miRNA-Mediated Fine Regulation of TLR-Induced M1 Polarization.

Macrophage polarization to the M1 spectrum is induced by bacterial cell wall components through stimulation of Toll-like family (TLR) receptors. By orchestrating the expression of relevant mediators of the TLR cascade, as well as associated pathways and feedback loops, macrophage polarization is coordinated to ensure an appropriate immune response. This is central to the successful control of pathogens and the maintenance of health. Macrophage polarization is known to be modulated at both the transcriptional and post-transcriptional levels. In recent years, the miRNA-based post-transcriptional regulation of M1 polarization has received increasing attention from the scientific community. Comparative studies have shown that TLR stimulation alters the miRNA profile of macrophages and that macrophages from the M1 or the M2 spectrum differ in terms of miRNAs expressed. Simultaneously, miRNAs are considered critical post-transcriptional regulators of macrophage polarization. In particular, miRNAs are thought to play a regulatory role in the switch between the early proinflammatory response and the resolution phase. In this review, we will discuss the current state of knowledge on the complex interaction of transcriptional and post-transcriptional regulatory mechanisms that ultimately determine the functionality of macrophages.

miRNA-Mediated Priming of Macrophage M1 Differentiation Differs in Gram-Positive and Gram-Negative Settings.

A proper regulation of macrophage polarization is essential for the organism's health and pathogen control. Differentiation control is known to occur at the transcriptional as well as the posttranscriptional levels. The mechanisms involved, however, have not yet been fully elucidated. In this study, we co-cultured macrophages with viable Gram-positive and Gram-negative bacteria to mimic macrophage differentiation to the M1-like type in an inflammatory milieu. We found that Gram-positive stimulation resulted in increased expressions of miR-7a-5p, miR-148a-3p, miR-155-5p, and miR-351-5p. Of note, these miRNAs were found to target inhibitory mediators of the Rac1-PI3K-Akt pathway and the MyD88-dependent pathway. In contrast, Gram-negative stimulation-induced downregulation of miR-9-5p, miR-27b-3p, miR-93-5p, and miR-106b-5p is known to target key members of the Rac1-PI3K-Akt pathway and the MyD88-dependent pathway. These results, taken together, point to a fine-tuning of macrophage polarization by TLR-induced changes in macrophage miRNA profiles. Here, the miRNA-mediated priming of M1 differentiation seems to differ in the Gram-positive and Gram-negative settings in terms of the mechanism and miRNAs involved.