Downregulation of <i>Mirlet7</i> 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 <i>let-7</i> microRNA (<i>Mirlet7</i> miRNA) family is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the <i>Mirlet7</i> 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 <i>Mirlet7</i> clusters, <i>Mirlet7b/Mirlet7c2</i> and <i>Mirlet7a1/Mirlet7f1/Mirlet7d</i>, 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 <i>Mirlet7b/Mirlet7c2</i> cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the <i>Mirlet7b/Mirlet7c2</i> cluster enhanced CD8⁺IL17a⁺ T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing <i>Mirlet7g</i> 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 <i>Mirlet7</i> in T cells. Overall, our findings shed light on the <i>Mirlet7/</i>RORγt axis with <i>Mirlet7</i> 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.