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Epithelial IL-33 appropriates exosome trafficking for secretion in chronic airway disease
- 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.
- Subjects :
- Male
0301 basic medicine
Pulmonology
medicine.medical_treatment
Immunology
Respiratory System
Inflammation
Ceramides
Exosomes
Benzylidene Compounds
Exosome
Mice
Pulmonary Disease, Chronic Obstructive
03 medical and health sciences
0302 clinical medicine
Immune system
Mediator
medicine
COPD
Animals
Humans
Secretion
Immunity, Cellular
Aniline Compounds
business.industry
Epithelial Cells
Cellular immune response
General Medicine
Interleukin-33
Microvesicles
Mice, Inbred C57BL
Interleukin 33
030104 developmental biology
Cytokine
030220 oncology & carcinogenesis
Cancer research
Medicine
Cytokines
medicine.symptom
business
Research Article
Subjects
Details
- ISSN :
- 23793708
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....ac40b8a06822ab8204f388084303b4d7
- Full Text :
- https://doi.org/10.1172/jci.insight.136166