Article
PU.1 regulation of human alveolar macrophage differentiation requires granulocyte-macrophage colony-stimulating factor.
Department of Pulmonary and Critical Care Medicine, The Cleveland Clinic Foundation, Cleveland, Ohio 44195-5038, USA.
AJP Lung Cellular and Molecular Physiology (impact factor:
3.66).
12/2003;
285(5):L1132-6.
DOI:10.1152/ajplung.00216.2003
Source: PubMed
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Citations (0)
- Cited In (6)
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Article: Adherent human alveolar macrophages exhibit a transient pro-inflammatory profile that confounds responses to innate immune stimulation.
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ABSTRACT: Alveolar macrophages (AM) are thought to have a key role in the immunopathogenesis of respiratory diseases. We sought to test the hypothesis that human AM exhibit an anti-inflammatory bias by making genome-wide comparisons with monocyte derived macrophages (MDM). Adherent AM obtained by bronchoalveolar lavage of patients under investigation for haemoptysis, but found to have no respiratory pathology, were compared to MDM from healthy volunteers by whole genome transcriptional profiling before and after innate immune stimulation. We found that freshly isolated AM exhibited a marked pro-inflammatory transcriptional signature. High levels of basal pro-inflammatory gene expression gave the impression of attenuated responses to lipopolysaccharide (LPS) and the RNA analogue, poly IC, but in rested cells pro-inflammatory gene expression declined and transcriptional responsiveness to these stimuli was restored. In comparison to MDM, both freshly isolated and rested AM showed upregulation of MHC class II molecules. In most experimental paradigms ex vivo adherent AM are used immediately after isolation. Therefore, the confounding effects of their pro-inflammatory profile at baseline need careful consideration. Moreover, despite the prevailing view that AM have an anti-inflammatory bias, our data clearly show that they can adopt a striking pro-inflammatory phenotype, and may have greater capacity for presentation of exogenous antigens than MDM.PLoS ONE 01/2012; 7(6):e40348. · 4.09 Impact Factor -
Article: In Lysinuric Protein Intolerance system y+L activity is defective in monocytes and in GM-CSF-differentiated macrophages.
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ABSTRACT: In the recessive aminoaciduria Lysinuric Protein Intolerance (LPI), mutations of SLC7A7/y+LAT1 impair system y+L transport activity for cationic amino acids. A severe complication of LPI is a form of Pulmonary Alveolar Proteinosis (PAP), in which alveolar spaces are filled with lipoproteinaceous material because of the impaired surfactant clearance by resident macrophages. The pathogenesis of LPI-associated PAP remains still obscure. The present study investigates for the first time the expression and function of y+LAT1 in monocytes and macrophages isolated from a patient affected by LPI-associated PAP. A comparison with mesenchymal cells from the same subject has been also performed. Monocytes from peripheral blood were isolated from a 21-year-old patient with LPI. Alveolar macrophages and fibroblastic-like mesenchymal cells were obtained from a whole lung lavage (WLL) performed on the same patient. System y+L activity was determined measuring the 1-min uptake of [3H]-arginine under discriminating conditions. Gene expression was evaluated through qRT-PCR. We have found that: 1) system y+L activity is markedly lowered in monocytes and alveolar macrophages from the LPI patient, because of the prevailing expression of SLC7A7/y+LAT1 in these cells; 2) on the contrary, fibroblasts isolated from the same patient do not display the transport defect due to compensation by the SLC7A6/y+LAT2 isoform; 3) in both normal and LPI monocytes, GM-CSF induces the expression of SLC7A7, suggesting that the gene is a target of the cytokine; 4) GM-CSF-induced differentiation of LPI monocytes is comparable to that of normal cells, demonstrating that GM-CSF signalling is unaltered; 5) general and respiratory conditions of the patient, along with PAP-associated parameters, markedly improved after GM-CSF therapy through aerosolization. Monocytes and macrophages, but not fibroblasts, derived from a LPI patient clearly display the defect in system y+L-mediated arginine transport. The different transport phenotypes are referable to the relative levels of expression of SLC7A7 and SLC7A6. Moreover, the expression of SLC7A7 is regulated by GM-CSF in monocytes, pointing to a role of y+LAT1 in the pathogenesis of LPI associated PAP.Orphanet Journal of Rare Diseases 01/2010; 5:32. · 5.83 Impact Factor -
Article: Pulmonary alveolar proteinosis.
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ABSTRACT: Pulmonary alveolar proteinosis is a rare but potentially treatable disease, characterized by impaired surfactant metabolism that leads to accumulation in the alveoli of proteinaceous material rich in surfactant protein and its component. Novel insights from an animal model aided the discovery of granulocyte macrophage colony stimulating factor (GM-CSF) antibodies as a pathogenetic mechanism in human pulmonary alveolar proteinosis. The vast majority of pulmonary alveolar proteinosis occurs as an autoimmune disease; less commonly, it is congenital or secondary to an underlying disorder such as infection, hematological malignancy, or immunodeficiency. The subacute indolent course of this disease often delays the diagnosis by months to years. Crazy-paving appearance in a geographic distribution is a characteristic feature of this disease visible on high-resolution computed tomography (CT). A definitive diagnosis, however, requires lung biopsy, which typically shows partial or complete filling of alveoli with periodic-acid-Schiff-positive granular and eosinophilic material in preserved alveolar architecture. Patients with minimal symptoms are managed conservatively, whereas patients with hypoxemia require a more aggressive approach. Whole-lung lavage is the most widely accepted therapy for symptomatic pulmonary alveolar proteinosis. Correction of GM-CSF deficiency with exogenous GM-CSF is an alternative therapy. The combination of a systemic treatment (GM-CSF) and a local treatment (whole-lung lavage) augmenting the action of one another is a promising new approach. As the knowledge about this rare disease increases, the role of novel therapies is likely to be better defined and optimized.Respiratory care 04/2011; 56(7):1016-28. · 2.01 Impact Factor
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Keywords
anti-GM-CSF autoimmunity
GM-CSF gene
GM-CSF knockout mouse
GM-CSF knockout mouse model
Granulocyte-macrophage colony-stimulating factor
healthy control
human alveolar macrophages
human alveolar proteinosis
human PAP alveolar macrophages
lung homeostasis
M-CSFR gene expression
macrophage colony-stimulating factor receptor
mannose receptor
PAP alveolar macrophages
PAP bronchoalveolar lavage cells
PU.1-dependent terminal differentiation markers CD32
pulmonary alveolar proteinosis
terminal differentiation
vitro studies
vivo studies
