Endoplasmic reticulum stress mediates inflammatory response triggered by ultra-small superparamagnetic iron oxide nanoparticles in hepatocytes

Abstract

Ultra-small superparamagnetic iron oxide nanoparticles (USPIO-NPs) are widely used as clinical magnetic resonance imaging contrast agents for hepatic diseases diagnosis. USPIO-NPs often damage the hepatocytes and affect the function of liver but its mechanism of action remains unclear. In the present study, USPIO-NPs caused higher cytotoxicity and lactate dehydrogenase (LDH) leakage in hepatic L02 cells than SPIO-NPs. Subsequently, USPIO-NPs affected more genes’ expression than SPIO-NPs analyzed through microarray and bioinformatics analysis. The affected genes were involved in several biological processes, including calcium ion homeostasis, inflammatory response-related leukocyte chemotaxis, and migration. In addition, the level of endoplasmic reticulum (ER) calcium ion was increased by USPIO-NPs. USPIO-NPs also upregulated the genes related to acute-phase inflammation, including IL1B, IL6, IL18, TNFSF12, TNFRSF12, SAA1, SAA2, JAK1, STAT5B, and CXCL14. Furthermore, interleukin-6 (IL-6) secretion was elevated by USPIO-NPs as detected using ELISA. On the other hand, USPIO-NPs changed the morphology of ER and triggered the ER stress and unfolded protein response PERK/ATF4 pathway. Furthermore, blocking ER stress with inhibitor or ATF4 small interfering RNA counteracted IL-6-related acute-phase inflammation and cytotoxicity caused by USPIO-NPs. Taken together, we found that the USPIO-NPs could trigger stronger IL-6-related acute-phase inflammation than SPIO-NPs in hepatocytes. We demonstrated, for the first time, that IL-6-related acute-phase inflammation caused by NPs was regulated by PERK/ATF4 signaling. The PERK/ATF4 pathway explored in this study could be a candidate for diagnostic and therapeutic target against NPs-induced liver injury and cytotoxicity, which would be helpful for USPIO-NPs medical application.

Keywords:

• Ultra-small superparamagnetic iron oxide nanoparticles
• endoplasmic reticulum (ER) stress
• acute-phase inflammation
• interleukin-6
• hepatotoxicity

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81573181, 81472997, 81773465, and U1705281), the Major State Basic Research Development Program of China (No. 2017YFA0205201), the Natural Science Foundation of Fujian Province of China (Nos. 2014J01372 and 2015J01344), the Fundamental Research Funds for the Central Universities (No. 20720180045), the Regional Demonstration of Marine Economy Innovative Development Project (No. 16PYY007SF17), and the Scientific Research Foundation of State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics (No. 2017ZY003).