Abstract
Mice with a functional human immune system serve as an invaluable tool to study the development and function of 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 (G-CSFR) in existing MISTRG mice. By targeting the GCSF 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.
Key Points
Targeting the GCSF cytokine-receptor axis dramatically improves circulating and tissue-infiltrating human neutrophils in MISTRGGR mice.
Human neutrophils generated in MISTRGGR mice are functional and are able to respond robustly to inflammatory and infectious stimuli.
Competing Interest Statement
RAF is an advisor to Glaxo Smith Kline, Zai labs and Ventus Therapeutics.