GM-CSF, via PU.1, regulates alveolar macrophage FcγR-mediated phagocytosis and the IL-18/IFN-γ–mediated molecular connection between innate and adaptive immunity in the lung

Berclaz, Pierre-Yves; Shibata, Yoko; Whitsett, Jeffrey A.; Trapnell, Bruce C.

doi:10.1182/blood-2002-04-1102

Cited by 119 publications

(108 citation statements)

References 54 publications

(70 reference statements)

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…1B, upper panels). In contrast, the low-affinity IgG FcR Fc␥RIIb, which is suspected to be a target gene of PU.1 (43), was expressed on wild-type pro-B cell lines but was reduced or undetectable on PU.1 Ϫ/Ϫ Spi-B Ϫ/Ϫ cell lines (Fig. 1B, lower panels).…”

Section: Resultsmentioning

confidence: 99%

Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines

Schweitzer

DeKoter

2004

The Journal of Immunology

View full text Add to dashboard Cite

A number of presumptive target genes for the Ets-family transcription factor PU.1 have been identified in the B cell lineage. However, the precise function of PU.1 in B cells has not been studied because targeted null mutation of the PU.1 gene results in a block to lymphomyeloid development at an early developmental stage. In this study, we take advantage of recently developed PU.1−/−Spi-B−/− IL-7 and stromal cell-dependent progenitor B (pro-B) cell lines to analyze the function of PU.1 and Spi-B in B cell development. We show that contrary to previously published expectations, PU.1 and/or Spi-B are not required for Ig H chain (IgH) gene transcription in pro-B cells. In fact, PU.1−/−Spi-B−/− pro-B cells have increased levels of IgH transcription compared with wild-type pro-B cells. In addition, high levels of Igκ transcription are induced after IL-7 withdrawal of wild-type or PU.1−/−Spi-B−/− pro-B cells. In contrast, we found that Igλ transcription is reduced in PU.1−/−Spi-B−/− pro-B cells relative to wild-type pro-B cells after IL-7 withdrawal. These results suggest that Igλ, but not IgH or Igκ, transcription, is dependent on PU.1 and/or Spi-B. The PU.1−/−Spi-B−/− pro-B cells have other phenotypic changes relative to wild-type pro-B cells including increased proliferation, increased CD25 expression, decreased c-Kit expression, and decreased RAG-1 expression. Taken together, our observations suggest that reduction of PU.1 and/or Spi-B activity in pro-B cells promotes their differentiation to a stage intermediate between late pro-B cells and large pre-B cells.

show abstract

Section: Resultsmentioning

confidence: 99%

Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines

Schweitzer

DeKoter

2004

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…In order to determine whether hypomorphic expression of PU.1 affects transcription of target genes, we analyzed expression of a gene recently identified as PU.1-dependent, FcγRIIb, which encodes the low-affinity IgG Fc receptor [13,22]. We performed real-time RT-PCR analysis to measure steady-state levels of FcγRIIb transcripts in cells cultured from wild-type, Sfpi1 −/− , and Sfpi1 BN/BN mice.…”

Section: Reduction In Pu1 Activity Results In Reduction Of Target Gementioning

confidence: 99%

Reduction in PU.1 activity results in a block to B-cell development, abnormal myeloid proliferation, and neonatal lethality

Houston

Kamath

Schweitzer

et al. 2007

Experimental Hematology

View full text Add to dashboard Cite

Objective-It has been demonstrated that high concentration of the transcription factor PU.1 (encoded by Sfpi1) promotes macrophage development, whereas low concentration induces B cell development in vitro. This has led to the hypothesis that lower levels of PU.1 activity are required for B cell than for macrophage development in vivo. We utilized an allele of Sfpi1 (termed BN) with a mutation in the first coding exon which resulted in a reduction of PU.1 expression in order to test this hypothesis. Methods-Using gene targeting in ES cells, two ATG-start site codons of PU.1 were mutated, resulting in reduced PU.1 expression originating from a third start codon. Mice were assayed for phenotypic abnormalities using fluorescence activated cell sorting, microscopy, and colony forming ability. In addition, isolated cells were tested for their differentiation potential in vitro and in vivo.Results-Lymphoid and myeloid cells derived from cultured Sfpi1 BN/BN fetal liver cells had reduced levels of PU.1 expression and activity. B cell development was intrinsically blocked in cells isolated from Sfpi1 BN/BN mice. In addition, myeloid development was impaired in Sfpi1 BN/BN fetal liver. However, neonatal Sfpi1 BN/BN mice had a dramatic expansion and infiltration of immature myeloid cells.Conclusion-Contrary to our original hypothesis, high levels of PU.1 activity are required to induce both myeloid and B cell development. In addition, neonatal mice homozygous for the hypomorphic allele acquire a myeloproliferative disorder and die within 1 month of age.

show abstract

“…PU.1 levels and activity are reduced in alveolar macrophages in patients with idiopathic PAP and are restored by GM-CSF therapy (17). We propose that pulmonary GM-CSF is required to stimulate the terminal differentiation of alveolar macrophages in humans based on observations that GM-CSF, by PU.1, stimulates the terminal differentiation of alveolar macrophages in mice (20), and a similar pattern of macrophage abnormalities is seen in patients with idiopathic PAP (14,15,17), patients with hereditary PAP (6, 39), GM-CSF-deficient mice (16,(18)(19)(20), GM-CSF receptor-deficient mice (11,40), and GMAb-injected nonhuman primates (Figures 3-6). We further propose that GMAb cause PAP by blocking pulmonary GM-CSF signaling in vivo, thereby reducing PU.1 levels in alveolar macrophages impairing surfactant catabolism in alveolar macrophages.…”

Section: Implications For the Biologic Role Of Gm-csf And Pathogenesimentioning

confidence: 99%

“…GM-CSF by the ''master'' myeloid transcription factor PU.1 led to the conclusion that GM-CSF regulates the terminal differentiation of alveolar macrophages in the lungs of mice (3,(14)(15)(16)(17)(18)(19)(20). GM-CSF deficiency has not been reported in patients with PAP (21).…”

Section: What This Study Adds To the Fieldmentioning

confidence: 99%

Patient-derived Granulocyte/Macrophage Colony–Stimulating Factor Autoantibodies Reproduce Pulmonary Alveolar Proteinosis in Nonhuman Primates

Sakagami

Beck

Uchida

et al. 2010

Am J Respir Crit Care Med

Self Cite

View full text Add to dashboard Cite

Rationale: Granulocyte/macrophage colony-stimulating factor (GM-CSF) autoantibodies (GMAb) are strongly associated with idiopathic pulmonary alveolar proteinosis (PAP) and are believed to be important in its pathogenesis. However, levels of GMAb do not correlate with disease severity and GMAb are also present at low levels in healthy individuals. Objectives: Our primary objective was to determine whether human GMAb would reproduce PAP in healthy primates. A secondary objective was to determine the concentration of GMAb resulting in loss of GM-CSF signaling in vivo (i.e., critical threshold). Methods: Nonhuman primates (Macaca fascicularis) were injected with highly purified, PAP patient-derived GMAb in dose-ranging (2.2-50 mg) single and multiple administration studies, and after blocking antihuman immunoglobulin immune responses, in chronic administration studies maintaining serum levels greater than 40 mg/ml for up to 11 months. Measurements and Main Results: GMAb blocked GM-CSF signaling causing (1) a milky-appearing bronchoalveolar lavage fluid containing increased surfactant lipids and proteins; (2) enlarged, foamy, surfactant-filled alveolar macrophages with reduced PU.1 and PPARg mRNA, and reduced tumor necrosis factor-a secretion; (3) pulmonary leukocytosis; (4) increased serum surfactant protein-D; and (5) impaired neutrophil functions. GM-CSF signaling varied inversely with GMAb concentration below a critical threshold of 5 mg/ml, which was similar in lungs and blood and to the value observed in patients with PAP. Conclusions: GMAb reproduced the molecular, cellular, and histopathologic features of PAP in healthy primates, demonstrating that GMAb directly cause PAP. These results have implications for therapy of PAP and help define the therapeutic window for potential use of GMAb to treat other disorders.

show abstract

GM-CSF, via PU.1, regulates alveolar macrophage FcγR-mediated phagocytosis and the IL-18/IFN-γ–mediated molecular connection between innate and adaptive immunity in the lung

Cited by 119 publications

References 54 publications

Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines

Analysis of Gene Expression and Ig Transcription in PU.1/Spi-B-Deficient Progenitor B Cell Lines

Reduction in PU.1 activity results in a block to B-cell development, abnormal myeloid proliferation, and neonatal lethality

Patient-derived Granulocyte/Macrophage Colony–Stimulating Factor Autoantibodies Reproduce Pulmonary Alveolar Proteinosis in Nonhuman Primates

Contact Info

Product

Resources

About