miR-146a-5p Antagonized AGEs- and P.g-LPS-Induced ABCA1 and ABCG1 Dysregulation in Macrophages via IRAK-1 Downregulation

Abstract

The miR-146-mediated IL-1 receptor-associated kinase 1 (IRAK-1) feedback circuit has been shown to inhibit inflammatory response in macrophages against lipopolysaccharide (LPS). The aim of this study is to compare the antagonized effects of miR-146a-5p on Porphyromonas gingivalis (P.g) lipolysaccharide (LPS)- and advanced glycation end products (AGEs)-triggered ABCA1 and ABCG1 dysregulation and explore the underlying mechanism. THP-1-derived macrophages transfected with miRNA mimics or not were treated with P.g LPS or AGE-BSA, respectively. The mechanism of endotoxin tolerance was mimicked. miR-146a-5p levels and protein levels of IRAK-1, LXRα/β, ABCA1, and ABCG1 were detected by stem-loop reverse transcription followed by TaqMan PCR analysis and Western blotting. Our results showed that miR-146a-5p levels were significantly increased in macrophages after 24 h of stimulation with high dose of P.g LPS or AGE-BSA. Macrophages transfected with miR-146a-5p mimics attenuated the dysregulation of ABCA1/G1 induced by P.g LPS and AGEs through IRAK-1 downregulation. In low-dose LPS-tolerized cells, elevated miR-146a-5p antagonized the increase of ABCA1, ABCG1, and IRAK-1. However, low-dose AGE-BSA did not increase miR-146a-5p levels. In conclusion, the model of endotoxin tolerance is suitable for the antagonistic effects on the dysregulation of ABCA1/G1 induced by high dose of P.g LPS. Conversely, low-dose AGEs did not induce the model of P.g LPS-mediated tolerance.

microRNA‐146a and Hey2 form a mutual negative feedback loop to regulate the inflammatory response in chronic apical periodontitis

“…To further investigate the functional role of miR‐146a in CAP, we analyzed miR‐146a expression in P. endodontalis LPS‐treated MC3T3‐E1 cells. Similarly, we also found that miR‐146a expression was statistically increased in P. endodontalis LPS‐treated cells in a dose‐dependent manner, which was in good agreement with previous studies, showing an increase in the miR‐146a response to LPS stimulation . These data imply that miR‐146a might contribute to immuno‐inflammatory responses in CAP.…”

Melatonin in macrophage biology: Current understanding and future perspectives

“…MiR‐155 promotes M1 polarization of macrophages though the CCAAT/enhancer binding protein (C/EBP‐β) signaling cascade (Figure ) . MiR‐146 has a robust anti‐inflammatory role, and it favors M2 phenotype through targeting TNF receptor‐associated factor (TRAF)‐6, interleukin‐1 receptor‐associated kinase (IRAK1), STAT‐1, and TLR4 …”

“…65,181,182 MiR-146 has a robust anti-inflammatory role, and it favors M2 phenotype through targeting TNF receptor-associated factor (TRAF)-6, interleukin-1 receptor-associated kinase (IRAK1), STAT-1, and TLR4. [183][184][185] Melatonin modulates the expression of miRNAs, [186][187][188] effects that are meanwhile amply documented and gain increasing attention. Insofar, it is not surprising that melatonin can alter the macrophage polarization status via regulating miRNAs.…”

Periodontitis, pathogenesis and progression: miRNA-mediated cellular responses toPorphyromonas gingivalis

“…Li et al [23] reported that levels of miRNA-146a-5p were significantly elevated in macrophages 24 h after stimulation with a high dose of P. gingivalis LPS or an equivalent immunogen. The pro-inflammatory P. gingivalis LPS may participate in triggering dysregulation of the cassette transporters ABCA1 and ABCAG1 during periodontitis.…”

“…This demonstrates a potential therapeutic potential of candidate miRNA for dyslipidemic subjects. Li et al [23] suggested that in macrophages, miRNA-146a can operate as an inflammatory brake on LPS stimulation by decreasing the levels of two adapter proteins (IRAK1 and TRAF6) in an NF-κB-dependent manner [26], implying a strong therapeutic potential for miRNA-based therapies.…”