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Published on: November 1, 2019
Chlorin e6-Induced Photodynamic Effect Polarizes the Macrophage Into an M1 Phenotype Through Oxidative DNA Damage and
Ting-Ting Yu1,2,3, Ning Han1,2,3, Liu-Gen Li1,3
1School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, China.
Abstract:
The tumor-associated macrophage (TAM) serves as an immunosuppressive agent in the malignant tumor microenvironment, facilitating the development and metastasis of lung cancer. The photodynamic effect destabilizes cellular homeostasis owing to the generation of reactive oxygen species (ROS), resulting in the enhanced pro-inflammatory function of immunocytes. In our previous study, the Ce6-mediated photodynamic effect was found to have kept the viability of macrophages and to remodel them into the M1 phenotype. However, the mechanism remains unrevealed. The present study now explores the mechanism of photodynamic therapy (PDT)-mediated reprogramming of macrophages. As expected, Ce6-mediated PDT was capable of generating reactive oxygen species, which was continuously degraded, causing "low intensity" damage to DNA and thereby triggering subsequent DNA damage response in macrophages. The autophagy was thus observed in Ce6-treated macrophages and was shown to protect cells from being photodynamically apoptotic. More importantly, Ce6 PDT could activate the stimulator of interferon genes (STING) molecule, a sensor of DNA damage, which could activate the downstream nuclear factor kappa-B (NF-κB) upon activation, mediating the polarization of macrophages towards the M1 phenotype thereupon. In addition, inhibition of ROS induced by PDT attenuated the DNA damage, STING activation, and M1-phenotype reprogramming. Furthermore, the silence of the STING weakened Ce6 treatment-mediated M1 remodeling of macrophages as well. Altogether, these findings indicate the Ce6-induced photodynamic effect polarizes macrophages into an M1 phenotype through oxidative DNA damage and subsequent activation of the STING. This work reveals the crucial mechanism by which photodynamic therapy regulates the macrophage phenotype and also provides a novel intervenable signaling target for remodeling macrophages into the M1 phenotype.
Insights
Photodynamic therapy with Ce6 reprograms immunosuppressive tumor-associated macrophages (TAMs) into pro-inflammatory M1 cells. This occurs via reactive oxygen species-induced DNA damage, activating the STING pathway, crucial for macrophage polarization in lung cancer.
Area of Science:
- Immunology
- Oncology
- Biomedical Engineering
Background:
- Tumor-associated macrophages (TAMs) promote lung cancer progression and metastasis by creating an immunosuppressive tumor microenvironment.
- Photodynamic therapy (PDT) can remodel macrophages, but the underlying mechanisms require elucidation.
Purpose of the Study:
- To investigate the mechanism by which Ce6-mediated photodynamic therapy (PDT) reprograms macrophages towards an M1 phenotype.
- To identify the key signaling pathways involved in PDT-induced macrophage polarization.
Main Methods:
- Macrophages were treated with Ce6-mediated PDT, and reactive oxygen species (ROS) generation was measured.
- DNA damage response, autophagy, and STING (stimulator of interferon genes) pathway activation were assessed.
- The role of ROS and STING in M1 polarization was evaluated using inhibition and silencing techniques.
Main Results:
- Ce6-PDT generated ROS, causing low-intensity DNA damage and triggering a DNA damage response in macrophages.
- Autophagy was induced, protecting macrophages from PDT-induced apoptosis.
- Ce6-PDT activated the STING pathway, leading to NF-κB activation and M1 polarization.
- Inhibition of ROS or silencing of STING attenuated M1 reprogramming.
Conclusions:
- Ce6-PDT polarizes macrophages to an M1 phenotype through oxidative DNA damage and subsequent STING pathway activation.
- This study reveals a critical mechanism for PDT-mediated macrophage regulation.
- The STING pathway represents a novel target for manipulating macrophage phenotype in cancer therapy.
