A Novel Mechanism Underlying the Basic Defensive Response of Macrophages against <i>Mycobacterium</i> Infection

Iyoda, Takuya; Takada, Muneaki; Fukatsu, Yoshinobu; Kumokoshi, Shunsuke; Fujisawa, Toshimitsu; Shimada, Tomokazu; Shimokawa, Noriko; Matsunaga, Takuya; Makino, Kimiko; Doi, Norio; Terada, Hiroshi; Fukai, Fumio

doi:10.4049/jimmunol.1301526

Cited by 8 publications

(5 citation statements)

References 44 publications

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“…27 Our data are discrepant with this work as we maintain that mycobacteria-induced apoptosis is a feature exclusive to virulent strains. Using our experimental settings, and in agreement with other works 8 , we do not find cell death induced by BCG infection, or other attenuated strains, such as MTBVAC vaccine candidate.…”

Section: Discussioncontrasting

confidence: 93%

Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis

et al. 2014

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Mycobacterium tuberculosis, the causative agent of tuberculosis, induces apoptosis in infected macrophages in vitro and in vivo. However, the molecular mechanism controlling this process is not known. In order to study the involvement of the mitochondrial apoptotic pathway in M. tuberculosis-induced apoptosis, we analysed cell death in M. tuberculosis-infected embryonic fibroblasts (MEFs) derived from different knockout mice for genes involved in this route. We found that apoptosis induced by M. tuberculosis is abrogated in the absence of Bak and Bax, caspase 9 or the executioner caspases 3 and 7. Notably, we show that MEF deficient in the BH3-only BCL-2-interacting mediator of cell death (Bim) protein were also resistant to this process. The relevance of these results has been confirmed in the mouse macrophage cell line J774, where cell transfection with siRNA targeting Bim impaired apoptosis induced by virulent mycobacteria. Notably, only infection with a virulent strain, but not with attenuated ESX-1-defective strains, such as Bacillus Calmette-Guerin and live-attenuated M. tuberculosis vaccine strain MTBVAC, induced Bim upregulation and apoptosis, probably implicating virulence factor early secreted antigenic target 6-kDa protein in this process. Our results suggest that Bim upregulation and apoptosis is mediated by the p38MAPK-dependent pathway. Our findings show that Bim is a master regulator of apoptosis induced by M. tuberculosis.

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Section: Discussioncontrasting

confidence: 93%

Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis

et al. 2014

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“…7 An MEK/ERK inhibitor could rescue BCG-infected macrophages from apoptosis, which is accompanied by the complete suppression of Bim phosphorylation. 8 Other factors, such as eicosanoids, are involved in the regulation of apoptosis in Mtb-infected macrophages. 47 Avirulent Mtb strains such …”

Section: Discussionmentioning

confidence: 99%

“…Previous study showed that a JNK inhibitor failed to increase the number of viable BCGinfected macrophages. 8 However, JNK1 and JNK2, belonging to the JNK kinase family, have distinct or even opposing functions in different diseases. They phosphorylate and activate a number of nuclear and non-nuclear proteins, including the transcription factor AP-1, ATF-2, c-Myc, as well as cell apoptotic proteins (Fas, Bim, Bcl-xl).…”

Section: Cells Infected With Mir-20a-5p Lentivirus and Decreased In mentioning

confidence: 99%

“…6 Among them, Bim is a crucial regulator of apoptosis induced by Mtb, which is mediated by the MAPKdependent pathway. 7,8 Furthermore, FasL-induced apoptosis of infected human macrophages could be an immune effector mechanism not only depriving mycobacteria from their growth environment but also reducing viable bacterial counts. 9 Conversely, to facilitate the persistent infection, Mtb develops multiple strategies to avoid being killed by macrophages through inhibiting apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Down-regulation of miR-20a-5p triggers cell apoptosis to facilitate mycobacterial clearance through targeting JNK2 in human macrophages

et al. 2016

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Induction of cell apoptosis is one of the major host defense mechanisms through which macrophages control Mycobacterium tuberculosis (Mtb) infection. However, the mechanisms underlying macrophage apoptosis triggered by Mtb infection are still largely unknown. In this study, a microarray profiling survey revealed 14 miRNAs were down-regulated in CD14C monocytes from active pulmonary tuberculosis patients, and only the reduction of miR-20a-5p could be reversed after successful anti-tuberculosis treatment. Validation of miR-20a-5p expression was confirmed using real time qPCR. Moreover, miR-20a-5p expression also decreased in differentiated THP-1 macrophages after mycobacterial infection in vitro. Functional assays through forced or inhibited expression of miR-20a-5p in THP-1 macrophages demonstrated that miR-20a-5p functioned as a negative regulator of mycobacterial-triggered apoptosis. Importantly, inhibition of miR-20a-5p expression resulted in more efficient mycobacterial clearance from infected THP-1 macrophages while miR-20a-5p overexpression promoted mycobacterial survival. Mechanistically, miR-20a-5p was demonstrated to regulate Bim expression in a JNK2-dependent manner, unlike Bcl2, and luciferase assay showed JNK2 was a novel direct target of miR-20a-5p. Together, our findings indicate that downregulation of miR-20a-5p triggers macrophage apoptosis as a novel mechanism for host defense against mycobacterial infection.

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“…It is uncertain whether these data obtained with immortalized monocytic cells reflect death mechanisms in primary macrophages infected Mtb . Others found that M. bovis BCG, which lacks ESAT6/CFP10 and the Esx-1 secretion system, is a potent inducer of apoptosis [61, 83, 84]. …”

Section: Cell Death In Tbmentioning

confidence: 99%

Cell death and autophagy in tuberculosis

Moraco

Kornfeld

2014

Seminars in Immunology

103

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Mycobacterium tuberculosis has succeeded in infecting one third of the human race though inhibition or evasion of innate and adaptive immunity. The pathogen is a facultative intracellular parasite that uses the niche provided by mononuclear phagocytes for its advantage. Complex interactions determine whether the bacillus will or will not be delivered to acidified lysosomes, whether the host phagocyte will survive infection or die, and whether the timing and mode of cell death works to the advantage of the host or the pathogen. Here we discuss cell death and autophagy in TB. These fundamental processes of cell biology feature in all aspects of TB pathogenesis and may be exploited to the treatment or prevention of TB disease.

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A Novel Mechanism Underlying the Basic Defensive Response of Macrophages against Mycobacterium Infection

Cited by 8 publications

References 44 publications

Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis

Bim is a crucial regulator of apoptosis induced by Mycobacterium tuberculosis

Down-regulation of miR-20a-5p triggers cell apoptosis to facilitate mycobacterial clearance through targeting JNK2 in human macrophages

Cell death and autophagy in tuberculosis

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