Downregulation ofLet-7miRNA 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. 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, how they cause emphysema remains unclear. 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-clusterenhanced CD8+IL17a+T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressinglet-7in 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 oflet-7miRNA in T cells. Overall, our findings support of thelet-7/RORγt as a driver and braking regulatory circuit in the generation of Tc17 cells, suggesting novel therapeutic approaches for tempering the augmented IL-17-mediated response in emphysema.

Let-7restrains an oncogenic epigenetic circuit in AT2 cells to prevent ectopic formation of fibrogenic transitional cell intermediates and pulmonary fibrosis

“…To understand the mechanism of let-7 function in AT2 cell compartment, we utilized our let-7bc2 and let-7afd conditional knockout (KO) mice 29 . We employed let-7bc2 f/f ; Sftpc-Cre ERT 2 /+ , let-7afd f/f ;Sftpc-Cre ERT 2 /+ mice with and without the R26R-LSL-tdTomato reporter ( Sftpc-tdT ) for phenotypic analysis – hereafter referred to as let-7bc2 AT2 and let-7afd AT2 mice (Supplementary Fig.…”