The Effect of miR-146a on the Gene Expression of Immunoregulatory Cytokines in Human Mesenchymal Stromal Cells

Abstract

Mounting evidence indicates that microRNAs (miRNAs), including miR-146a, have an impact on the immunomodulatory activities of mesenchymal stem/stromal cells (MSCs). Suppression of inflammatory macrophage activation is one of the main immunomodulatory mechanisms of MSCs. Here, we investigated whether miR-146a in MSCs might play a role in the effects of MSCs on macrophage activation. A miRNA microarray revealed that miR-146a was the most highly upregulated miRNA in MSCs upon co-culture with activated macrophages. Inhibition of miR-146a in MSCs through miR-146a inhibitor transfection had a different effect on the expression of immunoregulatory factors secreted by MSCs. Pentraxin 3, tumor necrosis factor-inducible gene 6, and cyclooxygenase-2, which are well-known mediators of the immunomodulatory functions of MSCs, were significantly upregulated in MSCs after miR-146a knockdown. By contrast, hepatocyte growth factor and stanniocalcin 1, other immunoregulatory molecules expressed by MSCs, were downregulated by miR-146a knockdown. Consequently, the inhibition of miR-146a in MSCs did not change the overall effect of MSCs on the suppression of inflammatory macrophage activation or the induction of anti-inflammatory macrophage polarization.

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“…Zhang and colleagues recently demonstrated that MSC-Exo-containing miR-146a represents one of the major regulators of NLRP3 inflammasome activation and pro-inflammatory cytokine secretion in macrophages [ 30 ]. MSC-derived miR-146a is able to efficiently suppress NLRP3 inflammasome activation in inflammatory immune cells, crucially contributing to the alleviation of ongoing inflammation [ 30 , 31 ]. MSC-sourced miR-146a directly targets and binds to the 3’ untranslated regions (UTRs) of NLRP3 and ASC proteins, two key components of the NLRP3 inflammasome complex.…”

“…MSC-sourced miR-146a directly targets and binds to the 3’ untranslated regions (UTRs) of NLRP3 and ASC proteins, two key components of the NLRP3 inflammasome complex. The binding of miR-146a to the 3’ UTRs of NLRP3 and ASC leads to the degradation of their mRNA, resulting in reduced expression levels of these proteins [ 31 ]. MSC-derived miR-146a also targets and suppresses the expression of downstream signaling molecules involved in the activation of the NLRP3 inflammasome [ 26 ].…”