Immunotoxicity of titanium dioxide nanoparticles via simultaneous induction of apoptosis and multiple toll-like receptors signaling through ROS-dependent SAPK/JNK and p38 MAPK activation

Madhusmita Dhupal, Jae Min Oh, Dipti Ranjan Tripathy, Soo Ki Kim, Sang Baek Koh, Kyu Sang Park

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

Background: Titanium dioxide nanoparticles (TiO 2 NPs) represent a scientific breakthrough in the areas of biological and medicinal applications. Interaction of TiO 2 NPs with components of innate immune system remains elusive. Aim: This study explored in vitro immunotoxicity of murine macrophage RAW 264.7 to TiO 2 NPs (20 nm, negative charge) and its underlying molecular mechanism by way of immunoredox profiling. Materials and methods: In this study, chemically synthesized BSA-functionalized TiO 2 NPs (20 nm, negative charge) were characterized and immunotoxicity was investigated on RAW 264.7 cells. Results: We found that reactive oxygen species levels significantly increased with increasing nitric oxide production, whereas depleting endogenous antioxidant super oxide dismutase as well as nuclear factor erythroid 2-related factor 2 (Nrf2) protein levels. Furthermore, NPs exposure increased the expression of apoptotic factors such as BAX, BIM, and PUMA with disruption of mitochondrial membrane potential (Δψ m ) that lead to decrease in immunocytes. Molecular immune profiling revealed the activation of multiple toll-like receptors (TLRs) 4/9/12/13 simultaneously with the phosphorylation of p-p38MAPK and p-SAPK/c-Jun N-terminal kinase (JNK) compared to untreated control. Conclusion: Collectively, this study shows that the molecular nature of TiO 2 SA20(-) NP-induced immunotoxicity in RAW 264.7 macrophage is simultaneous induction of immunocyte apoptosis and multiple TLRs signaling through oxidative stress-dependent SAPK/JNK and p38 mitogen-associated protein kinase activation. This is the first study to address newer molecular mechanism of TiO 2 SA20(-) NP-induced immunotoxicity.

Original languageEnglish
Pages (from-to)6735-6750
Number of pages16
JournalInternational journal of nanomedicine
Volume13
DOIs
Publication statusPublished - 2018

Bibliographical note

Funding Information:
This research was supported by the Basic Science Research Program through the National Research Foundation (NRF) funded by the Ministry of Education (NRF-2018-R1D1A1B07048194) and the Medical Research Center (MRC) Program, Ministry of Science, ICT and Future Planning (2017R1A5A2015369), Republic of Korea.

Publisher Copyright:
© 2018 Dhupal et al.

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Bioengineering
  • Biomaterials
  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry

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