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BMP-2 induces human mononuclear cell chemotaxis and adhesion and modulates monocyte-to-macrophage differentiation.

ABSTRACT: Type 2 diabetes mellitus (T2DM) is a cardiovascular risk factor which leads to atherosclerosis, an inflammatory disease characterized by the infiltration of mononuclear cells in the vessel. Bone morphogenetic protein (BMP)-2 is a cytokine which has been recently shown to be elevated in atherosclerosis and T2DM and to contribute to vascular inflammation. However, the role of BMP-2 in the regulation of mononuclear cell function remains to be established. Herein, we demonstrate that BMP-2 induced human monocyte chemotaxis via phosphoinositide 3 kinase and mitogen-activated protein kinases. Inhibition of endogenous BMP-2 signalling, by Noggin or a BMP receptor inhibitor, interfered with monocyte migration. Although BMP-2 expression was increased in monocytes from T2DM patients, it could still stimulate their migration. Furthermore, BMP-2 interfered with their differentiation into M2 macrophages. Finally, BMP-2 both induced the adhesion of monocytes to fibronectin and endothelial cells (ECs), and promoted the adhesive properties of ECs, by increasing expression of adhesion and pro-inflammatory molecules. Our data demonstrate that BMP-2 could exert its pro-inflammatory effects by inducing monocyte migration and adhesiveness to ECs and by interfering with the monocyte differentiation into M2 macrophages. Our findings provide novel insights into the mechanisms by which BMP-2 may contribute to the development of atherosclerosis.

SUBMITTER: Pardali E

PROVIDER: S-EPMC6201342 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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BMP-2 induces human mononuclear cell chemotaxis and adhesion and modulates monocyte-to-macrophage differentiation.

Pardali Evangelia E Makowski Lena-Maria LM Leffers Merle M Borgscheiper Andreas A Waltenberger Johannes J

Journal of cellular and molecular medicine 20180813 11

Type 2 diabetes mellitus (T2DM) is a cardiovascular risk factor which leads to atherosclerosis, an inflammatory disease characterized by the infiltration of mononuclear cells in the vessel. Bone morphogenetic protein (BMP)-2 is a cytokine which has been recently shown to be elevated in atherosclerosis and T2DM and to contribute to vascular inflammation. However, the role of BMP-2 in the regulation of mononuclear cell function remains to be established. Herein, we demonstrate that BMP-2 induced h ...[more]

PMID: 30102472

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Project description:Monocytes are primary targets for human cytomegalovirus (HCMV) infection and are proposed to be responsible for hematogenous dissemination of the virus. Biologically, monocytes have a short life span of 48 h in the circulation, a period of time during which monocytes must make a cell fate decision on whether to undergo apoptosis or differentiate into a macrophage. We have previously shown that HCMV infection stimulates monocyte-to-macrophage differentiation; however, the mechanism(s) by which HCMV-infected monocytes simultaneously navigate the 48-h "viability gate" and undergo macrophagic differentiation has remained elusive. Studies have demonstrated that the level of caspase 3 and 8 activities in monocytes may mediate the delicate balance between apoptosis and macrophage colony-stimulating factor (M-CSF)-induced myeloid differentiation. Here, we show that HCMV infection, unlike M-CSF treatment, does not induce caspase 8 activity to promote myeloid differentiation. However, HCMV infection does induce a temporal activation of caspase 3, with only a low level of active caspase 3 being observed after the 48-h viability checkpoint. Consistent with the role of a time-dependent activation of caspase 3 in promoting myeloid differentiation, the inhibition of caspase 3 blocked HCMV-induced monocyte-to-macrophage differentiation. Temporal transcriptome and functional analyses identified heat shock protein 27 (HSP27) and Mcl-1, two known regulators of caspase 3 activation, as being upregulated prior to the 48-h viability gate following HCMV infection. Using small interfering RNAs (siRNAs), we demonstrate that HCMV targets the rapid induction of HSP27 and Mcl-1, which cooperatively function to precisely control caspase 3 activity in order to allow for HCMV-infected monocytes to successfully traverse the 48-h cell fate decision checkpoint and commence macrophage maturation. Overall, this study highlights a unique regulatory mechanism employed by HCMV to tightly modulate the caspase 3 activity needed to promote myeloid differentiation, a key process in the viral dissemination and persistence strategy.

Dataset Information

BMP-2 induces human mononuclear cell chemotaxis and adhesion and modulates monocyte-to-macrophage differentiation.

Publications

BMP-2 induces human mononuclear cell chemotaxis and adhesion and modulates monocyte-to-macrophage differentiation.

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