Myeloid-specific deletion of Mcl-1 yields severely neutropenic mice that survive and breed in homozygous form

Janka Zsofia Csepregi, Anita Orosz, Erik Zajta, Orsolya Kasa, Tamas Nemeth, Edina Simon, Szabina Fodor, Katalin Csonka, Balazs L. Baratki, Dorottya Kovesdi, You Wen He, Attila Gacser, Attila Mocsai

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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 Lyz2 Cre/Cre Mcl1 flox/flox (Mcl1 Myelo ) mice leads to dramatic reduction of circulating and tissue neutrophil counts without affecting circulating lymphocyte, monocyte, or eosinophil numbers. Surprisingly, Mcl1DMyelo mice appeared normally, and their survival was mostly normal both under specific pathogen-free and conventional housing conditions. Mcl1 Myelo 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 Mcl1 Myelo mice from arthritis development in the K/B3N serumtransfer model and from skin inflammation in an autoantibody-induced mouse model of epidermolysis bullosa acquisita Mcl1 ?Myelo 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-CreMcl1 flox/flox (Mcl1 PMN ) 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 Mcl1 Myelo 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. The Journ Al of Immunology, 2018, 201: 3793-3803.

Original languageEnglish
Pages (from-to)3793-3803
Number of pages11
JournalJournal of Immunology
Volume201
Issue number12
DOIs
Publication statusPublished - Dec 15 2018

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Csepregi, J. Z., Orosz, A., Zajta, E., Kasa, O., Nemeth, T., Simon, E., Fodor, S., Csonka, K., Baratki, B. L., Kovesdi, D., He, Y. W., Gacser, A., & Mocsai, A. (2018). Myeloid-specific deletion of Mcl-1 yields severely neutropenic mice that survive and breed in homozygous form. Journal of Immunology, 201(12), 3793-3803. https://doi.org/10.4049/jimmunol.1701803