English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Alveolar Macrophages play a key role in the development of a robust adaptive immune response against the agent of Tuberculosis (TB),  Mycobacterium tuberculosis  ( M.tb ). However, macrophage response is often hampered by the production of IL-10, a potent suppressor of the host immune response. The secretion of IL-10 correlates with TB pathogenesis and persistence in host tissues. Concordantly, inhibition of IL-10 signaling, during BCG vaccination, confers higher protection against  M.tb  through a sustained Th1 and Th17 responses. Therefore, uncovering host effectors, underlying mycobacteria-induced expression of IL-10, may be beneficial toward the development of IL-10-blocking tools to be used either as adjuvants in preventive vaccination or as adjunct during standard treatment of TB. Here, we investigated the role of FOXO3 transcription factor in mycobacteria-induced secretion of IL-10. We observed that PI3K/Akt/FOXO3 axis regulates IL-10 expression in human macrophages. Knocking down of FOXO3 expression resulted in an increase of IL-10 production in BCG-infected macrophages. The gene reporter assay further confirmed the transcriptional regulation of IL-10 by FOXO3.  In silico  analysis identified four Forkhead binding motifs on the human IL-10 promoter, from which the typical FOXO3 one at position −203 was the major target as assessed by mutagenesis and CHIP binding assays. Further, we also observed a decrease in gene expression levels of the M1 typical markers (i.e., CD80 and CD86) in SiFOXO3-transfected macrophages while activation of FOXO3 led to the increase in the expression of CD86, MHCI, and MHCII. Finally, co-culture of human lymphocytes with siFOXO3-transfected macrophages, loaded with mycobacterial antigens, showed decreased expression of Th1/Th17 specific markers and a simultaneous increase in expression of IL-4 and IL-10. Taken together, we report for the first time that FOXO3 modulates IL-10 secretion in mycobacteria-infected macrophage, driving their polarization and the subsequent adaptive immune response. This work proposes FOXO3 as a potential target for the development of host-directed strategies for better treatment or prevention of TB.

frontiers in immunology

FOXO3 Transcription Factor Regulates IL-10 Expression in Mycobacteria-Infected Macrophages, Tuning Their Polarization and the Subsequent Adaptive Immune Response