NADPH oxidase regulates Toll-like receptor 2-dependent M2 tumor-associated macrophage polarization

  • 蕭 東哲

Student thesis: Master's Thesis


Tumor-associated macrophages (TAM) are considered to be a major cell population in the tumor microenvironment and can be differentiated into M2 phenotype supporting tumor existence However the switching mechanisms of polarized TAM by tumor cells are yet to be determined We previously showed that unknown factors in the hepatoma microenvironment trigger Toll like receptor 2 (TLR2) signaling to induce the degradation of NF-κB p65 via ERK1/2 activation and autophagy promoting the polarization of M2 macrophages The underlying mechanism is yet to be determined In this study we found hepatoma conditioned medium stimulates reactive oxygen species (ROS) to trigger ERK1/2 activation autophagy-mediated NF-κB degradation and M2 macrophage polarization This ROS-mediated NF-κB p65 degradation was attenuated in NADPH oxidase 2 (NOX2)-deficient cells In addition TLR2 signaling was found to be involved in NOX2-regulated M2 macrophage polarization An endogenous TLR2 ligand high-mobility group protein B1 (HMGB1) was found to be secreted by hepatoma cells HMGB1 suppression by RNA-silencing or neutralizing antibody reduces ROS generation ERK1/2 activation autophagy-mediated NF-κB p65 degradation and M2 macrophage polarization Our findings suggest that soluble HMGB1 can trigger TLR2 -dependent autophagy-mediated NF-κB p65 degradation and M2 macrophage polarization Furthermore we demonstrated that HMGB1 regulates tumor nodule formation and M2 macrophage recruitment in an in situ mice hepatoma model In conclusion we found a novel function of HMGB1 to regulate-TLR2/NOX2 dependent M2 polarization and TAM recruitment in hepatoma
Date of Award2015 Aug 27
Original languageEnglish
SupervisorChih-Peng Chang (Supervisor)

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