European journal of medical research · 2025
TLR4/NF-κB-mediated M1 macrophage polarization contributes to the promotive effects of ETS2 on ulcerative colitis.
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Liu Binbin, Yu Jianshun, Zhang Jie, Ye Wei, Yao Jiaming
Аннотация
OBJECTIVE: ETS2 is a core modulator of macrophages. This study aims to investigate the effects of ETS2 on macrophage polarization in ulcerative colitis (UC) and the involvement of TLR4/NF-κB pathway.
METHODS: A dextran sulfate sodium (DSS)-induced acute UC mice model was established, along with a lipopolysaccharide (LPS)/IFN-γ-stimulated RAW264.7 cell model to mimic inflammation. Immunofluorescence was employed to examine the co-localization of ETS2 with M1 macrophage markers (F4/80 and iNOS). Flow cytometry quantified the iNOS+/F4/80+ M1 macrophage subgroups. Inflammatory cytokine (TNF-α and IL-1β) levels in cell supernatants were detected using enzyme-linked immunosorbent assay. Western blot analyzed the expressions of M1 markers (CD86 and iNOS) and TLR4/NF-κB pathway components (TLR4, p-p65/p65, and p-IκBα/IκBα). An sh-ETS2 lentiviral vector was constructed for ETS2 knockdown in vitro and in vivo. The TLR4 agonist RS 09 was used to rescue macrophage polarization and inflammatory responses.
RESULTS: In DSS-induced UC mice, ETS2 was significantly upregulated in colon tissues and co-localized with F4/80. LPS/IFN-γ-treated RAW264.7 cells also exhibited elevated ETS2 expression, accompanied by increased inflammatory cytokine secretion, expansion of iNOS+/F4/80+ macrophage subgroups, and activated TLR4/NF-κB pathway. Furthermore, ETS2 deficiency in RAW264.7 cells significantly inhibited the macrophage polarization towards M1 pro-inflammatory phenotype and blocked the TLR4/NF-κB pathway. However, RS 09 counteracted the anti-inflammatory effects of ETS2 knockdown. In vivo silencing of ETS2 attenuated M1 macrophage polarization and inflammatory cytokine production, while ameliorating pathology in UC mice.
CONCLUSION: ETS2 enhanced the inflammatory response in UC by activating TLR4/NF-κB-mediated M1 macrophage polarization.
METHODS: A dextran sulfate sodium (DSS)-induced acute UC mice model was established, along with a lipopolysaccharide (LPS)/IFN-γ-stimulated RAW264.7 cell model to mimic inflammation. Immunofluorescence was employed to examine the co-localization of ETS2 with M1 macrophage markers (F4/80 and iNOS). Flow cytometry quantified the iNOS+/F4/80+ M1 macrophage subgroups. Inflammatory cytokine (TNF-α and IL-1β) levels in cell supernatants were detected using enzyme-linked immunosorbent assay. Western blot analyzed the expressions of M1 markers (CD86 and iNOS) and TLR4/NF-κB pathway components (TLR4, p-p65/p65, and p-IκBα/IκBα). An sh-ETS2 lentiviral vector was constructed for ETS2 knockdown in vitro and in vivo. The TLR4 agonist RS 09 was used to rescue macrophage polarization and inflammatory responses.
RESULTS: In DSS-induced UC mice, ETS2 was significantly upregulated in colon tissues and co-localized with F4/80. LPS/IFN-γ-treated RAW264.7 cells also exhibited elevated ETS2 expression, accompanied by increased inflammatory cytokine secretion, expansion of iNOS+/F4/80+ macrophage subgroups, and activated TLR4/NF-κB pathway. Furthermore, ETS2 deficiency in RAW264.7 cells significantly inhibited the macrophage polarization towards M1 pro-inflammatory phenotype and blocked the TLR4/NF-κB pathway. However, RS 09 counteracted the anti-inflammatory effects of ETS2 knockdown. In vivo silencing of ETS2 attenuated M1 macrophage polarization and inflammatory cytokine production, while ameliorating pathology in UC mice.
CONCLUSION: ETS2 enhanced the inflammatory response in UC by activating TLR4/NF-κB-mediated M1 macrophage polarization.