Inhibition of Kupffer Cell Autophagy Abrogates Nanoparticle‐Induced Liver Injury

Abstract

The possible adverse effects of engineered nanomaterials on human health raise increasing concern as our research on nanosafety intensifies. Upon entry into a human body, whether intended for a theranostic purpose or through unintended exposure, nanomaterials tend to accumulate in the liver, leading to hepatic damage. A variety of nanoparticles, including rare earth upconversion nanoparticles (UCNs), have been reported to elicit hepatotoxicity, in most cases through inducing immune response or activating reactive oxygen species. Many of these nanoparticles also induce autophagy, and autophagy inhibition has been shown to decrease UCN-induced liver damage. Herein, using UCNs as a model engineered nanomaterial, this study uncovers a critical role for Kupffer cells in nanomaterial-induced liver toxicity, as depletion of Kupffer cells significantly exacerbates UCN-induced liver injury. Furthermore, UCN-induced prodeath autophagy in Kupffer cells, and inhibition of autophagy with 3-MA, a well-established chemical inhibitor of autophagy, enhances Kupffer cell survival and further abrogates UCN-induced liver toxicity. The results reveal the critical importance of Kupffer cell autophagy for nanoparticle-induced liver damage, and inhibition of autophagy may constitute a novel strategy for abrogating nanomaterial-elicited liver toxicity.

Importance of integrating nanotechnology with pharmacology and physiology for innovative drug delivery and therapy – an illustration with firsthand examples

“…Meanwhile, continuous investigations on intricate interactions between nanomaterials and biological systems will uncover underlying mechanisms of "black boxes" after the bio-distribution of NPs administered to the body, leading to new strategies for manipulating physiological conditions to maximize the impact of nanotherapeutics on disease treatments [185][186][187][188] . Moreover, understanding molecular interactions among NP components (ie, nanomaterials, loaded drugs) within the nanostructure can shed light on valuable mechanisms leading to the rational design of drug delivery systems with desirable physicochemical properties for precisely controlled drug loading and release [51,173,[189][190][191] .…”

Review of toxicological effect of quantum dots on the liver

“…There are some studies confirming that hepatocyte toxicity caused by nanomaterials was mediated by autophagy. (Fan et al, ; Paesano et al, ; Zhang et al, ; Zhu et al, ). Studies have shown that low‐dose (3 μg ml −1 ) CdS QDs can lead to upregulation of autophagy related genes ATG3, ATG7, ATG13 and ATG14, whereas in high doses (14 μg/ml), there is no such inducement effect in HepG2 cells (Paesano et al, ), which suggest the significance of autophagy in preventing intracellular damage.…”

“…There are some studies confirming that hepatocyte toxicity caused by nanomaterials was mediated by autophagy. (Fan et al, 2016;Paesano et al, 2016;Zhang et al, 2017;Zhu et al, 2017). Studies have shown that low-dose (3 μg ml −1 ) CdS QDs can lead to upregulation of autophagy related genes ATG3, ATG7, ATG13 and ATG14, whereas in high doses (14 μg/ml),…”

“…The results of the existing studies also showed that the QDs inevitably enter the organism through a variety of ways and are mainly accumulated in the liver. Furthermore, by interacting with the cells of the liver, the QDs would probably affect the liver's function and histopathology (Cho et al, ; Fischer et al, ; Zhang et al, ; Zhu et al, ). However, the results about hepatotoxicity of the QDs are inconsistent and determined from the diversities of QDs (including the composition and method of synthesis of the QDs), size, surface modification (surface charge and affinity), route and time of exposure, exposure dose, the types of cell and animal models.…”

A review of hepatic nanotoxicology – summation of recent findings and considerations for the next generation of study designs

“…Due to the locality of the KCs in the wall of sinusoids, this subpopulation might act as a barrier to the nonsoluble NMs, preventing them from reaching the hepatocytes. In addition, activated KCs are one of the most important hepatic cell populations in modulation and governance of the organs immune response both in health and disease states (Bottcher, Knolle, and Stabenow 2011;Kermanizadeh et al 2014a;Tiegs and Lohse 2010;Zhu et al 2017).…”