Mechanism of M2 macrophage-derived extracellular vesicles carrying lncRNA MEG3 in inflammatory responses in ulcerative colitis

Abstract

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. M2 macrophages possess certain anti-inflammation activity. Accordingly, the current study set out to investigate the potential mechanism of M2 macrophage-derived extracellular vesicles (M2-EVs) in UC inflammation. Firstly, mouse peritoneal macrophages were induced to M2 phenotype, and M2-EVs were isolated. , the murine model of UC was established, and the length and weight of the colon, disease activity index (DAI), apoptosis, and inflammatory response of UC mice were measured. Young adult mouse colon (YAMC) cells were induced with the help of lipopolysaccharide. LncRNA maternally expressed 3 (LncRNA MEG3), miR-20b-5p, and cAMP responsive element binding protein 1 (CREB1) expression patterns were detected in UC models. In addition, we analyzed the binding relationship among MEG3, miR-20b-5p, and CREB1. UC mice presented with shortened colon length, lightened weight, increased DAI score, enhanced apoptosis, and significant inflammatory cell infiltration, while M2-EVs reversed these trends. In vitro , M2-EVs increased UC cell viability and reduced inflammation. Mechanistic experimentation revealed that M2-EVs transferred MEG3 into YAMC cells to up-regulate MEG3 expression and promote CREB1 transcription by competitively binding to miR-20b-5p. Moreover, up-regulation of MEG3 in M2-EVs enhanced the protective effect of M2-EVs on UC cells, while over-expression of miR-20b-5p attenuated the aforementioned protective effect of M2-EVs on UC mice and cells. Collectively, our findings revealed that M2-EVs carrying MEG3 enhanced UC cell viability and reduced inflammatory responses via the miR-20b-5p/CREB1 axis, thus alleviating UC inflammation.

A review of current evidence about lncRNA MEG3: A tumor suppressor in multiple cancers

“…Moreover, Wang et al (2021c) stated that MEG3 might regulate IL-10 expression by targeting miR-98-5p, which may lead to its protective effect against ulcerative colitis (UC). Another study showed how MEG3 alleviated UC inflammation via the miR-206-5p/CREB1 pathway ( Wang et al, 2021d ). Finally, Li et al (2019c) reported that MEG3 may inhibit rheumatoid arthritis through the miR-141/AKT/mTOR signaling pathway ( Figure 2 ).…”

Therapeutic potential of exosome‐based personalized delivery platform in chronic inflammatory diseases

“…After transfection with plasmids, exosomes rich in miR-590–3p isolated from M2 macrophages inhibited LATS1 expression by activating YAP/β-catenin regulated transcription, which promoted epithelial regeneration and repair of damaged colon. In another research, the LncRNA maternally expressed 3 (MEG3) overexpression lentiviral vector was used to transfect M2 macrophages, and the high expression of MEG3 EVs was obtained after isolation [109] . After drug administration through the tail vein, the MEG3 enters the colon epithelial cells, and competitively binds with mir-20b-5p to promote the transcription of, mir-20b-5p/cAMP responsive element binding protein 1, further enhancing cell vitality and alleviating the inflammatory response of UC.…”

LncRNA MEG3: Potential stock for precision treatment of cardiovascular diseases

“…M2 macrophages themselves have certain anti-inflammatory activity. MEG3 can regulate the miR-20b-5p/CREB1 axis and induce M2 macrophage-derived extracellular vesicles (M2-EVs) to reduce the inflammatory response ( Wang et al, 2021d ). Upregulation of MEG3 in ulcerative colitis (UC) can enhance the protective effect of M2-macrophage-derived extracellular vesicles (M2-evs) against UC and reduce inflammation ( Wang et al, 2021d ).…”

“…MEG3 can regulate the miR-20b-5p/CREB1 axis and induce M2 macrophage-derived extracellular vesicles (M2-EVs) to reduce the inflammatory response ( Wang et al, 2021d ). Upregulation of MEG3 in ulcerative colitis (UC) can enhance the protective effect of M2-macrophage-derived extracellular vesicles (M2-evs) against UC and reduce inflammation ( Wang et al, 2021d ). MEG3 upregulation in methylene blue (MB)-induced peripheral nerve axons alleviates pain and inflammation associated with obstructive sleep apnea by inhibiting P2X3 protein expression ( Li et al, 2018b ).…”