The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ

Abstract

Interferon-γ (IFN-γ) has a critical role in immune responses to intracellular bacterial infection. MicroRNAs (miRNAs) are important in the regulation of innate and adaptive immunity. However, whether miRNAs can directly target IFN-γ and regulate IFN-γ production post-transcriptionally remains unknown. Here we show that infection of mice with Listeria monocytogenes or Mycobacterium bovis bacillus Calmette-Guérin (BCG) downregulated miR-29 expression in IFN-γ-producing natural killer cells, CD4(+) T cells and CD8(+) T cells. Moreover, miR-29 suppressed IFN-γ production by directly targeting IFN-γ mRNA. We developed mice with transgenic expression of a 'sponge' target to compete with endogenous miR-29 targets (GS29 mice). We found higher serum concentrations of IFN-γ and lower L. monocytogenes burdens in L. monocytogenes-infected GS29 mice than in their littermates. GS29 mice had enhanced T helper type 1 (T(H)1) responses and greater resistance to infection with BCG or Mycobacterium tuberculosis. Therefore, miR-29 suppresses immune responses to intracellular pathogens by targeting IFN-γ.

Integrin CD11b Negatively Regulates TLR9-Triggered Dendritic Cell Cross-Priming by Upregulating microRNA-146a

“…Hence, targeting of Notch1 by miR146a may be responsible for the miR-146a-mediated repression of IL-12p70 production in CpG-ODN-stimulated DCs. However, because a single miRNA might tune protein synthesis from thousands of genes by direct or indirect effects (23)(24)(25)(26), there may be other molecules or signaling pathways that are targeted by miR-146a in CpG-ODN-stimulated DCs. This presumption may lead to future work that reveals the comprehensive functions of miR-146a in the immune response.…”

“…miRNAs are important regulators of the immune response (23)(24)(25)(26)(27). Thus, we wondered whether CD11b is involved in miRNA in DCs induced by CpG-ODN, as well as which kind of miRNAs may contribute to the decreased IL-12p70 production.…”

“…Because miRNAs are first transcribed as pri-miRNAs and then processed to the mature sequences (23)(24)(25)(26)(27), we tested whether CpG-ODN stimulation upregulated pri-miR-146a transcripts. In wild-type DCs, both LPS and CpG-ODN induced pri-miR-146a expression, and CD11b deficiency also abolished CpG-ODN-triggered, but not LPStriggered, pri-miR-146a expression (Fig.…”

“…They control gene expression at the posttranscriptional level by inhibiting translation or inducing mRNA degradation. miRNAs are emerging as important regulators in immune responses (23)(24)(25)(26)(27). Among them, miR-146a plays key roles in innate immunity, inflammatory response, and viral infection.…”

MicroRNAs in the regulation of TLR and RIG-I pathways

“…Il-12p35 mRNA can be targeted by miR-21 in macrophages and DCs, leading to restricted adaptive Th1 responses. [99][100][101] miR-106 has been demonstrated to target Il-10 mRNA, 102 while miR-29 suppresses immune responses against intracellular pathogens by targeting IFN-c. 103 Numerous cytokine encoding mRNAs are regulated by RNA-binding proteins (RBPs) through the AU-rich elements in their 39-UTR, which may play a vital role in mRNA stabilization. MiRNAs can also cooperate with these RBPs to regulate mRNA stability or translation.…”