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Regulation of the maturation of human monocytes into immunosuppressive macrophages.

ABSTRACT: Human monocytes differentiate into either proinflammatory or immunosuppressive macrophages in response to distinct stimuli. Results show that the Toll-like receptor 2/1 agonist PAM3 replicates the ability of macrophage colony-stimulating factor (M-CSF) to induce the preferential generation of immunosuppressive macrophages in vitro, an activity confirmed by in vivo studies of rhesus macaques. By comparing the gene expression pattern of monocytes treated with M-CSF vs PAM3, the pathways regulating macrophage maturation were identified. NF-?B and Akt were found to play a central role in the overall process of monocyte into macrophage differentiation. Pathways regulated by p38 MAPK and PTGS2 biased this process toward the generation of immunosuppressive rather than proinflammatory macrophages. ERK and JNK contribute to PAM3- but not M-CSF-driven monocyte maturation. These findings clarify the mechanisms underlying the generation of immunosuppressive macrophages and support the use of PAM3 in the treatment of autoimmune and inflammatory diseases.

SUBMITTER: Bayik D

PROVIDER: S-EPMC5728638 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Regulation of the maturation of human monocytes into immunosuppressive macrophages.

Bayik Defne D Tross Debra D Haile Lydia A LA Verthelyi Daniela D Klinman Dennis M DM

Blood advances 20171204 26

Human monocytes differentiate into either proinflammatory or immunosuppressive macrophages in response to distinct stimuli. Results show that the Toll-like receptor 2/1 agonist PAM3 replicates the ability of macrophage colony-stimulating factor (M-CSF) to induce the preferential generation of immunosuppressive macrophages in vitro, an activity confirmed by in vivo studies of rhesus macaques. By comparing the gene expression pattern of monocytes treated with M-CSF vs PAM3, the pathways regulating ...[more]

PMID: 29296902

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Project description:BackgroundImmunomodulation by mesenchymal stromal cells (MSCs) can occur through trophic factor mechanisms, however, intravenously infused MSCs are rapidly cleared from the body yet a potent immunotherapeutic response is still observed. Recent work suggests that monocytes contribute to the clearance of MSCs via efferocytosis, the body's natural mechanism for clearing dead and dying cells in a non-inflammatory manner. This begs the questions of how variations in MSC quality affect monocyte phenotype and if viable MSCs are even needed to elicit an immunosuppressive response.MethodsHerein, we sought to dissect MSC's trophic mechanism from their efferocytic mechanisms and determine if the viability of MSCs prior to efferocytosis influences the resultant phenotype of monocytes. We cultured viable or heat-inactivated human umbilical cord MSCs with human peripheral blood mononuclear cells for 24 h and observed changes in monocyte surface marker expression and secretion profile. To isolate the effect of efferocytosis from MSC trophic factors, we used cell separation techniques to remove non-efferocytosed MSCs before challenging monocytes to suppress T-cells or respond to inflammatory stimuli. For all experiments, viable and heat-inactivated efferocytic-licensing of monocytes were compared to non-efferocytic-licensing control.ResultsWe found that monocytes efferocytose viable and heat-inactivated MSCs equally, but only viable MSC-licensed monocytes suppress activated T-cells and suppression occurred even after depletion of residual MSCs. This provides direct evidence that monocytes that efferocytose viable MSCs are immunosuppressive. Further characterization of monocytes after efferocytosis showed that uptake of viable-but not heat inactivated-MSC resulted in monocytes secreting IL-10 and producing kynurenine. When monocytes were challenged with LPS, IL-2, and IFN-γ to simulate sepsis, monocytes that had efferocytosed viable MSC had higher levels of IDO while monocytes that efferocytosed heat inactivated-MSCs produced the lowest levels of TNF-α.ConclusionCollectively, these studies show that the quality of MSCs efferocytosed by monocytes polarize monocytes toward distinctive immunosuppressive phenotypes and highlights the need to tailor MSC therapies for specific indications.

Dataset Information

Regulation of the maturation of human monocytes into immunosuppressive macrophages.

Publications

Regulation of the maturation of human monocytes into immunosuppressive macrophages.

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