{"doi":"10.7554/elife.92879","title":"Downregulation of Mirlet7 miRNA family promotes Tc17 differentiation and emphysema via de-repression of RORγt","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.","journal":"eLife","year":2024,"id":463600,"datarank":0.26876392038420827,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.0,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":3,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE57148"]},"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":639062,"name":"Xinyan Huang","orcid":"0000-0003-2775-6409","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":84,"raw_metadata":null,"created_at":"2026-07-19T02:04:33.257852Z","pmid":"38722677","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":[]}