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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

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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.


Loss of MKP-1 activity impairs macrophage autophagy in atherosclerotic lesions.(A+B) Autophagy in the atherosclerotic aortic roots of mice that received either wildtype or MKP-1−/− bone marrow and were fed a high-fat diet for 12 weeks was assessed by immunofluorescence. The autophagy marker p62/SQSTM1 (red) was concurrently imaged with CD68 (green). Experiments were performed using 5 mice per experimental group. Results shown are mean ± SE.
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f3: Loss of MKP-1 activity impairs macrophage autophagy in atherosclerotic lesions.(A+B) Autophagy in the atherosclerotic aortic roots of mice that received either wildtype or MKP-1−/− bone marrow and were fed a high-fat diet for 12 weeks was assessed by immunofluorescence. The autophagy marker p62/SQSTM1 (red) was concurrently imaged with CD68 (green). Experiments were performed using 5 mice per experimental group. Results shown are mean ± SE.

Mentions: This mechanistic link between metabolic priming of blood monocytes, loss of MKP-1 activity and impaired macrophage autophagy is further supported by immunofluorescence data we obtained in atherosclerotic lesions from chimeric LDL-R−/− mice that received either wildtype or MKP-1-deficient bone marrow. We found a 49% increase in p62 levels in macrophages in atherosclerotic lesions of LDL-R−/− mice with hematopoietic MKP-1 deficiency compared to mice with MKP-1-expressing macrophages (Fig. 3A+B). This finding confirms our in vitro data and strongly suggests that loss of MKP-1 activity impairs macrophage autophagy in atherosclerotic lesions.


Monocytic MKP-1 is a Sensor of the Metabolic Environment and Regulates Function and Phenotypic Fate of Monocyte-Derived Macrophages in Atherosclerosis
Loss of MKP-1 activity impairs macrophage autophagy in atherosclerotic lesions.(A+B) Autophagy in the atherosclerotic aortic roots of mice that received either wildtype or MKP-1−/− bone marrow and were fed a high-fat diet for 12 weeks was assessed by immunofluorescence. The autophagy marker p62/SQSTM1 (red) was concurrently imaged with CD68 (green). Experiments were performed using 5 mice per experimental group. Results shown are mean ± SE.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037453&req=5

f3: Loss of MKP-1 activity impairs macrophage autophagy in atherosclerotic lesions.(A+B) Autophagy in the atherosclerotic aortic roots of mice that received either wildtype or MKP-1−/− bone marrow and were fed a high-fat diet for 12 weeks was assessed by immunofluorescence. The autophagy marker p62/SQSTM1 (red) was concurrently imaged with CD68 (green). Experiments were performed using 5 mice per experimental group. Results shown are mean ± SE.
Mentions: This mechanistic link between metabolic priming of blood monocytes, loss of MKP-1 activity and impaired macrophage autophagy is further supported by immunofluorescence data we obtained in atherosclerotic lesions from chimeric LDL-R−/− mice that received either wildtype or MKP-1-deficient bone marrow. We found a 49% increase in p62 levels in macrophages in atherosclerotic lesions of LDL-R−/− mice with hematopoietic MKP-1 deficiency compared to mice with MKP-1-expressing macrophages (Fig. 3A+B). This finding confirms our in vitro data and strongly suggests that loss of MKP-1 activity impairs macrophage autophagy in atherosclerotic lesions.

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.