Human neutrophil development and functionality are enabled in a humanized mouse model
Yunjiang Zheng, Esen Sefik, John Astle, Kutay Karatepe, Hasan Halit Öz, Angel G. Solis, Ruaidhrí Jackson, Hongbo R. Luo, Emanuela M. Bruscia, Stephanie Halene, Liang Shan, Richard A. Flavell
Abstract
Mice with a functional human immune system serve as an invaluable tool to study the development and function of the human immune system in vivo. A major technological limitation of all current humanized mouse models is the lack of mature and functional human neutrophils in circulation and tissues. To overcome this, we generated a humanized mouse model named MISTRGGR, in which the mouse granulocyte colony-stimulating factor (G-CSF) was replaced with human G-CSF and the mouse G-CSF receptor gene was deleted in existing MISTRG mice. By targeting the G-CSF cytokine-receptor axis, we dramatically improved the reconstitution of mature circulating and tissue-infiltrating human neutrophils in MISTRGGR mice. Moreover, these functional human neutrophils in MISTRGGR are recruited upon inflammatory and infectious challenges and help reduce bacterial burden. MISTRGGR mice represent a unique mouse model that finally permits the study of human neutrophils in health and disease.