Cigarette smoke induces miR-132 in Th17 cells that enhance osteoclastogenesis in inflammatory arthritis
Edited by Marc Feldmann, University of Oxford, Oxford, United Kingdom, and approved November 18, 2020 (received for review August 15, 2020)
Significance
This report reveals a mechanism by which cigarette smoke (CS) could exacerbate local inflammatory disease. CS is a key environmental pollutant affecting millions of people globally and continues to be of considerable interest to the biomedical communities. We found that CS activates the AhR on Th17 cells, leading to the up-regulation of miR-132, which is then packaged into extracellular vesicles that induce osteoclastogenesis via the suppression of Cox2 that catalyzes prostaglandins. Clinically, rheumatoid arthritis (RA) patients who smoke express a higher level of miRNA-132 compared to nonsmoking RA patients. This finding not only reveals a mechanism of CS signaling but also may provide a potential target for therapeutic intervention for inflammatory disease in general and RA in particular.
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint destruction and severe morbidity. Cigarette smoking (CS) can exacerbate the incidence and severity of RA. Although Th17 cells and the Aryl hydrocarbon receptor (AhR) have been implicated, the mechanism by which CS induces RA development remains unclear. Here, using transcriptomic analysis, we show that microRNA-132 is specifically induced in Th17 cells in the presence of either AhR agonist or CS-enriched medium. miRNA-132 thus induced is packaged into extracellular vesicles produced by Th17 and acts as a proinflammatory mediator increasing osteoclastogenesis through the down-regulation of COX2. In vivo, articular knockdown of miR-132 in murine arthritis models reduces the number of osteoclasts in the joints. Clinically, RA patients express higher levels of miR-132 than do healthy individuals. This increase is further elevated by cigarette smoking. Together, these results reveal a hitherto unrecognized mechanism by which CS could exacerbate RA and further advance understanding of the impact of environmental factors on the pathogenesis of chronic inflammatory diseases.
Data Availability
Microarray data analysis data have been deposited in the Gene Expression Omnibus database (GSE149169).
Acknowledgments
We thank Sergio L. C. Almeida, Patricia Rolim, and members of the Rheumatoid Arthritis team for their advice and clinical assistance; Dr. Fausto Almeida research group for support with Nanosight analysis; Ieda R. S. Schivo, Sergio R. Rosa, Ana Katia dos Santos, Denise Ferraz, and Tadeu F. Vieira (in memory) for technical assistance. This work was supported by grants from the São Paulo Research Foundation (FAPESP, 2012/02438-0 and 2013/08216-2 Center for Research in Inflammatory Disease) and from the University of São Paulo (NAP-DIN, 11.1.21625.01.0).
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© 2021. Published under the PNAS license.
Data Availability
Microarray data analysis data have been deposited in the Gene Expression Omnibus database (GSE149169).
Submission history
Received: August 15, 2020
Accepted: November 18, 2020
Published online: December 28, 2020
Published in issue: January 5, 2021
Change history
October 18, 2021: Figure 3 and the SI Appendix have been updated; please see accompanying Correction for details. Previous version (December 28, 2020)
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Acknowledgments
We thank Sergio L. C. Almeida, Patricia Rolim, and members of the Rheumatoid Arthritis team for their advice and clinical assistance; Dr. Fausto Almeida research group for support with Nanosight analysis; Ieda R. S. Schivo, Sergio R. Rosa, Ana Katia dos Santos, Denise Ferraz, and Tadeu F. Vieira (in memory) for technical assistance. This work was supported by grants from the São Paulo Research Foundation (FAPESP, 2012/02438-0 and 2013/08216-2 Center for Research in Inflammatory Disease) and from the University of São Paulo (NAP-DIN, 11.1.21625.01.0).
Notes
This article is a PNAS Direct Submission.
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The authors declare no competing interest.
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Cigarette smoke induces miR-132 in Th17 cells that enhance osteoclastogenesis in inflammatory arthritis, Proc. Natl. Acad. Sci. U.S.A.
118 (1) e2017120118,
https://doi.org/10.1073/pnas.2017120118
(2021).
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