TGF-β1 Inhibition of ACE2 Mediated by miRNA Uncovers Novel Mechanism of SARS-CoV-2 Pathogenesis.
TGF-β1 Inhibition of ACE2 Mediated by miRNA Uncovers Novel Mechanism of SARS-CoV-2 Pathogenesis.
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miRNA介导的TGF-β1对ACE 2的抑制揭示了SARS-CoV-2发病机制的新机制
DOI：
10.1159/000533606
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发表时间：
2023
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
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作者：
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for COVID-19, utilizes receptor binding domain (RBD) of spike glycoprotein to interact with angiotensin (Ang)-converting enzyme 2 (ACE2). Altering ACE2 levels may affect entry of SARS-CoV-2 and recovery from COVID-19. Decreased cell surface density of ACE2 leads to increased local levels of Ang II and may contribute to mortality resulting from acute lung injury and fibrosis during COVID-19. Studies published early during the COVID-19 pandemic reported that people with cystic fibrosis (PwCF) had milder symptoms, compared to people without CF. This finding was attributed to elevated ACE2 levels and/or treatment with the high efficiency CFTR modulators. Subsequent studies did not confirm these findings reporting variable effects of CFTR gene mutations on ACE2 levels. Transforming growth factor (TGF)-β signaling is essential during SARS-CoV-2 infection and dominates the chronic immune response in severe COVID-19, leading to pulmonary fibrosis. TGF-β1 is a gene modifier associated with more severe lung disease in PwCF but its effects on the COVID-19 course in PwCF is unknown. To understand whether TGF-β1 affects ACE2 levels in the airway, we examined miRNAs and their gene targets affecting SARS-CoV-2 pathogenesis in response to TGF-β1. Small RNAseq and micro(mi)RNA profiling identified pathways uniquely affected by TGF-β1, including those associated with SARS-CoV-2 invasion, replication, and the host immune responses. TGF-β1 inhibited ACE2 expression by miR-136-3p and miR-369-5p mediated mechanism in CF and non-CF bronchial epithelial cells. ACE2 levels were higher in two bronchial epithelial cell models expressing the most common CF-causing mutation in CFTR gene F508del, compared to controls without the mutation. After TGF-β1 treatment, ACE2 protein levels were still higher in CF, compared to non-CF cells. TGF-β1 prevented the modulator-mediated rescue of F508del-CFTR function while the modulators did not prevent the TGF-β1 inhibition of ACE2 levels. Finally, TGF-β1 reduced the interaction between ACE2 and the recombinant spike RBD by lowering ACE2 levels and its binding to RBD. Our data demonstrate novel mechanism whereby TGF-β1 inhibition of ACE2 in CF and non-CF bronchial epithelial cells may modulate SARS-CoV-2 pathogenicity and COVID-19 severity. By reducing ACE2 levels, TGF-β1 may decrease entry of SARS-CoV-2 into the host cells while hindering the recovery from COVID-19 due to loss of the anti-inflammatory and regenerative effects of ACE2. The above outcomes may be modulated by other, miRNA-mediated effects exerted by TGF-β1 on the host immune responses, leading to a complex and yet incompletely understood circuitry.
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FXR抑制作用可以通过减少ACE2来防止SARS-COV-2感染。
影响因子：
64.8
作者：
Brevini, Teresa;Maes, Mailis;Webb, Gwilym J.;John, Binu, V;Fuchs, Claudia D.;Buescher, Gustav;Wang, Lu;Griffiths, Chelsea;Brown, Marnie L.;Scott, William E., III;Pereyra-Gerber, Pehuen;Gelson, William T. H.;Brown, Stephanie;Dillon, Scott;Muraro, Daniele;Sharp, Jo;Neary, Megan;Box, Helen;Tatham, Lee;Stewart, James;Curley, Paul;Pertinez, Henry;Forrest, Sally;Mlcochova, Petra;Varankar, Sagar S.;Darvish-Damavandi, Mahnaz;Mulcahy, Victoria L.;Kuc, Rhoda E.;Williams, Thomas L.;Heslop, James A.;Rossetti, Davide;Tysoe, Olivia C.;Galanakis, Vasileios;Vila-Gonzalez, Marta;Crozier, Thomas W. M.;Bargehr, Johannes;Sinha, Sanjay;Upponi, Sara S.;Fear, Corrina;Swift, Lisa;Saeb-Parsy, Kourosh;Davies, Susan E.;Wester, Axel;Hagstrom, Hannes;Melum, Espen;Clements, Darran;Humphreys, Peter;Herriott, Jo;Kijak, Edyta;Cox, Helen;Bramwell, Chloe;Valentijn, Anthony;Illingworth, Christopher J. R.;Dahman, Bassam;Bastaich, Dustin R.;Ferreira, Raphaella D.;Marjot, Thomas;Barnes, Eleanor;Moon, Andrew M.;Barritt, Alfred S.;Gupta, Ravindra K.;Baker, Stephen;Davenport, Anthony P.;Corbett, Gareth;Gorgoulis, Vassilis G.;Buczacki, Simon J. A.;Lee, Joo-Hyeon;Matheson, Nicholas J.;Trauner, Michael;Fisher, Andrew J.;Gibbs, Paul;Butler, Andrew J.;Watson, Christopher J. E.;Mells, George F.;Dougan, Gordon;Owen, Andrew;Lohse, Ansgar W.;Vallier, Ludovic;Sampaziotis, Fotios
通讯作者：
Sampaziotis, Fotios
影响因子：
4.7
作者：
Cruz DF;Mitash N;Mu F;Farinha CM;Swiatecka-Urban A
通讯作者：
Swiatecka-Urban A
影响因子：
16.6
作者：
Ferreira-Gomes M;Kruglov A;Durek P;Heinrich F;Tizian C;Heinz GA;Pascual-Reguant A;Du W;Mothes R;Fan C;Frischbutter S;Habenicht K;Budzinski L;Ninnemann J;Jani PK;Guerra GM;Lehmann K;Matz M;Ostendorf L;Heiberger L;Chang HD;Bauherr S;Maurer M;Schönrich G;Raftery M;Kallinich T;Mall MA;Angermair S;Treskatsch S;Dörner T;Corman VM;Diefenbach A;Volk HD;Elezkurtaj S;Winkler TH;Dong J;Hauser AE;Radbruch H;Witkowski M;Melchers F;Radbruch A;Mashreghi MF
通讯作者：
Mashreghi MF
DOI：
10.1165/rcmb.2004-0012oc
发表时间：
2004-08-01
影响因子：
6.4
作者：
Hentchel-Franks, K;Lozano, D;Clancy, JP
通讯作者：
Clancy, JP
miR-136 通过靶向角质形成细胞中的 PPP2R2A 调节 TGF-β1 诱导的增殖抑制
影响因子：
--
作者：
Zhang D;Wang J;Wang Z;Zhang T;Shi P;Wang X;Zhao F;Liu X;Lin X;Pang X
通讯作者：
Pang X