MicroRNA in extracellular vesicles regulates inflammation through macrophages under hypoxia

Abstract

Extracellular vesicle (EV), critical mediators of cell-cell communication, allow cells to exchange proteins, lipids, and genetic material and therefore profoundly affect the general homeostasis. A hypoxic environment can affect the biogenesis and secrete of EVs, and the cargoes carried can participate in a variety of physiological and pathological processes. In hypoxia-induced inflammation, microRNA(miRNA) in EV participates in transcriptional regulation through various pathways to promote or reduce the inflammatory response. Meanwhile, as an important factor of immune response, the polarization of macrophages is closely linked to miRNAs, which will eventually affect the inflammatory state. In this review, we outline the possible molecular mechanism of EV changes under hypoxia, focusing on the signaling pathways of several microRNAs involved in inflammation regulation and describing the process and mechanism of EV-miRNAs regulating macrophage polarization in hypoxic diseases.

Extracellular Vesicles in Redox Signaling and Metabolic Regulation in Chronic Kidney Disease

“…In this context, scientific reports provide evidence that supports the role of miRNAs as potential therapeutic targets in acute and chronic diseases through modulation of signaling pathways, autophagy, mitochondrial metabolism, glycolysis, and redox, among others [ 45 , 46 , 47 ]. Interestingly, miRNAs contained in EVs are more stable than free miRNAs and are also more specific because they are selectively secreted into the extracellular space and because EV surface proteins can selectively interact with proteins in targets cells [ 42 , 48 ]. There is a big diversity of miRNAs’ cargo in EVs; however, the sorting and loading process of EV-miRNAs is highly selective and is regulated by specific endogenous target sequences.…”

“…There is a big diversity of miRNAs’ cargo in EVs; however, the sorting and loading process of EV-miRNAs is highly selective and is regulated by specific endogenous target sequences. These topics are not the subject of the present work and can be reviewed in recent and beautiful reviews [ 42 , 48 , 49 ]. Thus, changes in EVs-contained miRNAs’ expression result in impaired cellular function and later lead to metabolic reprogramming and the genesis and development of diseases.…”

Immune Modulation Using Extracellular Vesicles Encapsulated with MicroRNAs as Novel Drug Delivery Systems

“…In contrast, exosomes can induce the activation of HIF-1a, which mediates the release of cytokines, indicating a synergistic role between exosomes and HIF1α in regulating the process of immune inflammation. Hypoxia-driven exosome secretion is modulated by the activation of the STAT3 pathway due to the association of HIF-1a with a family of small GTPases, Rab GTPases, through cytoskeletal and sub-membranous actin rearrangement [ 111 ].…”

“…Furthermore, the suppression of NLRP3 or the production of excess ROS by targeting the chemokine CXC receptor 4 (CXCR4) or the peptidylprolyl isomerase F (PPIF), which is the gatekeeper of the mitochondrial permeability transition pore, with miR-23a, respectively, induced anti-inflammatory effects [ 122 ]. The targeting of programmed cell death 4 (PDCD4)/caspase-3 and NFκB-TNF-α-TLR pathways by HIF-1α-induced miR-21 upregulation induces anti-apoptotic and anti-inflammatory effects, respectively, by suppressing the secretion of inflammatory cytokines, including IL-6, IL-1β, and TNF-α [ 111 , 123 ].…”

“…M2 macrophage polarization is suppressed by the inhibition of IL-4-mediated JAK1/STAT6 or IRF4/PPARg pathways with miR-23a or miR-27 expression, respectively ( Figure 2 ) [ 128 ]. However, the polarization of M2 macrophages is promoted by the reduction in IFN-g-and IL-6 and induction of IL-10 through the targeting of Pknox1 with miR-223, and the decreased production of PGE2 through STAT3 targeting with miR-21 [ 111 , 129 , 130 , 131 , 132 ]. M2 macrophage polarization is also suppressed by the indirect regulation of the TNF-α signaling pathways, such as MyD88 and TRAF6 with miR-146a, and the inhibition of IL-6 through TLR4 signaling; the association of HIF-1α with the promoter region of TLR4 under hypoxia enhances the response of inflammation in macrophages with miR-let-7b [ 111 , 133 ].…”