Downregulation of Mirlet7 miRNA Family Promotes Tc17 Differentiation and Emphysema via De-repression of RORγt

Authors

Phillip A Erice
Xinyan Huang
Matthew J Seasock
Matthew J Robertson
Hui-Ying Tung
Melissa A Perez-Negron
Shivani L Lotlikar
David B Corry
Farrah Kheradmand
Antony Rodriguez

Publication Date

5-9-2024

Journal

Elife

DOI

10.7554/eLife.92879

PMID

38722677

PMCID

PMC11081633

PubMedCentral® Posted Date

5-9-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Female, Humans, Male, Mice, Cell Differentiation, Down-Regulation, Interleukin-17, Lung, Mice, Inbred C57BL, MicroRNAs, Nuclear Receptor Subfamily 1, Group F, Member 3, Pulmonary Emphysema, Th17 Cells

Abstract

Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 microRNA (Mirlet7 miRNA) family is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the Mirlet7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here, we show that overall expression of the Mirlet7 clusters, Mirlet7b/Mirlet7c2 and Mirlet7a1/Mirlet7f1/Mirlet7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with cigarette smoke (CS)- or nCB-elicited emphysema. We demonstrate that loss of the Mirlet7b/Mirlet7c2 cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the Mirlet7b/Mirlet7c2 cluster enhanced CD8+IL17a+ T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing Mirlet7g in T cells are resistant to Tc17 and CD4+IL17a+ T cells (Th17) development when exposed to nCB. Mechanistically, our findings reveal the master regulator of Tc17/Th17 differentiation, RAR-related orphan receptor gamma t (RORγt), as a direct target of Mirlet7 in T cells. Overall, our findings shed light on the Mirlet7/RORγt axis with Mirlet7 acting as a molecular brake in the generation of Tc17 cells and suggest a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema.

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