The role of miR-146a on experimental lung inflammation: two sides of the same coin

MiR-146a emerges as a promising posttranscriptional regulator in various inflammatory conditions and presents with different roles of the two isoforms, miR-146a-5p and miR-146a-3p. The understanding of the interaction between miR-146a-5p and miR-146a-3p has not yet been sufficiently clarified. The aim of this study is to examine their role in the modulation of inflammation in human pulmonary epithelial cells (A549), neutrophilic granulocytes (HL60) and in M1 macrophages (THP1). Experimental inflammation via the NF-kB pathway resulted in increased levels of the inflammatory cytokines IL-6 and IL-8 and leads to upregulation of inflammation-associated miRNA expression, including miR-146a, across all three cell lines. Interestingly, miR-146a-5p was the major miRNA being upregulated in all three cell lines, while miR-146a-3p was not upregulated in HL60 cells. Modulation by transfection with miRNA mimics and inhibitors demonstrated an anti-inflammatory effect of miR-146a-5p and a pro-inflammatory effect of miR-146a-3p. The miR-146a-5p mimic as well as the miR-146a-3p inhibitor significantly downregulated inflammation. The combination of both did not improve the anti-inflammatory effect compared to individual components. A mutual interference between miR-146a-5p and miR-146a-3p was observed, with miR-146a-5p exerting a predominant influence. MiR-146a-5p and miR-146a-3p are two distinctive but interconnected miRNA isoforms with opposing functions in regulation of inflammation. Understanding their interaction provides important insights into the progression and persistence of inflammatory lung diseases and might offer potential therapeutic options.