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Abstract
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.
Highlights
Sepsis is the leading cause of death in patients who are critically ill [1] and the annual incidence of sepsis continues to increase [2]
Maximal TNFa levels were seen at 6 h with a fall in tumor necrosis factor-a (TNF-a) levels at 24 h (p,0.01 versus the TNF-a levels at 6 h) and this occurred in a dose-dependent manner (Figure 1A). miR-146a expression was induced by bacterial lipoprotein (BLP) stimulation in a dose-dependent manner (p,0.05 versus naive cells) (Figure 1B)
Whilst TNF-a levels decreased with a longer duration of BLP stimulation, miR-146a expression levels continued to rise after 24 h of BLP stimulation, indicating a strong negative correlation between TNF-a levels and miR-146a expression in response to BLP stimulation (r = 20.967; p,0.001)
Summary
Sepsis is the leading cause of death in patients who are critically ill [1] and the annual incidence of sepsis continues to increase [2]. Sepsis is the systemic inflammatory response to infection and the initial host response to infection is mediated via activation of the innate immune system [3]. The cells of the innate immune system express pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs) which recognize and transduce signals on contact with bacterial components [3]. The immune response is initiated following recognition of these structural components of bacteria, called pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) or endotoxin in gram-negative bacteria and peptidoglycan (PGN) in gram-positive bacteria [4]. There are 10 functional TLRs in humans and each has a distinct function in terms of PAMP recognition and immune responses [5]. TLR2 responds to PGN, lipoteichoic acid (LTA) and bacterial lipoprotein (BLP), whereas TLR4 responds to LPS [5,6]. TLR2 signals via the myeloid differentiation factor 88 (MyD88)-dependent signaling pathway [7]
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