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Epithelial IL-33 appropriates exosome trafficking for secretion in chronic airway disease

Authors :
Dawn M. Katafiasz
Catie Newsom-Stewart
Kristina L. Bailey
Derek E. Byers
Steven L. Brody
Michael J. Holtzman
Colin E. Kluender
Arjun Baronia
Jennifer Alexander-Brett
Deborah F. Steinberg
Mark J. Miller
Ella Katz-Kiriakos
Omar A. Osorio
Source :
JCI Insight, JCI Insight, Vol 6, Iss 4 (2021)
Publication Year :
2021
Publisher :
American Society for Clinical Investigation, 2021.

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.

Details

ISSN :
23793708
Database :
OpenAIRE
Journal :
JCI Insight
Accession number :
edsair.doi.dedup.....ac40b8a06822ab8204f388084303b4d7
Full Text :
https://doi.org/10.1172/jci.insight.136166