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

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.

Mitogen-activated protein kinase phosphatase 1 (MKP-1) in macrophage biology and cardiovascular disease. A redox-regulated master controller of monocyte function and macrophage phenotype

“…More recently, it was reported that histone H3 also interacts with and is dephosphorylated by MKP-1 to mediate epigenetic regulation on vascular endothelial growth factor (VEGF)-induced gene transcription [66]. In agreement with this report, we found that histone H3 phosphorylation (Ser10) was increased in the MKP-1-deficient macrophage exposed to metabolic stress [21], making H3 the only known bona fide non-MAPK substrate candidate for MKP-1.…”

“…Compared with wild-type mice, MKP-1–deficient mice produced substantially greater amounts of TNF, IL-1β, CC-chemokine ligand 2 (CCL2; also known as MCP1), granulocyte/macrophage colony-stimulating factor (GM-CSF), IL-6, IL-10 and IL-12p70 and showed a considerably higher incidence of multi-organ failure and mortality after LPS challenge in vivo compared with wild-type mice [25, 121, 122]. These findings are consistent with our report mentioned above that MKP-1 deficiency induced by metabolic stress predisposing macrophages to a hyper-inflammatory M1-like polarization state [21]. …”

“…However, it continues to be broadly utilized to characterize in vivo macrophage phenotypes [117]. We reported that MKP-1 deficient macrophages exhibit severally skewed activation profiles, demonstrating an exaggerated pro-inflammatory “M1-like” phenotype in response to INFγ+TNFα and a severely suppressed “M2-like” inflammation resolving phenotype after IL-4 stimulation [21]. …”

“…However, our understanding of the specific roles of these MKPs in monocyte and macrophages is still very limited. Recent evidence from our group and others suggests that MKP-1 is a central regulator of monocyte and macrophage activation, function and phenotypic fate, and loss of MKP-1 activity in these cells may play an important role in dysregulated inflammatory responses and the onset and development of metabolic and chronic inflammatory diseases, including atherosclerosis [21–25]. The focus of this review will therefore be on MKP-1 and its role in monocyte and macrophage biology in the context of cardiovascular disease.…”

Liver Kinase B1 Links Macrophage Metabolism Sensing and Atherosclerosis

“…In some cases, exposure of macrophages to increased nutrients increase their inflammatory activation 9–11 . Thus, the nutritional state of the cell governs activation of the LKB1/AMPK pathway (in states of nutrient deprivation) and inflammatory activation in response to LPS and other inflammatory mediators (in states of nutrient plenty).…”