Organ-specific Autoimmunity in Granulocyte Macrophage-colony Stimulating Factor (GM-CSF) Deficient Mice

Mice made granulocyte macrophage-colony stimulating factor (GM-CSF)-deficient by homologous recombination maintain normal steady-state hematopoiesis but have an alveolar accumulation of surfactant lipids and protein that is similar to pulmonary alveolar proteinosis in humans. We asked how GM-CSF deficiency alters surfactant metabolism and function in mice. Alveolar and lung tissue saturated phosphatidylcholine (Sat PC) were increased six- to eightfold in 7- to 9-wk-old GM-CSF-deficient mice relative to controls. Incorporation of radiolabeled palmitate and choline into Sat PC was higher in GM-CSF deficient mice than control mice, and no loss of labeled Sat PC occurred from the lungs of GM-CSF-deficient mice. Secretion of radiolabeled Sat PC to the alveolus was similar in GM-CSF-deficient and control mice. Labeled Sat PC and surfactant protein A (SP-A) given by tracheal instillation were cleared rapidly in control mice, but there was no measurable loss from the lungs of GM-CSF-deficient mice. The function of the surfactant from GM-CSF-deficient mice was normal when tested in preterm surfactant-deficient rabbits. GM-CSF deficiency results in a catabolic defect for Sat PC and SP-A.

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Impaired response to GM-CSF and G-CSF, and enhanced apoptosis in C/EBPβ-deficient hematopoietic cells

Blood ◽

10.1182/blood-2007-04-087213 ◽

2008 ◽

Vol 111 (6) ◽

pp. 2999-3004 ◽

Cited By ~ 34

Author(s):

Tadayuki Akagi ◽

Takayuki Saitoh ◽

James O'Kelly ◽

Shizuo Akira ◽

Adrian F. Gombart ◽

...

Keyword(s):

Bone Marrow Cells ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Susceptibility To Infection ◽

Expression Of Genes ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Deficient Mice

Abstract Transcription factors known as CCAAT enhancer binding proteins (C/EBPs) are involved in hematopoietic differentiation, including myelopoiesis and granulopoiesis. C/EBPβ-deficient mice develop normally; however, they exhibit defective macrophage function, resulting in increased susceptibility to infection. Little is known about the role of C/EBPβ in granulopoiesis; therefore, we examined granulopoiesis in C/EBPβ-deficient mice. Morphology, the number of peripheral blood and bone marrow cells, and the expression of genes specific for the myeloid lineage were normal in C/EBPβ-deficient mice. Interestingly, the hematopoietic progenitor cells of C/EBPβ-deficient mice did not respond normally to granulocyte/macrophage-colony stimulating factor and granulocyte colony stimulating factor. In addition, C/EBPβ-deficient neutrophils displayed enhanced apoptosis compared with wild-type neutrophils. Our present results indicate that C/EBPβ helps regulate survival of neutrophils, downstream of the granulocyte colony stimulating factor receptor.

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Granulocyte-macrophage colony-stimulating factor is not responsible for the correction of hematopoietic deficiencies in the maturing op/op mouse

Blood ◽

10.1182/blood.v86.1.66.bloodjournal86166 ◽

1995 ◽

Vol 86 (1) ◽

pp. 66-72 ◽

Cited By ~ 44

Author(s):

SK Nilsson ◽

GJ Lieschke ◽

CC Garcia-Wijnen ◽

B Williams ◽

D Tzelepis ◽

...

Keyword(s):

Biologically Active ◽

Colony Stimulating Factor ◽

Hematopoietic Stem ◽

Marrow Cavity ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Deficient Mice ◽

Hematopoietic Activity

Osteopetrotic (op/op) mice are characterized by an autosomal recessive inactivating mutation resulting in the absence of biologically active colony-stimulating factor-1 (CSF-1). Consequently, young op/op mice have a severe deficiency of macrophages and osteoclasts resulting in excessive bone formation, occlusion of the marrow cavity, and reduced marrow hematopoietic activity. Recently, we showed that the osteopetrosis and hematopoietic deficiencies evident in young op/op mice are not permanent but are progressively corrected with age. There are increases in osteoclast activity; bone resorption; femoral marrow space; and marrow hematopoietic activity, cellularity, and macrophage content. In the present study we show that CSF-1-/- granulocyte- macrophage colony-stimulating factor (GM-CSF)(-/-)-deficient mice also undergo the same pattern of hematopoietic correction as the op/op mouse. Also, like the op/op mouse, the peritoneal cellularity and macrophage content of CSF-1/GM-CSF-deficient mice remains severely reduced. Our data show that the “knockout” of GM-CSF does not change the op/op phenotype, and that GM-CSF is not essential for the correction of the hematopoietic deficiencies in the op/op mouse. Importantly, the data also show that neither GM-CSF nor CSF-1 is an absolute requirement for the commitment of primitive hematopoietic stem cells to the macrophage lineage or for the differentiation of at least some classes of macrophages. This finding suggests that an alternate regulatory factor can be involved in macrophage and osteoclast commitment, differentiation, and function in vivo.

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Overlapping roles for granulocyte-macrophage colony-stimulating factor and interleukin-3 in eosinophil homeostasis and contact hypersensitivity

Blood ◽

10.1182/blood.v97.4.922 ◽

2001 ◽

Vol 97 (4) ◽

pp. 922-928 ◽

Cited By ~ 33

Author(s):

Silke Gillessen ◽

Nicolas Mach ◽

Clayton Small ◽

Martin Mihm ◽

Glenn Dranoff

Keyword(s):

Es Cells ◽

Embryonic Stem ◽

Contact Hypersensitivity ◽

Colony Stimulating Factor ◽

Interleukin 3 ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Deficient Mice

Abstract Studies of mice rendered deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) have established unique roles for these cytokines in pulmonary homeostasis, resistance to infection, and antigen-specific T- and B-cell responses. In addition to these distinctive properties, however, GM-CSF and IL-3 also stimulate the development and activation of hematopoietic cells in many similar ways, raising the possibility that each factor might partially compensate for the other's absence in singly deficient mice. To test whether endogenous GM-CSF and IL-3 mediate redundant functions in vivo, we generated mice lacking both cytokines through sequential gene targeting experiments in embryonic stem (ES) cells. Surprisingly, doubly deficient animals, but not single knockouts, showed increased numbers of circulating eosinophils. Doubly deficient mice, moreover, developed weaker contact hypersensitivity reactions to haptens applied epicutaneously than mice deficient in either factor alone. Together, these findings delineate overlapping roles for GM-CSF and IL-3 in hematopoiesis and immunity.

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Alterations in the vascular extracellular matrix of granulocyte macrophage colony‐stimulating factor (GM‐CSF) ‐deficient mice

The FASEB Journal ◽

10.1096/fj.02-1035com ◽

2003 ◽

Vol 17 (11) ◽

pp. 1451-1457 ◽

Cited By ~ 14

Author(s):

Gabriele Plenz ◽

Heike Eschert ◽

Stefan Beissert ◽

Volker Arps ◽

Jürgen R. Sindermann ◽

...

Keyword(s):

Extracellular Matrix ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Deficient Mice

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Mice lacking both macrophage- and granulocyte-macrophage colony- stimulating factor have macrophages and coexistent osteopetrosis and severe lung disease

Blood ◽

10.1182/blood.v84.1.27.27 ◽

1994 ◽

Vol 84 (1) ◽

pp. 27-35 ◽

Cited By ~ 92

Author(s):

GJ Lieschke ◽

E Stanley ◽

D Grail ◽

G Hodgson ◽

V Sinickas ◽

...

Keyword(s):

Lung Pathology ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Alveolar Proteinosis ◽

Macrophage Colony ◽

And Function ◽

Stimulating Factor ◽

Deficient Mice

Abstract Mice deficient in granulocyte-macrophage colony-stimulating factor (GM- CSF) and macrophage colony-stimulating factor (M-CSF, CSF-1) were generated by interbreeding GM-CSF-deficient mice generated by gene targeting (genotype GM-/-) with M-CSF-deficient osteopetrotic mice (genotype M-/-, op/op). Mice deficient in both GM-CSF and M-CSF (genotype GM-/-M-/-) are viable and have coexistent features corresponding to mice deficient in either factor alone. Like M-CSF- deficient mice, they have osteopetrosis and are toothless because of failure of incisor eruption. Like GM-CSF-deficient mice, they have a characteristic alveolar-proteinosis-like lung pathology, but it is more severe than that of GM-CSF-deficient mice and is often fatal. In particular, in GM-/-M-/- mice the accumulation of lipo-proteinaceous alveolar material is more marked, and bacterial pneumonic infections are more prevalent and more extensive, particularly involving Gram- negative bacteria. Neutrophilia consistently accompanies pulmonary infections, and some older GM-/-M-/- mice have polycythemia. Survival of GM-/-M-/- mice is significantly reduced compared with mice deficient in either factor alone, and all GM-/-M-/- mice have broncho- or lobar- pneumonia at death. These observations indicate that in vivo, M-CSF is involved in modulating the consequences of GM-CSF deficiency in the lung. Interestingly, GM-/-M-/- mice have circulating monocytes at levels comparable with those in M-CSF-deficient mice and the diseased lungs of all GM-/-M-/- mice contain numerous phagocytically active macrophages, indicating that in addition to GM-CSF and M-CSF, other factors can be used for macrophage production and function in vivo.

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Mice lacking both macrophage- and granulocyte-macrophage colony- stimulating factor have macrophages and coexistent osteopetrosis and severe lung disease

Blood ◽

10.1182/blood.v84.1.27.bloodjournal84127 ◽

1994 ◽

Vol 84 (1) ◽

pp. 27-35 ◽

Cited By ~ 6

Author(s):

GJ Lieschke ◽

E Stanley ◽

D Grail ◽

G Hodgson ◽

V Sinickas ◽

...

Keyword(s):

Lung Pathology ◽

Colony Stimulating Factor ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Alveolar Proteinosis ◽

Macrophage Colony ◽

And Function ◽

Stimulating Factor ◽

Deficient Mice

Mice deficient in granulocyte-macrophage colony-stimulating factor (GM- CSF) and macrophage colony-stimulating factor (M-CSF, CSF-1) were generated by interbreeding GM-CSF-deficient mice generated by gene targeting (genotype GM-/-) with M-CSF-deficient osteopetrotic mice (genotype M-/-, op/op). Mice deficient in both GM-CSF and M-CSF (genotype GM-/-M-/-) are viable and have coexistent features corresponding to mice deficient in either factor alone. Like M-CSF- deficient mice, they have osteopetrosis and are toothless because of failure of incisor eruption. Like GM-CSF-deficient mice, they have a characteristic alveolar-proteinosis-like lung pathology, but it is more severe than that of GM-CSF-deficient mice and is often fatal. In particular, in GM-/-M-/- mice the accumulation of lipo-proteinaceous alveolar material is more marked, and bacterial pneumonic infections are more prevalent and more extensive, particularly involving Gram- negative bacteria. Neutrophilia consistently accompanies pulmonary infections, and some older GM-/-M-/- mice have polycythemia. Survival of GM-/-M-/- mice is significantly reduced compared with mice deficient in either factor alone, and all GM-/-M-/- mice have broncho- or lobar- pneumonia at death. These observations indicate that in vivo, M-CSF is involved in modulating the consequences of GM-CSF deficiency in the lung. Interestingly, GM-/-M-/- mice have circulating monocytes at levels comparable with those in M-CSF-deficient mice and the diseased lungs of all GM-/-M-/- mice contain numerous phagocytically active macrophages, indicating that in addition to GM-CSF and M-CSF, other factors can be used for macrophage production and function in vivo.

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Cholesterol loading suppresses the atheroinflammatory gene polarization of human macrophages induced by colony stimulating factors

Scientific Reports ◽

10.1038/s41598-021-84249-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Jani Lappalainen ◽

Nicolas Yeung ◽

Su D. Nguyen ◽

Matti Jauhiainen ◽

Petri T. Kovanen ◽

...

Keyword(s):

Expression Profiles ◽

Gene Expression Profiles ◽

Foam Cells ◽

Colony Stimulating Factor ◽

Human Macrophages ◽

Gm Csf ◽

Macrophage Subpopulations ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

AbstractIn atherosclerotic lesions, blood-derived monocytes differentiate into distinct macrophage subpopulations, and further into cholesterol-filled foam cells under a complex milieu of cytokines, which also contains macrophage-colony stimulating factor (M-CSF) and granulocyte–macrophage-colony stimulating factor (GM-CSF). Here we generated human macrophages in the presence of either M-CSF or GM-CSF to obtain M-MØ and GM-MØ, respectively. The macrophages were converted into cholesterol-loaded foam cells by incubating them with acetyl-LDL, and their atheroinflammatory gene expression profiles were then assessed. Compared with GM-MØ, the M-MØ expressed higher levels of CD36, SRA1, and ACAT1, and also exhibited a greater ability to take up acetyl-LDL, esterify cholesterol, and become converted to foam cells. M-MØ foam cells expressed higher levels of ABCA1 and ABCG1, and, correspondingly, exhibited higher rates of cholesterol efflux to apoA-I and HDL2. Cholesterol loading of M-MØ strongly suppressed the high baseline expression of CCL2, whereas in GM-MØ the low baseline expression CCL2 remained unchanged during cholesterol loading. The expression of TNFA, IL1B, and CXCL8 were reduced in LPS-activated macrophage foam cells of either subtype. In summary, cholesterol loading converged the CSF-dependent expression of key genes related to intracellular cholesterol balance and inflammation. These findings suggest that transformation of CSF-polarized macrophages into foam cells may reduce their atheroinflammatory potential in atherogenesis.

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Growth stimulation of non-small cell lung cancer xenografts by granulocyte-macrophage colony-stimulating factor (GM-CSF)

European Journal of Cancer ◽

10.1016/s0959-8049(98)00236-6 ◽

1998 ◽

Vol 34 (12) ◽

pp. 1958-1961 ◽

Cited By ~ 15

Author(s):

Y. Oshika ◽

M. Nakamura ◽

Y. Abe ◽

Y. Fukuchi ◽

M. Yoshimura ◽

...

Keyword(s):

Lung Cancer ◽

Growth Stimulation ◽

Small Cell ◽

Colony Stimulating Factor ◽

Small Cell Lung ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor ◽

Stimulation Of

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The Truncated Splice Variant of the Granulocyte-Macrophage-Colony-Stimulating Factor Receptor β- Chain in Peripheral Blood Serves as Severity Biomarker of Respiratory Failure in Newborns

Neonatology ◽

10.1159/000513356 ◽

2021 ◽

pp. 1-7

Author(s):

Verena Schulte ◽

Alexandra Sipol ◽

Stefan Burdach ◽

Esther Rieger-Fackeldey

Keyword(s):

Respiratory Failure ◽

Peripheral Blood ◽

Colony Stimulating Factor ◽

Term Infants ◽

Respiratory Impairment ◽

Gm Csf ◽

A Subunit ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony ◽

Stimulating Factor

Background: The granulocyte-macrophage-colony-stimulating factor (GM-CSF) plays an important role in surfactant homeostasis. βC is a subunit of the GM-CSF receptor (GM-CSF-R), and its activation mediates surfactant catabolism in the lung. βIT is a physiological, truncated isoform of βC and is known to act as physiological inhibitor of βC. Objective: The aim of this study was to determine the ratio of βIT and βC in the peripheral blood of newborns and its association with the degree of respiratory failure at birth. Methods: We conducted a prospective cohort study in newborns with various degrees of respiratory impairment at birth. Respiratory status was assessed by a score ranging from no respiratory impairment (0) to invasive respiratory support (3). βIT and βC expression were determined in peripheral blood cells by real-time PCR. βIT expression, defined as the ratio of βIT and βC, was correlated with the respiratory score. Results: βIT expression was found in all 59 recruited newborns with a trend toward higher βIT in respiratory ill (score 2, 3) newborns than respiratory healthy newborns ([score 0, 1]; p = 0.066). Seriously ill newborns (score 3) had significantly higher βIT than healthy newborns ([score 0], p = 0.010). Healthy preterm infants had significantly higher βIT expression than healthy term infants (p = 0.019). Conclusions: βIT is expressed in newborns with higher expression in respiratory ill than respiratory healthy newborns. We hypothesize that βIT may have a protective effect in postnatal pulmonary adaptation acting as a physiological inhibitor of βC and, therefore, maintaining surfactant in respiratory ill newborns.

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