A Distinct Inhibitory Function for miR-18a in Th17 Cell Differentiation

Abstract

T helper (Th)17 cell responses orchestrate immunity against extracellular pathogens, but also underlie autoimmune disease pathogenesis. Here, we uncovered a distinct and critical role for miR-18a in limiting Th17 cell differentiation. miR-18a was the most dynamically upregulated miRNA of the miR-17∼92 cluster in activated T cells. miR-18a deficiency enhanced CCR6+RORγt+ Th17 cell differentiation in vitro and increased the number of tissue Th17 cells expressing CCR6, RORγt and IL-17A in airway inflammation models in vivo. Sequence-specific miR-18 inhibitors increased CCR6 and RORγt expression in both mouse and human CD4+ T cells, revealing functional conservation. miR-18a directly targeted Smad4, Hif1a, and Rora, all key transcription factors in the Th17 cell gene expression program. These findings indicate that activating signals influence the outcome of T helper cell differentiation via differential regulation of mature miRNAs within a common cluster.

Long non‐coding RNA and mRNA expression profiles in peri‐implantitis vs periodontitis

“…These lncRNAs and mRNAs, especially those with high fold changes, might account for differences in pathologic processes. For example, a validated lncRNA LINC01007 , with a 5.9‐fold up‐regulated expression in peri‐implantitis, was predicted to have a binding site with miR‐18ab by TargetScan (http://www.targetscan.org), which regulates Th17 differentiation . We further explored pathological mechanisms by applying coding and non‐coding gene regulatory network analysis, as lncRNAs are important transcriptional regulators .…”

MicroRNA‐mediated regulation of T follicular helper and T follicular regulatory cell identity

“…60,72,73 Indeed, miR-17~92 has been shown to promote the proliferation and survival of CD4 + T cells by directly repressing the tumor-suppressor phosphatase and tensin homolog (Pten). 58,72,75 Besides its general role in promoting proliferation and survival of CD4 + T cells, miR-17~92 also has Thelper cell subset-specific functions. Members of the cluster that belong to the same miRNA family often act synergistically.…”

“…Members of the cluster that belong to the same miRNA family often act synergistically. 75,78 This complexity is further reflected in the various effects of miR-17~92 on Tregs. For example, miR-19b is the predominant miRNA among the individual cluster members that promotes proliferation and survival via targeting Pten, whereas miR-18a antagonizes the cluster's function.…”

“…For example, miR-19b is the predominant miRNA among the individual cluster members that promotes proliferation and survival via targeting Pten, whereas miR-18a antagonizes the cluster's function. 58,72,75 Besides its general role in promoting proliferation and survival of CD4 + T cells, miR-17~92 also has Thelper cell subset-specific functions. 76 For example, the cluster was shown to promote Th1 58,72 and Th2 77 cell differentiation.…”

“…While miR-17 family RNAs were shown to promote Th17 cell differentiation, miR-18 was shown to be a potent inhibitor of Th17 cells, which highlights the heterogeneity of this cluster. 75,78 This complexity is further reflected in the various effects of miR-17~92 on Tregs. 72,79,80 Several studies have highlighted a function for the miR-17~92 cluster specifically in Tfh cells ( Figure 2).…”