MiR-23a-5p modulates mycobacterial survival and autophagy during mycobacterium tuberculosis infection through TLR2/MyD88/NF-κB pathway by targeting TLR2

Gu, Xiaorong; Gao, Yan; Mu, Deguang; Fu, Enqing

doi:10.1016/j.yexcr.2017.03.039

Cited by 79 publications

(62 citation statements)

References 32 publications

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“…Meanwhile, this study demonstrated at both the mRNA and protein levels that miR-378d mimic decreased but the inhibitor facilitated production of cytokines IL-1β, TNF-α, and IL-6 in M. tb infected THP-1 cells via Rab10. These results are in agreement with a previous publication (Zhang et al, 2017a), which reported that increase of these three cytokines in macrophages induced by M. tb infection relied on activation of TLR2/MyD88/NF-κB (Gu et al, 2017). Therefore, there would be a direct but negative regulatory relationship from miR-378d expression to NF-κB signal pathway.…”

Section: Mir-378d Regulation Are Mediated By Nf-κb Signalingsupporting

confidence: 93%

Down-Regulation of miR-378d Increased Rab10 Expression to Help Clearance of Mycobacterium tuberculosis in Macrophages

Zhu

Xiao

Delai

et al. 2020

Front. Cell. Infect. Microbiol.

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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.

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Section: Mir-378d Regulation Are Mediated By Nf-κb Signalingsupporting

confidence: 93%

Down-Regulation of miR-378d Increased Rab10 Expression to Help Clearance of Mycobacterium tuberculosis in Macrophages

Zhu

Xiao

Delai

et al. 2020

Front. Cell. Infect. Microbiol.

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“…The miR-33 also inhibits fatty acid oxidation to support bacterial replication by a mechanism not yet described ( 177 ). How M. tuberculosis alters cell signaling to control miRNAs is not known, but the initial signal might come from TLR2 ( 176 , 179 ). Finally, the scavenger receptor CD36 participates in surfactant lipid uptake by alveolar macrophages, and M. tuberculosis exploits this function for growth ( 180 ).…”

Section: Microbial Control Of Phagocytosismentioning

confidence: 99%

“…Promising therapeutic approaches will be designed based on our new understanding of the tactics pathogens use to interfere with phagocytosis. For example, studies with miRNA in mycobacteria infections identified TLR2 as a potential target to prevent the blockage of phagosome maturation ( 179 ) (Figure 5 ). Recently, it was also found by gene expression profiling of human macrophages treated with glucocorticoids and/or IFN-γ that glucocorticoids, in contrast to IFN-γ, failed to trigger expression and phagolysosome recruitment of V-ATPase ( 289 ).…”

Section: Novel Therapeutic Opportunitiesmentioning

confidence: 99%

Control of Phagocytosis by Microbial Pathogens

2017

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Phagocytosis is a fundamental process of cells to capture and ingest foreign particles. Small unicellular organisms such as free-living amoeba use this process to acquire food. In pluricellular organisms, phagocytosis is a universal phenomenon that all cells are able to perform (including epithelial, endothelial, fibroblasts, etc.), but some specialized cells (such as neutrophils and macrophages) perform this very efficiently and were therefore named professional phagocytes by Rabinovitch. Cells use phagocytosis to capture and clear all particles larger than 0.5 µm, including pathogenic microorganisms and cellular debris. Phagocytosis involves a series of steps from recognition of the target particle, ingestion of it in a phagosome (phagocytic vacuole), maturation of this phagosome into a phagolysosome, to the final destruction of the ingested particle in the robust antimicrobial environment of the phagolysosome. For the most part, phagocytosis is an efficient process that eliminates invading pathogens and helps maintaining homeostasis. However, several pathogens have also evolved different strategies to prevent phagocytosis from proceeding in a normal way. These pathogens have a clear advantage to perpetuate the infection and continue their replication. Here, we present an overview of the phagocytic process with emphasis on the antimicrobial elements professional phagocytes use. We also summarize the current knowledge on the microbial strategies different pathogens use to prevent phagocytosis either at the level of ingestion, phagosome formation, and maturation, and even complete escape from phagosomes.

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“… Guo et al (2017) revealed that M. bovis BCG infection of macrophages leads to increased expression of miR-144-3p, which induces autophagy-related gene 4a (ATG4a) to inhibit autophagy. In another study, overexpression of miR-23a-5p dramatically prevented Mtb -induced activation of autophagy in macrophages by modulating TLR2/MyD88/NF-κB signaling ( Gu et al, 2017 ). Similarly, miRNA-20a targets ATG7 and ATG16L1 and is able to inhibit autophagy ( Guo et al, 2016 ).…”

Section: Mirnas As Regulators Of Tb Immunitymentioning

confidence: 99%

miRNAs in Tuberculosis: New Avenues for Diagnosis and Host-Directed Therapy

et al. 2018

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Tuberculosis (TB) is one of the most fatal infectious diseases and a leading cause of mortality, with 95% of these deaths occurring in developing countries. The causative agent, Mycobacterium tuberculosis (Mtb), has a well-established ability to circumvent the host’s immune system for its intracellular survival. microRNAs (miRNAs) are small, non-coding RNAs having an important function at the post-transcriptional level and are involved in shaping immunity by regulating the repertoire of genes expressed in immune cells. It has been established in recent studies that the innate immune response against TB is significantly regulated by miRNAs. Moreover, differential expression of miRNA in Mtb infection can reflect the disease progression and may help distinguish between active and latent TB infection (LTBI). These findings encouraged the application of miRNAs as potential biomarkers. Similarly, active participation of miRNAs in modulation of autophagy and apoptosis responses against Mtb opens an exciting avenue for the exploitation of miRNAs as host directed therapy (HDT) against TB. Nanoparticles mediated delivery of miRNAs to treat various diseases has been reported and this technology has a great potential to be used in TB. In reality, this exploitation of miRNAs as biomarkers and in HDT is still in its infancy stage, and more studies using animal models mimicking human TB are advocated to assess the role of miRNAs as biomarkers and therapeutic targets. In this review, we attempt to summarize the recent advancements in the role of miRNAs in TB as immune modulator, miRNAs’ capability to distinguish between active and latent TB and, finally, usage of miRNAs as therapeutic targets against TB.

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MiR-23a-5p modulates mycobacterial survival and autophagy during mycobacterium tuberculosis infection through TLR2/MyD88/NF-κB pathway by targeting TLR2

Cited by 79 publications

References 32 publications

Down-Regulation of miR-378d Increased Rab10 Expression to Help Clearance of Mycobacterium tuberculosis in Macrophages

Down-Regulation of miR-378d Increased Rab10 Expression to Help Clearance of Mycobacterium tuberculosis in Macrophages

Control of Phagocytosis by Microbial Pathogens

miRNAs in Tuberculosis: New Avenues for Diagnosis and Host-Directed Therapy

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