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In vivo functional analysis and genetic modification of in vitro-derived mouse neutrophils

McDonald, Jacqueline U., Cortini, Andrea, Rosas, Marcela ORCID:, Fossati-Jimack, Liliane, Ling, Guang Sheng, Lewis, Kimberley, Dewitt, Sharon ORCID:, Liddiard, Kate ORCID:, Brown, Gordon D., Jones, Simon Arnett ORCID:, Hallett, Maurice Bartlett ORCID:, Botto, Marina and Taylor, Philip Russel ORCID: 2011. In vivo functional analysis and genetic modification of in vitro-derived mouse neutrophils. The FASEB Journal 25 (6) , pp. 1972-1982. 10.1096/fj.10-178517

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Mature neutrophils are notoriously short-lived immune cells that cannot be genetically manipulated. Analysis of gene function therefore requires genetically modified animals, which is expensive, time-consuming, and costly in animal life. Analysis of gene function in neutrophils in a physiologically relevant context thus represents a significant problem in the field. We sought to overcome this obstruction in the field by developing a strategy for the analysis of gene function in neutrophils in a physiologically relevant context. Here, we demonstrate the functional relevance of in vitro conditional-Hoxb8 immortalized precursor-derived neutrophils. In vitro-derived neutrophils functionally resembled primary neutrophils, but critically, neutrophils generated in this way can be adoptively transferred into live animals and tracked during inflammatory responses using single-cell analysis to define functional attributes. We have validated this approach using CD11b-deficient neutrophils and replicated the key findings observed in gene-targeted animals and in naturally CD11b-deficient humans. Furthermore, we show that by retroviral transduction, one can generate stable alterations in the precursor cell lines and thus a continuous supply of functionally altered neutrophils. This novel technological advance offers for the first time the possibility of applying higher-throughput genetic modification and in vivo functional analysis to the neutrophil-lineage.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QH Natural history > QH426 Genetics
Q Science > QR Microbiology > QR180 Immunology
Uncontrolled Keywords: inflammation; animal models; conditional immortalization
Publisher: Federation of American Society of Experimental Biology
ISSN: 0892-6638
Last Modified: 06 Nov 2022 13:14

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