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 Peritonitis

Abstract

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 role of granulocyte macrophage-colony-stimulating factor in acute intestinal inflammation

“…Moreover, the significantly increased colonic MCP-1, TNF-α, and IL-17 ( Figure 5) in DSStreated GM-CSF −/− mice implies that those inflammatory mediators may substitute for the usual role of GM-CSF and contribute to the recruitment of macrophages/ monocytes in this model. Also, of course, compensation from two other CSFs, namely G-CSF and M-CSF, cannot be excluded [29]. All these compensatory effects may result in an overwhelming macrophage response, which…”

Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease

“…Hematopoietic progenitors were quantified in semisolid 0.3% agar cultures comprising 100,000 spleen cells as described previously (83). Colony formation was stimulated by M-CSF (10 ng/ml), IL-3 (10 ng/ml), GM-CSF (10 ng/ml), SCF (50 ng/ ml), or G-CSF (10 ng/ml) (PeproTech).…”

Macrophages and CSF-1

“…24 Moreover, mouse models deficient in tissue macrophages display a range of developmental abnormalities including skeletal and neurological deficiencies and impaired growth and fertility. [25][26][27][28] Furthermore, there is no viable transgenic mutant model that is totally devoid of macrophages during organogenesis, 29 highlighting the relevance of macrophages to development.…”