A double feedback loop mediated by microRNA-23a/27a/24-2 regulates M1versusM2 macrophage polarization and thus regulates cancer progression

Abstract

In response to microenvironmental signals, macrophages undergo different types of activation, including the “classic” pro-inflammatory phenotype (also called M1) and the “alternative” anti-inflammatory phenotype (also called M2). Macrophage polarized activation has profound effects on immune and inflammatory responses, but mechanisms underlying the various types of macrophage is still in its infancy. In this study, we reported that M1-type stimulation could down-regulate miR-23a/27a/24-2 cluster transcription through the binding of NF-κB to this cluster's promoter and that miR-23a in turn activated the NF-κB pathway by targeting A20 and thus promoted the production of pro-inflammatory cytokines. Furthermore, STAT6 occupied the miR-23a/27a/24-2 cluster promoter and activated their transcription in IL-4-stimulated macrophages. In addition, miR-23a in turn suppressed the JAK1/STAT-6 pathway and reduced the production of M2 type cytokines by targeting JAK1 and STAT-6 directly, while miR-27a showed the same phenotype by targeting IRF4 and PPAR-γ. The miR-23a/27a/24-2 cluster was shown to be significantly decreased in TAMs of breast cancer patients, and macrophages overexpressing the miR-23a/27a/24-2 cluster inhibited tumor growth in vivo. Taken together, these data integrated microRNA expression and function into macrophage polarization networks and identified a double feedback loop consisting of the miR-23a/27a/24-2 cluster and the key regulators of the M1 and M2 macrophage polarization pathway. Moreover, miR-23a/27a/24-2 regulates the polarization of tumor-associated macrophages and thus promotes cancer progression.

Melatonin in macrophage biology: Current understanding and future perspectives

“…This cluster is downregulated during M1 polarization by NF‐κB binding to the cluster promoter. However, miR‐23a has been also reported to promote NF‐κB signaling via the NF‐κB pathway inhibitor A20, a zinc‐finger protein encoded by the TNFAIP3 gene . The expression of miR‐23a is inhibited by melatonin, which, thereby, attenuates the inflammatory response (Figure C) .…”

“…STAT‐6 activates miR‐23a/miR‐27a/miR‐24‐2 transcription by binding to the cluster promoter during M2 polarization. In a negative feedback loop, miR‐23a inhibits the formation of M2 cytokines via directly targeting JAK1 and STAT‐6 . The jointly regulated miR‐27a acts in parallel by downregulating IRF4 and PPAR‐γ .…”

Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment

“…miR-155 was also reported to activate STAT3 signaling and promote breast cancer cells (BCC) progression [40,41]. miR-23a/24-2/27a modulate macrophage polarization in BCC through the Janus kinase (JAK)/STAT pathway [48]. miRNAs indirect regulation of PD-L1 expression miRNAs indirectly modulate the PD-L1 expression through the epigenetic regulation of upstream signaling pathways such as phosphatase and tensin homolog (PTEN)/PI3K/Akt and signal transducer and activator of transcription (STAT).…”

The role of IL-10 in Mycobacterium avium subsp. paratuberculosis infection

“…Recent studies found that miRNAs have critical role in both innate and adoptive immune response [140], such as macrophage polarization, T cell and B cell differentiation [141]. The role of miRNAs has been investigated in the regulation of IL-10 and its related pathways in immune modulating cells [142, 143]. Feng et al, [144] demonstrated that miR-466 l up-regulate IL-10 expression in TLR-triggered macrophages both at mRNA and protein levels.…”

“…As reported by Ouiment and colleagues that, miR-33 promote M1 phenotype by up-regulating the expression of M1 markers such as Il6 , Nos2 , and Il1b, while reduced the expression of the M2 macrophages markers, Mrc1 (mannose receptor CD206) and Fizz1/Retnla [152]. Sisi et al, [143] reported that miR-23a and 27a inhibit the polerization of M2 phenotype while promote M1 phenotype by targeting 3UTR of JAK1/STAT6 and IRF4/PPAR-γ. The cluster of miR-23a/27a/24-2 enhance the production of inflammatory mediators (IL-1b, IL-6, IL-12 and TNF-a) while inhibit anti-inflammatory cytokine such as IL-10 [144].…”