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miR-18a promotes Mycobacterial survival in macrophages via inhibiting autophagy by down-regulation of ATM.
- Source :
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Journal of cellular and molecular medicine [J Cell Mol Med] 2020 Jan; Vol. 24 (2), pp. 2004-2012. Date of Electronic Publication: 2019 Dec 17. - Publication Year :
- 2020
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Abstract
- Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of leading causes of global deaths. This study aimed to explore the role of miR-18a in RAW264.7 cells response to Mtb infection. Exosomes derived from Mtb-infected cells were isolated and further validated by size, transmission electron microscopy and Western blot. RT-PCR was utilized to measure miR-18a expression. Cell viability and ultrastructure were examined by CFU counting, CCK-8 and electron microscope, respectively. Potential target genes of miR-18a were predicted with bioinformatics and further confirmed using RT-PCR, Western blot and laser confocal microscope analysis, respectively. LC3, AMPK and mTOR were measured using Western blot. We found that miR-18a was induced both in Mtb-infected RAW264.7 cells and its derived exosomes compared with the controls. In addition, up-regulation of miR-18a promoted intracellular Mtb survival, attenuated cell viability and reduced LC3-II level, while its down-regulation had the opposite effect. miR-18a overexpression suppressed level of ATM, one possible target of miR-18a, while its underexpression enhanced ATM. We also found that inhibition of ATM induced LC3-II decrease in Mtb-infected cells and could reverse the increase of LC3-II caused by inhibition of miR-18a. Moreover, down-regulation of miR-18a increased p-AMPK level while reduction of ATM could reverse the change. Taken together, our results suggest that miR-18a is up-regulated in macrophages response to Mtb infection, and it promotes intracellular Mtb survival through repressing autophagic process by down-regulation of ATM pathway. This provides new thought for TB pathogenesis, diagnosis and treatment.<br /> (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)
- Subjects :
- Adenylate Kinase metabolism
Animals
Ataxia Telangiectasia Mutated Proteins metabolism
Exosomes metabolism
Exosomes ultrastructure
Macrophages ultrastructure
Mice
RAW 264.7 Cells
Signal Transduction
Ataxia Telangiectasia Mutated Proteins genetics
Autophagy
Down-Regulation genetics
Macrophages microbiology
MicroRNAs metabolism
Microbial Viability genetics
Mycobacterium tuberculosis physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 24
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 31845528
- Full Text :
- https://doi.org/10.1111/jcmm.14899