Epithelial miR-206 targets CD39/extracellular ATP to upregulate airway IL-25 and TSLP in type 2–high asthma
The epithelial cell–derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) initiate type 2 inflammation in allergic diseases, including asthma. However, the signaling pathway regulating these cytokines expression remains elusive. Since microRNAs are pivotal regulators of gene expres...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2021-06-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.148103 |
| _version_ | 1818236599970824192 |
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| author | Kan Zhang Yuchen Feng Yuxia Liang Wenliang Wu Chenli Chang Dian Chen Shengchong Chen Jiali Gao Gongqi Chen Lingling Yi Dan Cheng Guohua Zhen |
| author_facet | Kan Zhang Yuchen Feng Yuxia Liang Wenliang Wu Chenli Chang Dian Chen Shengchong Chen Jiali Gao Gongqi Chen Lingling Yi Dan Cheng Guohua Zhen |
| author_sort | Kan Zhang |
| collection | DOAJ |
| description | The epithelial cell–derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) initiate type 2 inflammation in allergic diseases, including asthma. However, the signaling pathway regulating these cytokines expression remains elusive. Since microRNAs are pivotal regulators of gene expression, we profiled microRNA expression in bronchial epithelial brushings from type 2–low and type 2–high asthma patients. miR-206 was the most highly expressed epithelial microRNA in type 2–high asthma relative to type 2–low asthma but was downregulated in both subsets compared with healthy controls. CD39, an ectonucleotidase degrading ATP, was a target of miR-206 and upregulated in asthma. Allergen-induced acute extracellular ATP accumulation led to miR-206 downregulation and CD39 upregulation in human bronchial epithelial cells, forming a feedback loop to eliminate excessive ATP. Airway ATP levels were markedly elevated and strongly correlated with IL-25 and TSLP expression in asthma patients. Intriguingly, airway miR-206 antagonism increased Cd39 expression; reduced ATP accumulation; suppressed IL-25, IL-33, and Tslp expression and group 2 innate lymphoid cell expansion; and alleviated type 2 inflammation in a mouse model of allergic airway inflammation. In contrast, airway miR-206 overexpression had opposite effects. Overall, epithelial miR-206 upregulates airway IL-25 and TSLP expression by targeting the CD39–extracellular ATP axis, which represents a potentially novel therapeutic target in type 2–high asthma. |
| first_indexed | 2024-12-12T12:12:26Z |
| format | Article |
| id | doaj.art-400a90ddedd042488696d4eaa51fb087 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-12-12T12:12:26Z |
| publishDate | 2021-06-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-400a90ddedd042488696d4eaa51fb0872022-12-22T00:24:51ZengAmerican Society for Clinical investigationJCI Insight2379-37082021-06-01611Epithelial miR-206 targets CD39/extracellular ATP to upregulate airway IL-25 and TSLP in type 2–high asthmaKan ZhangYuchen FengYuxia LiangWenliang WuChenli ChangDian ChenShengchong ChenJiali GaoGongqi ChenLingling YiDan ChengGuohua ZhenThe epithelial cell–derived cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) initiate type 2 inflammation in allergic diseases, including asthma. However, the signaling pathway regulating these cytokines expression remains elusive. Since microRNAs are pivotal regulators of gene expression, we profiled microRNA expression in bronchial epithelial brushings from type 2–low and type 2–high asthma patients. miR-206 was the most highly expressed epithelial microRNA in type 2–high asthma relative to type 2–low asthma but was downregulated in both subsets compared with healthy controls. CD39, an ectonucleotidase degrading ATP, was a target of miR-206 and upregulated in asthma. Allergen-induced acute extracellular ATP accumulation led to miR-206 downregulation and CD39 upregulation in human bronchial epithelial cells, forming a feedback loop to eliminate excessive ATP. Airway ATP levels were markedly elevated and strongly correlated with IL-25 and TSLP expression in asthma patients. Intriguingly, airway miR-206 antagonism increased Cd39 expression; reduced ATP accumulation; suppressed IL-25, IL-33, and Tslp expression and group 2 innate lymphoid cell expansion; and alleviated type 2 inflammation in a mouse model of allergic airway inflammation. In contrast, airway miR-206 overexpression had opposite effects. Overall, epithelial miR-206 upregulates airway IL-25 and TSLP expression by targeting the CD39–extracellular ATP axis, which represents a potentially novel therapeutic target in type 2–high asthma.https://doi.org/10.1172/jci.insight.148103Pulmonology |
| spellingShingle | Kan Zhang Yuchen Feng Yuxia Liang Wenliang Wu Chenli Chang Dian Chen Shengchong Chen Jiali Gao Gongqi Chen Lingling Yi Dan Cheng Guohua Zhen Epithelial miR-206 targets CD39/extracellular ATP to upregulate airway IL-25 and TSLP in type 2–high asthma JCI Insight Pulmonology |
| title | Epithelial miR-206 targets CD39/extracellular ATP to upregulate airway IL-25 and TSLP in type 2–high asthma |
| title_full | Epithelial miR-206 targets CD39/extracellular ATP to upregulate airway IL-25 and TSLP in type 2–high asthma |
| title_fullStr | Epithelial miR-206 targets CD39/extracellular ATP to upregulate airway IL-25 and TSLP in type 2–high asthma |
| title_full_unstemmed | Epithelial miR-206 targets CD39/extracellular ATP to upregulate airway IL-25 and TSLP in type 2–high asthma |
| title_short | Epithelial miR-206 targets CD39/extracellular ATP to upregulate airway IL-25 and TSLP in type 2–high asthma |
| title_sort | epithelial mir 206 targets cd39 extracellular atp to upregulate airway il 25 and tslp in type 2 high asthma |
| topic | Pulmonology |
| url | https://doi.org/10.1172/jci.insight.148103 |
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