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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.


Both MKP-1-deficient and metabolically primed macrophages exhibit defective autophagy.(A+B) Autophagic activity was assessed by Western blot analysis as the ratio of LC3-II to LC3-I and p62/SQSTM1 levels in peritoneal macrophages isolated wildtype (WT) and from MKP-1−/− (KO) mice and (C+D) in unprimed (Control) and metabolically primed (LDL + HG) peritoneal macrophages. Results shown are mean ± SE of 3 independent experiments.
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f2: Both MKP-1-deficient and metabolically primed macrophages exhibit defective autophagy.(A+B) Autophagic activity was assessed by Western blot analysis as the ratio of LC3-II to LC3-I and p62/SQSTM1 levels in peritoneal macrophages isolated wildtype (WT) and from MKP-1−/− (KO) mice and (C+D) in unprimed (Control) and metabolically primed (LDL + HG) peritoneal macrophages. Results shown are mean ± SE of 3 independent experiments.

Mentions: Autophagy is one of the cell’s survival responses to the stress, and protects macrophages in the plaque by degrading damaged, potentially noxious and proinflammatory material formed within the cells2021. Autophagy is regulated by MAPK-dependent pathways11222324. MAPKs are counter-regulated by MKPs, including MKP-115. We therefore examined whether MKP-1 deficiency impairs macrophage autophagy. To this end, we isolated peritoneal macrophages from wildtype and MKP-1−/− mice, and assessed the ratio of light chain 3 (LC3)-II to LC3-I levels as measures of autophagic flux25 and p62/ sequestosome 1 (SQSTM1) as an indicator of flux impairment26, respectively. As a positive control of the LC3-II to LC3-I ratio shift, peritoneal macrophages were treated with mechanistic target of rapamycin (mTOR) inhibitor (Suppl. Fig. 4). The ratio of LC3-II to LC3-I was decreased by 29% and p62/SQSTM1 levels were increased by 86% in MKP-1-deficient macrophages (Fig. 2A+B), confirming that MKP-1 activity is critical for the maintenance of macrophage autophagy.


Monocytic MKP-1 is a Sensor of the Metabolic Environment and Regulates Function and Phenotypic Fate of Monocyte-Derived Macrophages in Atherosclerosis
Both MKP-1-deficient and metabolically primed macrophages exhibit defective autophagy.(A+B) Autophagic activity was assessed by Western blot analysis as the ratio of LC3-II to LC3-I and p62/SQSTM1 levels in peritoneal macrophages isolated wildtype (WT) and from MKP-1−/− (KO) mice and (C+D) in unprimed (Control) and metabolically primed (LDL + HG) peritoneal macrophages. Results shown are mean ± SE of 3 independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f2: Both MKP-1-deficient and metabolically primed macrophages exhibit defective autophagy.(A+B) Autophagic activity was assessed by Western blot analysis as the ratio of LC3-II to LC3-I and p62/SQSTM1 levels in peritoneal macrophages isolated wildtype (WT) and from MKP-1−/− (KO) mice and (C+D) in unprimed (Control) and metabolically primed (LDL + HG) peritoneal macrophages. Results shown are mean ± SE of 3 independent experiments.
Mentions: Autophagy is one of the cell’s survival responses to the stress, and protects macrophages in the plaque by degrading damaged, potentially noxious and proinflammatory material formed within the cells2021. Autophagy is regulated by MAPK-dependent pathways11222324. MAPKs are counter-regulated by MKPs, including MKP-115. We therefore examined whether MKP-1 deficiency impairs macrophage autophagy. To this end, we isolated peritoneal macrophages from wildtype and MKP-1−/− mice, and assessed the ratio of light chain 3 (LC3)-II to LC3-I levels as measures of autophagic flux25 and p62/ sequestosome 1 (SQSTM1) as an indicator of flux impairment26, respectively. As a positive control of the LC3-II to LC3-I ratio shift, peritoneal macrophages were treated with mechanistic target of rapamycin (mTOR) inhibitor (Suppl. Fig. 4). The ratio of LC3-II to LC3-I was decreased by 29% and p62/SQSTM1 levels were increased by 86% in MKP-1-deficient macrophages (Fig. 2A+B), confirming that MKP-1 activity is critical for the maintenance of macrophage autophagy.

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.