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Mice Lacking Three Myeloid Colony-Stimulating Factors (G-CSF, GM-CSF, and M-CSF) Still Produce Macrophages and Granulocytes and Mount an Inflammatory Response in a Sterile Model of Peritonitis¹

Margaret L. Hibbs^2,*, Cathy Quilici^*, Nicole Kountouri^*, John F. Seymour, Jane E. Armes^¶, Antony W. Burgess and Ashley R. Dunn

^* Signal Transduction, Molecular Biology, and Epithelial Biochemistry Laboratories, Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, Royal Melbourne Hospital, Victoria, Australia; Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia, and Department of Medicine, University of Melbourne, Parkville, Australia; and ^¶ Department of Anatomical Pathology, Mater Adult Hospital, South Brisbane, Queensland, Australia

To assess the combined role of G-CSF, GM-CSF, and M-CSF in myeloid cell production, mice deficient in all three myeloid CSFs were generated (G^–/–GM^–/–M^–/– mice). G^–/–GM^–/–M^–/– mice share characteristics found in mice lacking individual cytokines: they are toothless and osteopetrotic and furthermore acquire alveolar proteinosis that is more severe than that found in either GM^–/– or G^–/–GM^–/– mice. G^–/–GM^–/–M^–/– mice have a significantly reduced lifespan, which is prolonged by antibiotic administration, suggesting compromised ability to control bacterial infection. G^–/–GM^–/–M^–/– mice have circulating neutrophils and monocytes, albeit at significantly reduced numbers compared with wild-type mice, but surprisingly, have more circulating monocytes than M^–/– mice and more circulating neutrophils than G^–/–GM^–/– mice. Due to severe osteopetrosis, G^–/–GM^–/–M^–/– mice show diminished numbers of myeloid cells, myeloid progenitors, and B lymphocytes in the bone marrow, but have significantly enhanced compensatory splenic hemopoiesis. Although G^–/–GM^–/–M^–/– mice have a profound deficiency of myeloid cells in the resting peritoneal cavity, the animals mount a moderate cellular response in a model of sterile peritonitis. These data establish that in the absence of G-CSF, GM-CSF, and M-CSF, additional growth factor(s) can stimulate myelopoiesis and acute inflammatory responses.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Health and Medical Research Council of Australia. M.L.H. is a Senior Research Fellow of the National Health and Medical Research Council of Australia.

² Address correspondence and reprint requests to Dr. Margaret L. Hibbs, Ludwig Institute for Cancer Research, Melbourne Tumour Biology Branch, P.O. Royal Melbourne Hospital, Victoria 3050, Australia. E-mail address: Margaret.Hibbs{at}ludwig.edu.au

³ Abbreviations used in this paper: BM, bone marrow; SPF, specific pathogen-free; WT, wild type; SCF, stem cell factor; WBC, white blood cell; CFC, colony-forming cell; PMN, polymorphonuclear leukocyte.