Long Xu1, Yang Yang2, Yankai Wen2, Jong-Min Jeong2, Christoph Emontzpohl2, Constance L Atkins2, Zhaoli Sun3, Kyle L Poulsen2, David R Hall4, J Steve Bynon4, Bin Gao5, William M Lee6, Jody Rule6, Elizabeth A Jacobsen7, Hua Wang8, Cynthia Ju9. 1. Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA; School of Basic Medical Science, Anhui Medical University, Hefei, Anhui, China. 2. Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA. 3. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 4. Department of Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA. 5. Laboratory of Liver Disease, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA. 6. Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA. 7. Division of Allergy, Asthma and Clinical Immunology, Mayo Clinic Arizona, Scottsdale, AZ, USA. 8. Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China. Electronic address: wanghua@ahmu.edu.cn. 9. Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA. Electronic address: changqing.ju@uth.tmc.edu.
Abstract
BACKGROUND & AIMS: Beyond the classical description of eosinophil functions in parasite infections and allergic diseases, emerging evidence supports a critical role of eosinophils in resolving inflammation and promoting tissue remodeling. However, the role of eosinophils in liver injury and the underlying mechanism of their recruitment into the liver remain unclear. METHODS: Hepatic eosinophils were detected and quantified using flow cytometry and immunohistochemical staining. Eosinophil-deficient (ΔdblGata1) mice were used to investigate the role of eosinophils in 3 models of acute liver injury. In vivo experiments using Il33-/- mice and macrophage-depleted mice, as well as in vitro cultures of eosinophils and macrophages, were performed to interrogate the mechanism of eotaxin-2 (CCL24) production. RESULTS: Hepatic accumulation of eosinophils was observed in patients with acetaminophen (APAP)-induced liver failure, whereas few eosinophils were detectable in healthy liver tissues. In mice treated with APAP, carbon tetrachloride or concanavalin A, eosinophils were recruited into the liver and played a profound protective role. Mice deficient of macrophages or IL-33 exhibited impaired hepatic eosinophil recruitment during acute liver injury. CCL24, but not CCL11, was increased after treatment of each hepatotoxin in an IL-33 and macrophage-dependent manner. In vitro experiments demonstrated that IL-33, by stimulating IL-4 release from eosinophils, promoted the production of CCL24 by macrophages. CONCLUSIONS: This is the first study to demonstrate that hepatic recruitment of and protection by eosinophils occur commonly in various models of acute liver injury. Our findings support further exploration of eosinophils as a therapeutic target to treat APAP-induced acute liver injury. LAY SUMMARY: The current study unveils that eosinophils are recruited into the liver and play a protective function during acute liver injury caused by acetaminophen overdose. The data demonstrate that IL-33-activated eosinophils trigger macrophages to release high amounts of CCL24, which promotes hepatic eosinophil recruitment. Our findings suggest that eosinophils could be an effective cell-based therapy for the treatment of acetaminophen-induced acute liver injury.
BACKGROUND & AIMS: Beyond the classical description of eosinophil functions in parasite infections and allergic diseases, emerging evidence supports a critical role of eosinophils in resolving inflammation and promoting tissue remodeling. However, the role of eosinophils in liver injury and the underlying mechanism of their recruitment into the liver remain unclear. METHODS: Hepatic eosinophils were detected and quantified using flow cytometry and immunohistochemical staining. Eosinophil-deficient (ΔdblGata1) mice were used to investigate the role of eosinophils in 3 models of acute liver injury. In vivo experiments using Il33-/- mice and macrophage-depleted mice, as well as in vitro cultures of eosinophils and macrophages, were performed to interrogate the mechanism of eotaxin-2 (CCL24) production. RESULTS: Hepatic accumulation of eosinophils was observed in patients with acetaminophen (APAP)-induced liver failure, whereas few eosinophils were detectable in healthy liver tissues. In mice treated with APAP, carbon tetrachloride or concanavalin A, eosinophils were recruited into the liver and played a profound protective role. Mice deficient of macrophages or IL-33 exhibited impaired hepatic eosinophil recruitment during acute liver injury. CCL24, but not CCL11, was increased after treatment of each hepatotoxin in an IL-33 and macrophage-dependent manner. In vitro experiments demonstrated that IL-33, by stimulating IL-4 release from eosinophils, promoted the production of CCL24 by macrophages. CONCLUSIONS: This is the first study to demonstrate that hepatic recruitment of and protection by eosinophils occur commonly in various models of acute liver injury. Our findings support further exploration of eosinophils as a therapeutic target to treat APAP-induced acute liver injury. LAY SUMMARY: The current study unveils that eosinophils are recruited into the liver and play a protective function during acute liver injury caused by acetaminophen overdose. The data demonstrate that IL-33-activated eosinophils trigger macrophages to release high amounts of CCL24, which promotes hepatic eosinophil recruitment. Our findings suggest that eosinophils could be an effective cell-based therapy for the treatment of acetaminophen-induced acute liver injury.
Authors: Sang Hun Lee; Mariana M Chaves; Olena Kamenyeva; Pedro H Gazzinelli-Guimaraes; Byunghyun Kang; Gabriela Pessenda; Katiuska Passelli; Fabienne Tacchini-Cottier; Juraj Kabat; Elizabeth A Jacobsen; Thomas B Nutman; David L Sacks Journal: Sci Immunol Date: 2020-04-10
Authors: Samuel M Pope; Nives Zimmermann; Keith F Stringer; Margaret L Karow; Marc E Rothenberg Journal: J Immunol Date: 2005-10-15 Impact factor: 5.422
Authors: Davina Wu; Ari B Molofsky; Hong-Erh Liang; Roberto R Ricardo-Gonzalez; Hani A Jouihan; Jennifer K Bando; Ajay Chawla; Richard M Locksley Journal: Science Date: 2011-03-24 Impact factor: 47.728
Authors: Yen-Rei A Yu; Emily G O'Koren; Danielle F Hotten; Matthew J Kan; David Kopin; Erik R Nelson; Loretta Que; Michael D Gunn Journal: PLoS One Date: 2016-03-03 Impact factor: 3.240