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Monocytic MKP-1 is a Sensor of the Metabolic Environment and Regulates Function and Phenotypic Fate of Monocyte-Derived Macrophages in Atherosclerosis

View Article: PubMed Central - PubMed

ABSTRACT

Diabetes promotes the S-glutathionylation, inactivation and subsequent degradation of mitogen-activated protein kinase phosphatase 1 (MKP-1) in blood monocytes, and hematopoietic MKP-1-deficiency in atherosclerosis-prone mice accelerates atherosclerotic lesion formation, but the underlying mechanisms were not known. Our aim was to determine the mechanisms through which MKP-1 deficiency in monocytes and macrophages promotes atherogenesis. Transplantation of MKP-1-deficient bone marrow into LDL-R−/− (MKP-1LeuKO) mice accelerated high-fat diet (HFD)-induced atherosclerotic lesion formation. After 12 weeks of HFD feeding, MKP-1LeuKO mice showed increased lesion size in both the aortic root (1.2-fold) and the aorta (1.6-fold), despite reduced plasma cholesterol levels. Macrophage content was increased in lesions of MKP-1LeuKO mice compared to mice that received wildtype bone marrow. After only 6 weeks on a HFD, in vivo chemotactic activity of monocytes was already significantly increased in MKP-1LeuKO mice. MKP-1 deficiency in monocytes and macrophages promotes and accelerates atherosclerotic lesion formation by hyper-sensitizing monocytes to chemokine-induced recruitment, predisposing macrophages to M1 polarization, decreased autophagy and oxysterol-induced cell death whereas overexpression of MKP-1 protects macrophages against metabolic stress-induced dysfunction. MKP-1 serves as a master-regulator of macrophage phenotype and function and its dysregulation by metabolic stress may be a major contributor to atherogenesis and the progression of atherosclerotic plaques.

No MeSH data available.


Overexpression of MKP-1 protects macrophages against impaired autophagy, and accelerated cell death.Bone marrow-derived macrophages were infected with lentiviral vectors carrying either Flag-tagged MKP-1 or GFP. Cells were then treated for 24 hours with vehicle or primed with LDL + HG, and p62 protein levels (A), Caspase-3/7 activities (B Results are shown as mean ± SE (n = 3–4).
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f6: Overexpression of MKP-1 protects macrophages against impaired autophagy, and accelerated cell death.Bone marrow-derived macrophages were infected with lentiviral vectors carrying either Flag-tagged MKP-1 or GFP. Cells were then treated for 24 hours with vehicle or primed with LDL + HG, and p62 protein levels (A), Caspase-3/7 activities (B Results are shown as mean ± SE (n = 3–4).

Mentions: Metabolic stress promotes MKP-1 inactivation and degradation, and metabolically primed macrophages show all the phenotypic and functional hallmarks of macrophages with genetic MKP-1 deficiency. We therefore determined whether overexpression of MKP-1 protects metabolically stressed macrophages against defective autophagy, sensitization to oxysterol-induced cell death, and skewed M1/M2 polarization. To this end, we used a lentivirus-based transduction system to overexpress Flag-tagged MKP-1 (or green fluorescent protein, GFP) in bone marrow-derived macrophages. In contrast to GFP-expressing control macrophages, macrophages expressing Flag-MKP-1 were resistant to metabolic stress and showed no defects in autophagy (Fig. 6A) or any increased sensitivity to oxysterol-induced activation of caspase 3/7 (Fig. 6B). Furthermore, STAT1 phosphorylation induced by metabolic priming was suppressed in macrophages overexpressing MKP-1 (Fig. 7A) and the skewing of the polarization profile was prevented in MKP-1 overexpressing cells (Fig. 7B). These data provide further evidence that MKP-1 is essential for macrophages to maintain autophagy, resist cytotoxic stress induced by oxysterols and to properly respond to both pro-inflammatory as well as inflammation-resolving signals.


Monocytic MKP-1 is a Sensor of the Metabolic Environment and Regulates Function and Phenotypic Fate of Monocyte-Derived Macrophages in Atherosclerosis
Overexpression of MKP-1 protects macrophages against impaired autophagy, and accelerated cell death.Bone marrow-derived macrophages were infected with lentiviral vectors carrying either Flag-tagged MKP-1 or GFP. Cells were then treated for 24 hours with vehicle or primed with LDL + HG, and p62 protein levels (A), Caspase-3/7 activities (B Results are shown as mean ± SE (n = 3–4).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC5037453&req=5

f6: Overexpression of MKP-1 protects macrophages against impaired autophagy, and accelerated cell death.Bone marrow-derived macrophages were infected with lentiviral vectors carrying either Flag-tagged MKP-1 or GFP. Cells were then treated for 24 hours with vehicle or primed with LDL + HG, and p62 protein levels (A), Caspase-3/7 activities (B Results are shown as mean ± SE (n = 3–4).
Mentions: Metabolic stress promotes MKP-1 inactivation and degradation, and metabolically primed macrophages show all the phenotypic and functional hallmarks of macrophages with genetic MKP-1 deficiency. We therefore determined whether overexpression of MKP-1 protects metabolically stressed macrophages against defective autophagy, sensitization to oxysterol-induced cell death, and skewed M1/M2 polarization. To this end, we used a lentivirus-based transduction system to overexpress Flag-tagged MKP-1 (or green fluorescent protein, GFP) in bone marrow-derived macrophages. In contrast to GFP-expressing control macrophages, macrophages expressing Flag-MKP-1 were resistant to metabolic stress and showed no defects in autophagy (Fig. 6A) or any increased sensitivity to oxysterol-induced activation of caspase 3/7 (Fig. 6B). Furthermore, STAT1 phosphorylation induced by metabolic priming was suppressed in macrophages overexpressing MKP-1 (Fig. 7A) and the skewing of the polarization profile was prevented in MKP-1 overexpressing cells (Fig. 7B). These data provide further evidence that MKP-1 is essential for macrophages to maintain autophagy, resist cytotoxic stress induced by oxysterols and to properly respond to both pro-inflammatory as well as inflammation-resolving signals.

View Article: PubMed Central - PubMed

ABSTRACT

Diabetes promotes the S-glutathionylation, inactivation and subsequent degradation of mitogen-activated protein kinase phosphatase 1 (MKP-1) in blood monocytes, and hematopoietic MKP-1-deficiency in atherosclerosis-prone mice accelerates atherosclerotic lesion formation, but the underlying mechanisms were not known. Our aim was to determine the mechanisms through which MKP-1 deficiency in monocytes and macrophages promotes atherogenesis. Transplantation of MKP-1-deficient bone marrow into LDL-R−/− (MKP-1LeuKO) mice accelerated high-fat diet (HFD)-induced atherosclerotic lesion formation. After 12 weeks of HFD feeding, MKP-1LeuKO mice showed increased lesion size in both the aortic root (1.2-fold) and the aorta (1.6-fold), despite reduced plasma cholesterol levels. Macrophage content was increased in lesions of MKP-1LeuKO mice compared to mice that received wildtype bone marrow. After only 6 weeks on a HFD, in vivo chemotactic activity of monocytes was already significantly increased in MKP-1LeuKO mice. MKP-1 deficiency in monocytes and macrophages promotes and accelerates atherosclerotic lesion formation by hyper-sensitizing monocytes to chemokine-induced recruitment, predisposing macrophages to M1 polarization, decreased autophagy and oxysterol-induced cell death whereas overexpression of MKP-1 protects macrophages against metabolic stress-induced dysfunction. MKP-1 serves as a master-regulator of macrophage phenotype and function and its dysregulation by metabolic stress may be a major contributor to atherogenesis and the progression of atherosclerotic plaques.

No MeSH data available.