Epithelial IL-33 appropriates exosome trafficking for secretion in chronic airway disease
| Autor: | 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 |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | JCI Insight JCI Insight, Vol 6, Iss 4 (2021) |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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