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Genome-Wide Gene Expression Analysis of Mtb-Infected DC Highlights the Rapamycin-Driven Modulation of Regulatory Cytokines the mTOR/GSK-3β Axis. | LitMetric

AI Article Synopsis

  • Rapamycin enhances the immune response in human dendritic cells (DC) infected with Mycobacterium tuberculosis (Mtb) by overcoming autophagy blocks and promoting IL-12 secretion.
  • Transcriptome and translatome analyses revealed hundreds of differentially expressed genes influenced by rapamycin, indicating it affects many pathways related to immune responses.
  • The study highlights GSK-3β as a crucial regulator of cytokine balance in Mtb-infected DC and suggests that targeting autophagy and GSK-3β could be effective strategies for treating Mtb infections.

Article Abstract

In human primary dendritic cells (DC) rapamycin-an autophagy inducer and protein synthesis inhibitor-overcomes the autophagy block induced by (Mtb) and promotes a Th1 response IL-12 secretion. Here, the immunostimulatory activity of rapamycin in Mtb-infected DC was further investigated by analyzing both transcriptome and translatome gene profiles. Hundreds of differentially expressed genes (DEGs) were identified by transcriptome and translatome analyses of Mtb-infected DC, and some of these genes were found further modulated by rapamycin. The majority of transcriptome-associated DEGs overlapped with those present in the translatome, suggesting that transcriptionally stimulated mRNAs are also actively translated. analysis of DEGs revealed significant changes in intracellular cascades related to cytokine production, cytokine-induced signaling and immune response to pathogens. In particular, rapamycin treatment of Mtb-infected DC caused an enrichment of IFN-β, IFN-λ and IFN-stimulated gene transcripts in the polysome-associated RNA fraction. In addition, rapamycin led to an increase of IL-12, IL-23, IL-1β, IL-6, and TNF-α but to a reduction of IL-10. Interestingly, upon silencing or pharmacological inhibition of GSK-3β, the rapamycin-driven modulation of the pro- and anti-inflammatory cytokine balance was lost, indicating that, in Mtb-infected DC, GSK-3β acts as molecular switch for the regulation of the cytokine milieu. In conclusion, our study sheds light on the molecular mechanism by which autophagy induction contributes to DC activation during Mtb infection and points to rapamycin and GSK-3β modulators as promising compounds for host-directed therapy in the control of Mtb infection.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086600PMC
http://dx.doi.org/10.3389/fimmu.2021.649475DOI Listing

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