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Myeloid-Specific Deletion of Mcl-1 Yields Severely Neutropenic Mice That Survive and Breed in Homozygous Form

Janka Zsófia Csepregi, Anita Orosz, Erik Zajta, Orsolya Kása, Tamás Németh, Edina Simon, Szabina Fodor, Katalin Csonka, Balázs L. Barátki, Dorottya Kövesdi, You-Wen He, Attila Gácser and Attila Mócsai
J Immunol December 15, 2018, 201 (12) 3793-3803; DOI: https://doi.org/10.4049/jimmunol.1701803
Janka Zsófia Csepregi
*Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary;
†MTA-SE “Lendület” Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, 1094 Budapest, Hungary;
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Anita Orosz
*Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary;
†MTA-SE “Lendület” Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, 1094 Budapest, Hungary;
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Erik Zajta
‡Department of Microbiology, University of Szeged, 6726 Szeged, Hungary;
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Orsolya Kása
*Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary;
†MTA-SE “Lendület” Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, 1094 Budapest, Hungary;
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Tamás Németh
*Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary;
†MTA-SE “Lendület” Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, 1094 Budapest, Hungary;
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Edina Simon
*Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary;
†MTA-SE “Lendület” Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, 1094 Budapest, Hungary;
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Szabina Fodor
§Department of Computer Science, Corvinus University of Budapest, 1093 Budapest, Hungary;
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Katalin Csonka
‡Department of Microbiology, University of Szeged, 6726 Szeged, Hungary;
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Balázs L. Barátki
¶Department of Immunology, Eötvös Loránd University, 1117 Budapest, Hungary;
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Dorottya Kövesdi
¶Department of Immunology, Eötvös Loránd University, 1117 Budapest, Hungary;
‖Office of Supported Research Groups of the Hungarian Academy of Sciences, 1051 Budapest, Hungary; and
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You-Wen He
#Department of Immunology, Duke University Medical Center, Durham, NC 27710
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Attila Gácser
‡Department of Microbiology, University of Szeged, 6726 Szeged, Hungary;
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Attila Mócsai
*Department of Physiology, Semmelweis University School of Medicine, 1094 Budapest, Hungary;
†MTA-SE “Lendület” Inflammation Physiology Research Group of the Hungarian Academy of Sciences and Semmelweis University, 1094 Budapest, Hungary;
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Abstract

Mouse strains with specific deficiency of given hematopoietic lineages provide invaluable tools for understanding blood cell function in health and disease. Whereas neutrophils are dominant leukocytes in humans and mice, there are no widely useful genetic models of neutrophil deficiency in mice. In this study, we show that myeloid-specific deletion of the Mcl-1 antiapoptotic protein in Lyz2Cre/CreMcl1flox/flox (Mcl1ΔMyelo) mice leads to dramatic reduction of circulating and tissue neutrophil counts without affecting circulating lymphocyte, monocyte, or eosinophil numbers. Surprisingly, Mcl1ΔMyelo mice appeared normally, and their survival was mostly normal both under specific pathogen-free and conventional housing conditions. Mcl1ΔMyelo mice were also able to breed in homozygous form, making them highly useful for in vivo experimental studies. The functional relevance of neutropenia was confirmed by the complete protection of Mcl1ΔMyelo mice from arthritis development in the K/B×N serum-transfer model and from skin inflammation in an autoantibody-induced mouse model of epidermolysis bullosa acquisita. Mcl1ΔMyelo mice were also highly susceptible to systemic Staphylococcus aureus or Candida albicans infection, due to defective clearance of the invading pathogens. Although neutrophil-specific deletion of Mcl-1 in MRP8-CreMcl1flox/flox (Mcl1ΔPMN) mice also led to severe neutropenia, those mice showed an overt wasting phenotype and strongly reduced survival and breeding, limiting their use as an experimental model of neutrophil deficiency. Taken together, our results with the Mcl1ΔMyelo mice indicate that severe neutropenia does not abrogate the viability and fertility of mice, and they provide a useful genetic mouse model for the analysis of the role of neutrophils in health and disease.

Footnotes

  • This work was supported by the Lendület program of the Hungarian Academy of Sciences (LP2013-66 to A.M.), the European Commission's Horizon 2020 Framework Program (Grant 777357, RTCure Project), and the Hungarian National Agency for Research, Development and Innovation (K-NVKP_16-1-2016-0152956 and VEKOP-2.3.2-16-2016-00002 to A.M. and GINOP-2.3.2-15-2016-00015 to E.Z., K.C., and A.G.). A.M. was a recipient of a Wellcome Trust International Senior Research Fellowship (Grant 087782). T.N. was a recipient of a Bolyai Research Fellowship from the Hungarian Academy of Sciences. E.Z. was supported by the National Talent Programme of the Hungarian Ministry of Human Resources (NTP-NFTÖ-17-B-0382). D.K. was supported by the Hungarian Academy of Sciences Premium Post Doctorate Research Program.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    BHI
    brain–heart infusion
    CVII
    type VII collagen
    Mcl-1
    myeloid cell leukemia 1
    Mcl1ΔMyelo
    Lyz2Cre/CreMcl1flox/flox
    Mcl1ΔPMN
    MRP8-CreMcl1flox/flox
    YPD
    yeast extract/peptone/dextrose.

  • Received January 2, 2018.
  • Accepted October 9, 2018.
  • Copyright © 2018 The Authors

This article is distributed under the terms of the CC BY 4.0 Unported license.

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The Journal of Immunology: 201 (12)
The Journal of Immunology
Vol. 201, Issue 12
15 Dec 2018
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Myeloid-Specific Deletion of Mcl-1 Yields Severely Neutropenic Mice That Survive and Breed in Homozygous Form
Janka Zsófia Csepregi, Anita Orosz, Erik Zajta, Orsolya Kása, Tamás Németh, Edina Simon, Szabina Fodor, Katalin Csonka, Balázs L. Barátki, Dorottya Kövesdi, You-Wen He, Attila Gácser, Attila Mócsai
The Journal of Immunology December 15, 2018, 201 (12) 3793-3803; DOI: 10.4049/jimmunol.1701803

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Myeloid-Specific Deletion of Mcl-1 Yields Severely Neutropenic Mice That Survive and Breed in Homozygous Form
Janka Zsófia Csepregi, Anita Orosz, Erik Zajta, Orsolya Kása, Tamás Németh, Edina Simon, Szabina Fodor, Katalin Csonka, Balázs L. Barátki, Dorottya Kövesdi, You-Wen He, Attila Gácser, Attila Mócsai
The Journal of Immunology December 15, 2018, 201 (12) 3793-3803; DOI: 10.4049/jimmunol.1701803
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