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TLR signaling is a crucial component of the innate immune response to infection. MicroRNAs (miRNAs) have been shown to be upregulated during TLR signaling. Specifically, microRNA-146a (miR-146a) plays a key role in endotoxin tolerance by downregulating interleukin-1 receptor-associated kinase 1 (IRAK-1). The aim of this study was to assess the role of miR-146a in the TLR2 signaling and development of bacterial lipoprotein (BLP) self-tolerance and cross-tolerance to bacteria. Expression of miR-146a increased in a dose- and time-dependent manner in BLP-stimulated human THP-1 promonocytic cells. In BLP-tolerised cells miR-146a was even further upregulated in response to BLP re-stimulation ( p <0.001). Re-stimulation of BLP-tolerised cells with heat-killed gram-negative  Salmonella typhimurium  ( S. typhimurium ), but not gram-positive  Staphylococcus aureus  ( S. aureus ), led to significant overexpression of miR-146a ( p <0.05). Transfection of naive cells with a miR-146a mimic substantially suppressed TNF-α production ( p <0.05). Furthermore, overexpression of miR-146a resulted in strong reduction in IRAK-1 and phosphorylated IκBα expression in naive and  S. typhimurium -stimulated THP-1 cells. Collectively, miR-146a is upregulated in response to BLP and bacterial stimulation in both naive and BLP-tolerised cells. Overexpression of miR-146a induces a state analogous to tolerance in BLP-stimulated cells and therefore may represent a future target for exogenous modulation of tolerance during microbial infection and sepsis.

MicroRNA-146a Is Upregulated by and Negatively Regulates TLR2 Signaling