title: 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.
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, 230022, China.
authors.forename: Jiqian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Urology, The First Affiliated Hospital of Anhui Medical University and Institute of Urology, Anhui Medical University, Hefei, Anhui, 230022, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Wentao
authors.initials: W
authors.lastname: Ma
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Na
authors.initials: N
authors.lastname: Man
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.|School of Biological and Medical Engineering, Hefei University of Technology, Hefei, Anhui, 230009, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Wei
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Jin
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Yunjiao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, 230022, China.
authors.forename: Erwei
authors.initials: E
authors.lastname: Gu
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, 230022, China.
authors.forename: Xianfu
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, 230022, China.
authors.forename: Zhilai
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Anhui Medical University, Hefei, Anhui, 230022, China.
authors.forename: Xuesheng
authors.initials: X
authors.lastname: Liu
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Li
authors.initials: L
authors.lastname: Bai
authors.affiliation: The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, Anhui, 230027, China.
authors.forename: Longping
authors.initials: L
authors.lastname: Wen
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects; D007728:Kupffer Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000009:adverse effects* / Q000737:chemistry; D049329:Nanostructures / Q000009:adverse effects / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008081:Liposomes; D017382:Reactive Oxygen Species
keywords: 3-methyladenine (3-MA); Kupffer cell; autophagy; liver injury; upconversion nanoparticles (UCN)