@article{478081569ac74ae89895d20eda86d92a,
title = "Human neutrophil development and functionality are enabled in a humanized mouse model",
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.",
keywords = "bacterial infection, humanized mouse, innate immunity, neutrophils",
author = "Yunjiang Zheng and Esen Sefik and John Astle and Kutay Karatepe and {\"O}z, {Hasan H.} and Solis, {Angel G.} and Ruaidhr{\'i} Jackson and Luo, {Hongbo R.} and Bruscia, {Emanuela M.} and Stephanie Halene and Liang Shan and Flavell, {Richard A.}",
note = "Funding Information: We thank G. Yancopoulos, D. Valenzuela, A. Murphy, and W. Auerbach at Regeneron Pharmaceuticals, who generated, in collaboration with our groups, the individual knockin alleles combined in MISTRG; Jon Alderman, Caroline Lieber, Elizabeth Hughes-Picard and Beth Cadugan for administrative assistance; Carla Weibel, Patricia Ranney, and Cynthia Hughes for mouse colony management; Judith Stein and Linda Evangelisti for mouse engineering; David Urbanos for human CD34+ cell isolation; Yuanbin Song and Xiaoying Fu for help with cytospin and discussion; Caterina Di Pietro for assistance with liposaccharide nebulization; Li Zhao for help with chemotaxis assays using the EZ-taxiscan chamber; C. Lieber and B. Cadugan for manuscript submission; and Michael Chiorazzi, Ian Odell, Dietmar Herndler-Brandstetter; and Elizabeth Eynon for discussion. E.S. is an HHMI Fellow of the Damon Runyon Cancer Research Foundation (DRG-2316-18). K.K was supported by 5T32HL007974-17 and AWD0005608 (CCEH Type B P&F Grant). E.M.B and H.H.O were supported by NIH/NHLBI 1R01HL157776-01 to EMB. H.R.L was supported by NIH R01HL092020 and NIH R01 AI141386 to H.R.L. This work was funded by the HHMI (R.A.F.), the Animal Modeling Core of the YCCEH (NIDDK U54DK106857) (R.A.F. and S.H.), NIH/NHLBI 1R01HL157776-01 (E.M.B), NIH R01HL092020, NIH R01 AI141386 (H.R.L). Funding Information: ACKNOWLEDGMENTS. We thank G. Yancopoulos, D. Valenzuela, A. Murphy, and W. Auerbach at Regeneron Pharmaceuticals, who generated, in collaboration with our groups, the individual knockin alleles combined in MISTRG; Jon Alderman, Caroline Lieber, Elizabeth Hughes-Picard and Beth Cadugan for administrative assistance; Carla Weibel, Patricia Ranney, and Cynthia Hughes for mouse colony management; Judith Stein and Linda Evangelisti for mouse engineering; David Urbanos for human CD34+ cell isolation; Yuanbin Song and Xiaoying Fu for help with cytospin and discussion; Caterina Di Pietro for assistance with liposac-charide nebulization; Li Zhao for help with chemotaxis assays using the EZ-taxiscan chamber; C. Lieber and B. Cadugan for manuscript submission; and Michael Chior-azzi, Ian Odell, Dietmar Herndler-Brandstetter; and Elizabeth Eynon for discussion. E.S. is an HHMI Fellow of the Damon Runyon Cancer Research Foundation (DRG-2316-18). K.K was supported by 5T32HL007974-17 and AWD0005608 (CCEH Type B P&F Grant). E.M.B and H.H.O were supported by NIH/NHLBI 1R01HL157776-01 to EMB. H.R.L was supported by NIH R01HL092020 and NIH R01 AI141386 to H.R.L. This work was funded by the HHMI (R.A.F.), the Animal Modeling Core of the YCCEH (NIDDK U54DK106857) (R.A.F. and S.H.), NIH/NHLBI 1R01HL157776-01 (E.M.B), NIH R01HL092020, NIH R01 AI141386 (H.R.L). Publisher Copyright: Copyright {\textcopyright} 2022 the Author(s). Published by PNAS.",
year = "2022",
month = oct,
day = "25",
doi = "10.1073/pnas.2121077119",
language = "English",
volume = "119",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "43",
}