Silver Nanoparticle-Induced Apoptosis in ARPE-19 Cells Is Inhibited by Toxoplasma gondii Pre-Infection Through Suppression of NOX4-Dependent ROS Generation

Juan-Hua Quan,1,* Fei Fei Gao,2,* Hassan Ahmed Hassan Ahmed Ismail,3,* Jae-Min Yuk,2 Guang-Ho Cha,2 Jia-Qi Chu,4 Young-Ha Lee2 1Department of Gastroenterology, The Affiliated Hospital of Guangdong Medical University, Zhanjiang 524-001, People’s Republic of China; 2Department of Infection Biology and Department of Medical Science, Chungnam National University College of Medicine, Daejeon 301-131, Korea; 3Communicable and Non-Communicable Diseases Control Directorate, Federal Ministry of Health, Khartoum, Sudan; 4Stem Cell Research and Cellular Therapy Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong Province 524-001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Young-Ha LeeDepartment of Infection Biology and Department of Medical Science, Chungnam National University College of Medicine 6 Munhwa-Dong, Jung-Gu, Daejeon 35015, KoreaTel +82-42-580-8273Fax +82-42-583-8216Email yhalee@cnu.ac.krPurpose: External and internal stimuli easily affect the retina. Studies have shown that cells infected with Toxoplasma gondii are resistant to multiple inducers of apoptosis. Nanoparticles (NPs) have been widely used in biomedical fields; however, little is known about cytotoxicity caused by NPs in the retina and the modulators that inhibit nanotoxicity.Materials and Methods: ARPE-19 cells from human retinal pigment epithelium were treated with silver nanoparticles (AgNPs) alone or in combination with T. gondii. Then, the cellular toxicity, apoptosis, cell cycle analysis, autophagy, ROS generation, NOX4 expression, and MAPK/mTOR signaling pathways were investigated. To confirm the AgNP-induced cytotoxicity in ARPE-19 cells and its modulatory effects caused by T. gondii infection, the major experiments carried out in ARPE-19 cells were performed again using human foreskin fibroblast (HFF) cells and bone marrow-derived macrophages (BMDMs) from NOX4−/− mice.Results: AgN