InP/ZnS Quantum Dots Cause Inflammatory Response in Macrophages Through Endoplasmic Reticulum Stress and Oxidative stress

Abstract

Purpose

Quantum dots (QDs) are widely used semiconductor nanomaterials. Indium phosphide/zinc sulfide (InP/ZnS) QDs are becoming potential alternatives to toxic heavy metal-containing QDs. However, the potential toxicity and, in particular, the immunotoxicity of InP/ZnS QDs are unknown. This study aimed to investigate the impacts of InP/ZnS QDs on inflammatory responses both in vivo and in vitro.

Methods

Mice and mouse bone marrow-derived macrophages (BMMs) were exposed to polyethylene glycol (PEG) coated InP/ZnS QDs. The infiltration of neutrophils and the release of interleukin-6 (IL-6) were measured using a hematology analyzer and an enzyme-linked immunosorbent assay (ELISA) for the in vivo test. Cytotoxicity, IL-6 secretion, oxidative stress and endoplasmic reticulum (ER) stress were studied in the BMMs, and then, inhibitors of oxidative stress and ER stress were used to explore the mechanism of the InP/ZnS QDs.

Results

We found that 20 mg/kg PEG-InP/ZnS QDs increased the number of neutrophils and the levels of IL-6 in both peritoneal lavage fluids and blood, which indicated acute phase inflammation in the mice. PEG-InP/ZnS QDs also activated the BMMs and increased the production of IL-6. In addition, PEG-InP/ZnS QDs triggered oxidative stress and the ER stress-related PERK-ATF4 pathway in the BMMs. Moreover, the inflammatory response caused by the PEG-InP/ZnS QDs could be attenuated in the macrophages by blocking the oxidative stress or the ER stress with inhibitors.

Conclusion

InP/ZnS QDs can activate macrophages and induce acute phase inflammation both in vivo and in vitro, which may be regulated by oxidative stress and ER stress. Our present work is expected to help clarify the biosafety of InP/ZnS QDs and promote their safe application in biomedical and engineering fields.

Keywords:

• quantum dots
• indium phosphide
• inflammation
• endoplasmic reticulum stress
• reactive oxygen species

Acknowledgements

This work was supported by the Training Program of Outstanding Young Scientific Researcher of Fujian College, the Key Project of Natural Science Foundation for Young Scholars of Fujian College (No. JZ160496), the Education Scientific Research Project of Young Teachers of Fujian Province (No. JT180650), and the Innovation and Entrepreneurship Training Program for Undergraduates of Fujian Province (No. 201812631013).

Abbreviations

QDs, quantum dots; BMMs, bone marrow-derived macrophages; IL-6, interleukin-6; InP, indium phosphide; ZnS, zinc sulfide; ER, endoplasmic reticulum; AST, aspartate transaminase; LDH, lactate dehydrogenase; PEG, polyethylene glycol; ROS, reactive oxygen species; UPR, unfolded protein response; IRE1α, inositol-requiring enzyme 1α; XBP1, X-box binding protein-1; ATF6, activating transcription factor 6; PERK, protein kinase (PKR)-like endoplasmic reticulum kinase; eIF2α, eukaryotic protein synthesis initiation factor 2α; NPs, nanoparticles; ZnO, zinc oxide; TEM, transmission electron microscopy; PLF, peritoneal lavage fluid; Gapdh, glyceraldehyde-3-phosphate dehydrogenase; Nos2, nitric oxide synthase 2; Chop, C/EBP-homologous protein; TUDCA, tauroursodeoxycholic acid; 4-PBA, 4-phenylbutyric acid; NAC, N-acetylcysteine; DPI, diphenylene iodonium; LPS, lipopolysaccharides; M-CSF, macrophage-colony stimulating factor; DMEM, Dulbecco’s modified Eagle’s medium; FBS, fetal bovine serum; PBS, phosphate buffered saline; SPF, specific-pathogen-free; ELISA, enzyme-linked immunosorbent assay; mtROS, mitochondrial ROS; DCFH-DA, 2ʹ,7ʹ-dichlorodihydrofluorescein diacetate; WBC, white blood cell; ND, not detected.

Ethics Approval and Consent to Participate

All animal studies were performed in compliance with the guidelines of the Institutional Animal Care and Use Committee under the approval of the Administrative Committee of Laboratory Animals of Xiamen Medical College (Approval number 20180301014).

Disclosure

The authors report no conflicts of interest in this work.