ArticleAmerican journal of translational research2026
M2 macrophage-secreted exosomal miR-216a regulates microglial polarization by targeting the HMGB1/TLR4/NF-κB pathway to alleviate bone cancer pain.
Article in American journal of translational research, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveM2 macrophage-derived exosomes (M2-exos) hold promise for patients with bone cancer pain (BCP). This study aimed to investigate the therapeutic effect and related mechanisms of M2-exos in both in vitro and in vivo models of BCP.
methodRAW 264.7 macrophages were treated with IL-4 to generate M2-polarized macrophages. M2-exos were characterized by transmission electron microscope and Western blotting. A mouse model of BCP was established, and BV2 microglia were activated by lipopolysaccharide stimulation. The effects of M2-exos were evaluated in vitro by coculture with reactive BV2 microglia and in vivo by microinjection into the rostral ventromedial medulla (RVM) of BCP mice. CCK-8 assays, ELISAs, flow cytometry and immunofluorescence were used to determine the effects of M2-exos on microglial activation. The therapeutic effects of M2-exos were evaluated via pain behavior experiments. Bioinformatic analysis and rescue experiments were performed to investigate the mechanisms through which M2-exos affect the progression of BCP.
resultsIn vitro, M2-exos administration repolarized microglial toward the anti-inflammatory M2 phenotype in coculture systems. In vivo analysis indicated that microinjection of M2-exos into the RVM region improved neuroinflammation. Notably, miR-216a expression was significantly increased in M2-exos and could be delivered into BV2 microglia. Blockade of miR-216a abolished the therapeutic effects of M2-exos in vitro and in vivo. Mechanistically, miR-216a negatively regulates high mobility group Box 1 protein (HMGB1) expression, further inhibiting Toll-like receptor 4 (TLR4)/NF-κB and inducing M2 microglial polarization, thereby delaying BCP progression.
conclusionM2 macrophage-derived exosomal miR-216a could delay BCP progression by targeting HMGB1/TLR4/NF-κB-mediated microglial M2 polarization.
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