Journal
AGING-US
Volume 11, Issue 24, Pages 12661-12673Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/aging.102593
Keywords
Mycobacterium tuberculosis (MTB); macrophages; miR-1281; cyclophilin-D; programmed necrosis
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Funding
- Western Medicine Guide Project of STCSM [17411969300]
- China Tuberculosis Clinical Trial Consortium (CTCTC) Research Funding [2017KYJJ007]
- Clinical Research Plan of SHDC [16CR1028B]
- Clinical Key Discipline Construction Project of Shanghai Municipal Health Commission [2017ZZ02003]
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Mycobacterium tuberculosis (MTB) infection induces cytotoxicity to host human macrophages. The underlying signaling mechanisms are largely unknown. Here we discovered that MTB infection induced programmed necrosis in human macrophages, causing mitochondrial cyclophilin-D (CypD)-p53-adenine nucleotide translocator type 1 association, mitochondrial depolarization and lactate dehydrogenase medium release. In human macrophages MTB infection-induced programmed necrosis and apoptosis were largely attenuated by CypD inhibition (by cyclosporin A), silencing and knockout, but intensified with ectopic CypD overexpression. Further studies identified microRNA-1281 as a CypD-targeting miRNA. Ectopic overexpression of microRNA-1281 decreased CypD 3'-untranslated region activity and its expression, protecting human macrophages from MTB-induced programmed necrosis and apoptosis. Conversely, microRNA-1281 inhibition in human macrophages, by the antisense sequence, increased CypD expression and potentiated MTB-induced cytotoxicity. Importantly, in CypD-KO macrophages miR-1281 overexpression or inhibition was ineffective against MTB infection. Restoring CypD expression, by an untranslated region-depleted CypD construct, reversed miR-1281-induced cytoprotection against MTB in human macrophages. Collectively, these results show that targeting CypD by miR-1281 protects human macrophages from MTB-induced programmed necrosis and apoptosis.
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