{"doi":"10.7554/elife.92879.1","title":"Downregulation of Let-7 miRNA promotes Tc17 differentiation and emphysema via de-repression of RORγt","abstract":"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 family of miRNAs is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the let-7 family is downregulated in patients with COPD, however, how they cause emphysema remains unclear. Here we show that overall expression of the let-7 miRNA clusters, let-7b/let-7c2 and let-7a1/let-7f1/let-7d, 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 let-7b/let-7c2-cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the let-7b/let-7c2-cluster enhanced CD8+IL17a+ T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing let-7 in T cells were resistant to Tc17 and CD4+ 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 let-7 miRNA in T cells. Overall, our findings shed light on the let-7/RORγt axis as a braking and driving regulatory circuit in the generation of Tc17 cells and suggests a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema.","journal":"eLife","year":2024,"id":494057,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":403625,"name":"Xinyan Huang","orcid":null,"position":1,"is_corresponding":false},{"id":556160,"name":"Matthew J. Seasock","orcid":"0000-0002-5940-5913","position":2,"is_corresponding":false},{"id":276742,"name":"Matthew J. Robertson","orcid":null,"position":3,"is_corresponding":false},{"id":1178216,"name":"Hui-Ying Tung","orcid":null,"position":4,"is_corresponding":false},{"id":1178217,"name":"Melissa A. Perez-Negron","orcid":null,"position":5,"is_corresponding":false},{"id":1178218,"name":"Shivani L. Lotlikar","orcid":null,"position":6,"is_corresponding":false},{"id":325692,"name":"David B. Corry","orcid":"0000-0001-9729-1016","position":7,"is_corresponding":false},{"id":232202,"name":"Farrah Kheradmand","orcid":"0000-0001-5343-103X","position":8,"is_corresponding":false},{"id":731516,"name":"Antony Rodríguez","orcid":"0000-0001-7184-9413","position":9,"is_corresponding":false},{"id":1177880,"name":"Phillip A. Erice","orcid":"0000-0001-6349-4480","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:09:07.920649Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}