Dataset Information

Mycobacterium marinum down-regulates miR-148a in macrophages in an EsxA-dependent manner.

ABSTRACT: As a key virulence factor of Mycobacterium tuberculosis, EsxA is not only involved in phagosome rupture, but also functions in stimulation of immune responses in macrophages. Here, we report thatmiR-148a is down-regulated in the macrophages infected with Mycobacterium marinum (Mm). Using the knockout strain Mm?EsxA/B, recombinant EsxA, EsxB and EsxA/B heterodimer proteins, we provide evidence that down-regulation of miR-148ais dependent on EsxA, and up-regulation of miR-148a reduces Mm intracellular survival. Moreover, up-regulation of miR-148a down-regulates the pro-inflammatory cytokines (e.g. TNF-? and IL-1?) and the TLR4-mediated NF-?B activation. Together, miR-148a may function as an anti-inflammation modulator in responses to mycobacterial infection. Regulation of miR-148a may provide a novel venue in development of therapies in tuberculosis.

SUBMITTER: Wu H

PROVIDER: S-EPMC6616010 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Mycobacterium marinum down-regulates miR-148a in macrophages in an EsxA-dependent manner.

Wu Haichong H Bao Yanqing Y Wang Lin L Li Xiujun X Sun Jianjun J

International immunopharmacology 20190509

As a key virulence factor of Mycobacterium tuberculosis, EsxA is not only involved in phagosome rupture, but also functions in stimulation of immune responses in macrophages. Here, we report thatmiR-148a is down-regulated in the macrophages infected with Mycobacterium marinum (Mm). Using the knockout strain Mm∆EsxA/B, recombinant EsxA, EsxB and EsxA/B heterodimer proteins, we provide evidence that down-regulation of miR-148ais dependent on EsxA, and up-regulation of miR-148a reduces Mm intracell ...[more]

PMID: 31078924

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Project description:Mycobacterium tuberculosis (M. tb) can survive in the hostile microenvironment of cells by escaping host surveillance, but the molecular mechanisms are far from being fully understood. MicroRNAs might be involved in regulation of this intracellular process. By RNAseq of M. tb-infected PMA-differentiated THP-1 macrophages, we previously discovered down-regulation of miR-378d during M. tb infection. This study aimed to investigate the roles of miR-378d in M. tb infection of THP-1 cells by using a miR-378d mimic and inhibitor. First, M. tb infection was confirmed to decrease miR-378d expression in THP-1 and Raw 264.7 macrophages. Then, it was demonstrated that miR-378d mimic promoted, while its inhibitor decreased, M. tb survival in THP-1 cells. Further, the miR-378d mimic suppressed, while its inhibitor enhanced the protein production of IL-1β, TNF-α, IL-6, and Rab10 expression. By using siRNA of Rab10 (siRab10) to knock-down the Rab10 gene in THP-1 with or without miR-378d inhibitor transfection, Rab10 was determined to be a miR-378d target during M. tb infection. In addition, a dual luciferase reporter assay with the Rab10 wild-type sequence and mutant for miR-378d binding sites confirmed Rab10 as the target of miR-378d associated with M. tb infection. The involvement of four signal pathways NF-κB, P38, JNK, and ERK in miR-378d regulation was determined by detecting the effect of their respective inhibitors on miR-378d expression, and miR-378d inhibitor on activation of these four signal pathways. As a result, activation of the NF-κB signaling pathway was associated with the down-regulation of miR-378d. In conclusion, during M. tb infection of macrophages, miR-378d was down-regulated and functioned on decreasing M. tb intracellular survival by targeting Rab10 and the process was regulated by activation of the NF-κB and induction of pro-inflammatory cytokines IL-1β, TNF-α, IL-6. These findings shed light on further understanding the defense mechanisms in macrophages against M. tb infection.

Dataset Information

Mycobacterium marinum down-regulates miR-148a in macrophages in an EsxA-dependent manner.

Publications

Mycobacterium marinum down-regulates miR-148a in macrophages in an EsxA-dependent manner.

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