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.
Highlights
Macrophage numbers and functionalities within atherosclerotic lesions and their removal from plaques are controlled by four key processes: recruitment, autophagy, apoptosis, and macrophage polarization
Both groups of mice showed small atherosclerotic lesions in both the aortic arch and the descending aorta (Fig. 1A+B), but we did not detect a significant difference in lesion size between the two groups. These findings suggest that monocyte priming and dysfunction induced by mitogenactivated protein kinase phosphatase 1 (MKP-1) deficiency precedes the formation of atherosclerotic lesions
We hypothesized that dysregulation and loss of MAPK phosphatases (MKPs)-1 activity in blood monocytes induced by metabolic disorders may have profound effects on macrophages derived from these monocytes, which are recruited to sites of tissue injury and may affect macrophage functions associated with both inflammatory as well as inflammation resolving processes
Summary
Macrophage numbers and functionalities within atherosclerotic lesions and their removal from plaques are controlled by four key processes: recruitment, autophagy, apoptosis, and macrophage polarization. Macrophage chemotaxis[4], autophagy[11], apoptosis[12,13], and polarization[14] are mediated by mitogen-activated protein kinase (MAPK) pathways, which in turn are counter-regulated by MAPK phosphatases (MKPs)[15]. We recently identified MKP-1 as a critical regulator of monocyte adhesion and migration which, when inactivated and degraded in response to metabolic stress, promotes macrophage recruitment and accumulation in early atherosclerotic lesions[4]. In addition to promoting macrophage recruitment and accumulation, MKP-1 deficiency in monocytes and macrophages accelerates atherogenesis and lesion progression by impairing macrophage autophagy, enhancing apoptosis, and by dysregulating macrophage polarization whereas overexpression of MKP-1 protects macrophages against metabolic stress-induced dysfunction. Our findings identified MKP-1 as a master regulator of macrophage function and fate
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