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IL-34 induces the differentiation of human monocytes into immunosuppressive macrophages. antagonistic effects of GM-CSF and IFN?.

ABSTRACT: IL-34 is a recently identified cytokine that signals via the M-CSF receptor and promotes monocyte survival. Depending on the environment, monocytes can differentiate into macrophages (M?) or dendritic cells (DC). A wide spectrum of M? and DC subsets, with distinct phenotypes and functions, has been described. To date, the phenotype of monocytes exposed to IL-34 remains unexplored. We report here that IL-34 induces the differentiation of monocytes into CD14(high) CD163(high) CD1a(-) M? (IL-34-M?). Upon LPS stimulation, IL-34-M? exhibit an IL-10(high) IL-12(low) M2 profile and express low levels of the costimulatory molecules CD80 and CD86. IL-34-M? exhibit poor T cell costimulatory properties, and have potent immunosuppressive properties (decrease of TCR-stimulated T cell proliferation). For all the parameters analyzed, IL-34-M? are phenotypically and functionally similar to M-CSF-M?. IL-34 appears as efficient as M-CSF in inducing the generation of immunosuppressive M?. Moreover, the generation of IL-34-M? is mediated through the M-CSF receptor, is independent of endogenous M-CSF consumption and is potentiated by IL-6. In an attempt to identify strategies to prevent a deleterious M2 cell accumulation in some pathological situations, we observed that IFN? and GM-CSF prevent the generation of immunosuppressive M? induced by IL-34. IFN? also switches established IL-34-M? into immunostimulatory M?. In conclusion, we demonstrate that IL-34 drives the differentiation of monocytes into immunosuppressive M2, in a manner similar to M-CSF, and that IFN? and GM-CSF prevent this effect.

SUBMITTER: Foucher ED

PROVIDER: S-EPMC3568045 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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IL-34 induces the differentiation of human monocytes into immunosuppressive macrophages. antagonistic effects of GM-CSF and IFNγ.

Foucher Etienne D ED Blanchard Simon S Preisser Laurence L Garo Erwan E Ifrah Norbert N Guardiola Philippe P Delneste Yves Y Jeannin Pascale P

PloS one 20130208 2

IL-34 is a recently identified cytokine that signals via the M-CSF receptor and promotes monocyte survival. Depending on the environment, monocytes can differentiate into macrophages (Mφ) or dendritic cells (DC). A wide spectrum of Mφ and DC subsets, with distinct phenotypes and functions, has been described. To date, the phenotype of monocytes exposed to IL-34 remains unexplored. We report here that IL-34 induces the differentiation of monocytes into CD14(high) CD163(high) CD1a(-) Mφ (IL-34-Mφ) ...[more]

PMID: 23409120

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Project description:BackgroundIn 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.MethodsMonocytes 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.ResultsWe 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.ConclusionsMonocytes 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.

Dataset Information

IL-34 induces the differentiation of human monocytes into immunosuppressive macrophages. antagonistic effects of GM-CSF and IFN?.

Publications

IL-34 induces the differentiation of human monocytes into immunosuppressive macrophages. antagonistic effects of GM-CSF and IFNγ.

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