecreted with exosomes by the nSMase2-regulated multivesicular endosome (MVE) pathway as surface-bound cargo. In support of these findings, human chronic obstructive pulmonary disease (COPD) specimens exhibited increased epithelial expression of the abundantly secreted IL33Δ34 isoform and augmented nSMase2 expression compared with non-COPD specimens. Using an Alternaria-induced airway disease model, we found that the nSMase2 inhibitor GW4869 abrogated both IL-33 and exosome secretion as well as downstream inflammatory pathways. This work elucidates a potentially novel aspect of IL-33 biology that may be targeted for therapeutic benefit in chronic airway diseases driven by type 2 inflammation.
Highlights
IL-33 is a cytokine abundantly expressed at mucosal barriers [1] that has been shown to promote type 2– polarized immune programs in health and disease [2, 3]
Using an Alternaria-induced model of airway disease, we demonstrated that blockade of neutral sphingomyelinase 2 (nSMase2) with GW4869 resulted in reduced IL-33 and exosome secretion in bronchoalveolar lavage (BAL) fluid and downstream type 2 inflammation
This study addresses multiple fundamental questions in the field of IL-33 biology and advances our understanding of human chronic airway disease pathogenesis
Summary
IL-33 is a cytokine abundantly expressed at mucosal barriers [1] that has been shown to promote type 2– polarized immune programs in health and disease [2, 3]. A role for IL-33 in human type 2–driven chronic airway disease was highlighted by genome-wide association studies linking IL33 and IL1RL1/ST2 with asthma [4,5,6] and increased IL-33 in serum, sputum, or tissue from patients with asthma [7, 8] and patients with chronic obstructive pulmonary disease (COPD) [9,10,11]. Apoptotic and inflammatory proteases can process IL-33full in vitro, which can result in either enhanced function [19] or deactivation [20, 21] While these in vitro studies have shown that processed cytokine retains activity, it remains unknown whether proteolysis is required for activation or secretion of endogenous IL-33 in vivo
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