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bioRxiv · 10.1101/2022.02.25.481352

Human neutrophil development and functionality are enabled in a humanized mouse model

Zheng, Y.·Sefik, E.·Astle, J.·Solis, A. G.·Oz, H. H.·Jackson, R.·Bruscia, E. M.·Halene, S.·Shan, L.·Flavell, R. A.
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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 PointsO_LITargeting the GCSF cytokine-receptor axis dramatically improves circulating and tissue-infiltrating human neutrophils in MISTRGGR mice. C_LIO_LIHuman neutrophils generated in MISTRGGR mice are functional and are able to respond robustly to inflammatory and infectious stimuli. C_LI

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Zheng, Y., Sefik, E., Astle, J., Solis, A. G., Oz, H. H., Jackson, R., Bruscia, E. M., Halene, S., Shan, L., Flavell, R. A.. 2022-02-25. Human neutrophil development and functionality are enabled in a humanized mouse model. https://doi.org/10.1101/2022.02.25.481352

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