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 - 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
SN - 2379-3708
VL - 6
JO - JCI insight
JF - JCI insight
IS - 4
M1 - e136166
ER -