TY - JOUR
T1 - Epithelial IL-33 appropriates exosome trafficking for secretion in chronic airway disease
AU - Katz-Kiriakos, Ella
AU - Steinberg, Deborah F.
AU - Kluender, Colin E.
AU - Osorio, Omar A.
AU - Newsom-Stewart, Catie
AU - Baronia, Arjun
AU - Byers, Derek E.
AU - Holtzman, Michael J.
AU - Katafiasz, Dawn
AU - Bailey, Kristina L.
AU - Brody, Steven L.
AU - Miller, Mark J.
AU - Alexander-Brett, Jennifer
N1 - Funding Information:
Special thanks to Tom Brett, Gaya Amarasinghe, and Jeff Haspel for critical reading of the manuscript. We thank the Washington University Digestive Diseases Research Core (National Institute of Diabetes and Digestive and Kidney Diseases P30 DK052574) for providing qNano TRPS services. We thank Bill Eades and the Siteman Center Flow Cytometry Core for FACS support. We thank the Washington University Center for Cellular Imaging for Microscopy support (ORIP OD021629). We thank the Washington University Genome Engineering and iPSC Center for generating the HBE SMPD3-/- KO pool. We thank the Pulmonary Morphology Core for tissue histology preparation. Support for this work was provided by NIH/National Heart, Lung, and Blood Institute (K08 HL121168 and R01 HL152245, to JAB; T32 HL007317 to CEK and OAO), American Thoracic Society (Early Career Investigator Award, to JAB), Burroughs Wellcome Fund (Career Award for Medical Scientist, to JAB), and Doris Duke Foundation (Fund to Retain Clinical Scientists, to JAB).
Publisher Copyright:
© 2021, Katz-Kiriakos et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2021/2/22
Y1 - 2021/2/22
N2 - 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.
AB - 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.
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U2 - 10.1172/jci.insight.136166
DO - 10.1172/jci.insight.136166
M3 - Article
C2 - 33507882
AN - SCOPUS:85102152010
VL - 6
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 4
M1 - e136166
ER -