MiR-1303 Regulates Mycobacteria Induced Autophagy by Targeting Atg2B.

MicroRNAs are emerging post-transcriptional regulators of gene expressions in both innate immunity and adaptive immunity. In mycobacteria infection, autophagy plays an important role in innate defense mechanism and is tightly regulated by the autophagy-related proteins. Here, we show that Atg2B is involved in the regulation of mycobacteria-induced autophagy. MiR-1303, which function is not defined yet, is found to negatively regulate mycobacteria-induced Atg2B protein production, ultimately down-regulate mycobacteria-induced autophagy. MiR-1303 production is shown to be upregulated during BCG infection and its production is regulated by PI3K and NFκB. It is also demonstrated that miR-1303 targets putative target sites on Atg2B and possibly represses its translation.

A role for interleukin-17A in modulating intracellular survival of Mycobacterium bovis bacillus Calmette-Guérin in murine macrophages.

Interleukin 17A IL-17A is a crucial immunomodulator in various chronic immunological diseases including rheumatoid arthritis and inflammatory bowel disease. The cytokine has also been demonstrated to control the pathogenesis of the Mycobacterium tuberculosis by dysregulating production of cytokines and chemokines and promoting granuloma formation. Whether IL-17A regulates innate defence mechanisms of macrophages in response to mycobacterial infection remains to be elucidated. In the current report, we investigated the effects of IL-17A on modulating the intracellular survival of Mycobacterium bovis bacillus Calmette-Guérin (BCG) in RAW264.7 murine macrophages. We observed that IL-17A pre-treatment for 24 hr was able to synergistically enhance BCG-induced nitric oxide (NO) production and inducible nitric oxide synthase expression in dose- and time-dependent manners. We further delineated the mechanisms involved in this synergistic reaction. IL-17A was found to specifically enhanced BCG-induced phosphorylation of Jun N-terminal kinase (JNK), but not of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. By using a specific JNK inhibitor (SP600125), we found that the production of NO in BCG-infected macrophages was significantly suppressed. Taken together, we confirmed the involvement of the JNK pathway in IL-17A-enhanced NO production in BCG-infected macrophages. We further demonstrated that IL-17A significantly enhanced the clearance of intracellular BCG by macrophages through an NO-dependent killing mechanism. In conclusion, our study revealed an anti-mycobacterial role of IL-17A through priming the macrophages to produce NO in response to mycobacterial infection.

A role for c-Myc in regulating anti-mycobacterial responses.

c-Myc (Myc) is a well known transcription factor that regulates many essential cellular processes; however, its role in modulating immunity is not known. Here, we showed different species of mycobacteria can induce Myc expression via ERK1/2 and JNK activation. Unexpectedly, the induced Myc is localized in the cytoplasm but not in the nucleus. This induced Myc expression is associated with the induction of TNF-α and IL-6 and with the suppression of intracellular mycobacterial growth. To delineate the underlying mechanisms, we demonstrated that Myc enhances IRAK1 degradation, leading to specific activations of ERK1/2 and p38 MAPK but not Akt, and reduces IκBα protein recovery upon degradation. Hence, our findings may provide insights into a potential role for Myc in regulating the antimicrobial responses.