Downregulation ofLet-7miRNA promotes Tc17 differentiation and emphysema via de-repression of RORγt

Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. Thelet-7family of miRNAs is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests thelet-7family 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 thelet-7miRNA clusters,let-7b/let-7c2andlet-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 thelet-7b/let-7c2-cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of thelet-7b/let-7c2-cluster enhanced CD8⁺IL17a⁺T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressinglet-7in 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 oflet-7miRNA in T cells. Overall, our findings shed light on thelet-7/RORγt axis withlet-7acting as a molecular brake in the generation of Tc17 cells and suggests a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema.