MicroRNA-21 Limits In Vivo Immune Response-Mediated Activation of the IL-12/IFN-γ Pathway, Th1 Polarization, and the Severity of Delayed-Type Hypersensitivity

Abstract

An altered balance between Th1 and Th2 cytokines is responsible for a variety of immuno-inflammatory disorders such as asthma, yet the role of post-transcriptional mechanisms, such as those mediated by microRNAs, in adjusting the relative magnitude and balance of Th cytokine expression have been largely unexplored. Here we show that miR-21 has a central role in setting a balance between Th1 and Th2 responses to antigens. Targeted ablation of miR-21 in mice led to reduced lung eosinophilia after allergen challenge, with a broadly reprogrammed immunoactivation transcriptome, and significantly increased levels of the Th1 cytokine IFNγ. Biological network-based transcriptome analysis of OVA-challenged miR-21-/-mice identified an unexpected prominent dysregulation of IL-12/IFNγ pathways as the most significantly affected in the lungs with a key role for miR-21 in IFNγ signaling and T-cell polarization, consistent with a functional miR-21 binding site in IL-12p35. In support of these hypotheses, miR-21 deficiency led dendritic cells to produce more IL-12 after LPS stimulation, and OVA-challenged CD4+ T lymphocytes to produce increased IFNγ and decreased IL-4. Further, loss of miR-21 significantly enhanced the Th1-associated delayed-type hypersensitivity cutaneous responses. Thus, our results define miR-21 as a major regulator of Th1 vs. Th2 responses, defining a new mechanism for regulating polarized immuno-inflammatory responses.

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.…”

Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP

“…Myc activation was associated with gene expression profiling signatures suggesting decreased immune responses and a number of microRNAs overlapped with the molecular Burkitt lymphoma signature, 29,30 including MIR17HG, which was markedly upregulated, and MIR21 (ref. 44) and MIR155HG, which were significantly downregulated. Other studies have shown these microRNAs to be regulated by the Myc, Bcl-6, STAT3, and NF-κB pathways, and the MIR17HG locus was frequently amplified in Burkitt lymphoma.…”

Functional regulation of monocyte-derived dendritic cells by microRNAs

“…These researchers further generated miR-21 deficient mice. Compared to wild type mice, in vitro derived moDCs from these mutant mice had enhanced production of IL-12 but not several other cytokines (including TNF-α, IL-6 and IL-23) when they were stimulated with LPS (with or without IFN-γ) (Lu et al, 2011b). In vivo, miR-21 deficient mice also generated a stronger antigen-specific Th1 response, although which DCs contributed to Th polarization in vivo was not clear.…”