Nicotinic acetylcholine receptor alpha 7 stimulation dampens splenic myelopoiesis and inhibits atherogenesis in Apoe −/− mice

Al-Sharea, Annas; Lee, Man K.S.; Whillas, Alexandra; Flynn, Michelle; Chin-Dusting, Jaye; Murphy, Andrew

doi:10.1016/j.atherosclerosis.2017.08.010

Cited by 19 publications

(17 citation statements)

References 24 publications

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“…These events are necessary for the survival of the host, as inflammation is important for clearing invading pathogens and repairing damaged tissues (2). On the other hand, excessive inflammation can lead to detrimental effects, resulting in further damage to tissues, and the development of chronic inflammatory diseases such as atherosclerosis and other auto-inflammatory disorders (3–5). Therefore, understanding the underlying mechanisms that regulate monocyte adhesion can provide information on how to manipulate the cell's ability to adhere during acute or chronic inflammation.…”

Section: Introductionmentioning

confidence: 99%

Glycolysis Is Required for LPS-Induced Activation and Adhesion of Human CD14+CD16− Monocytes

et al. 2019

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Monocytes in humans consist of 3 subsets; CD14+CD16− (classical), CD14+CD16+ (intermediate) and CD14dimCD16+ (non-classical), which exhibit distinct and heterogeneous responses to activation. During acute inflammation CD14+CD16− monocytes are significantly elevated and migrate to the sites of injury via the adhesion cascade. The field of immunometabolism has begun to elucidate the importance of the engagement of specific metabolic pathways in immune cell function. Yet, little is known about monocyte metabolism and the role of metabolism in mediating monocyte activation and adherence to vessels. Accordingly, we aimed to determine whether manipulating the metabolism of CD14+CD16− monocytes alters their ability to become activated and adhere. We discovered that LPS stimulation increased the rate of glycolysis in human CD14+CD16− monocytes. Inhibition of glycolysis with 2-deoxy-D-glucose blunted LPS-induced activation and adhesion of monocytes. Mechanistically, we found that increased glycolysis was regulated by mTOR-induced glucose transporter (GLUT)-1. Furthermore, enhanced glycolysis increased accumulation of reactive oxygen species (ROS) and activation of p38 MAPK, which lead to activation and adhesion of monocytes. These findings reveal that glycolytic metabolism is critical for the activation of CD14+CD16− monocytes and contributes to our understanding of the interplay between metabolic substrate preference and immune cell function.

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Section: Introductionmentioning

confidence: 99%

Glycolysis Is Required for LPS-Induced Activation and Adhesion of Human CD14+CD16− Monocytes

et al. 2019

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“…Al‐Sharea et al . recently reported that another selective α7nAChR agonist GTS‐21 caused a reduction in atherosclerosis in the aortic arch and proximal aorta in ApoE −/− atherosclerotic mice fed a Western‐type diet (Al‐Sharea et al, ). In support of this finding, a group from Japan reported that stimulation of α7nAchRs by AR‐R17779 suppresses atherosclerosis and aortic aneurysm formation in ApoE −/− atherosclerotic mice (Hashimoto et al, ).…”

Section: Discussionmentioning

confidence: 99%

Nicotinic ACh receptor α7 inhibits PDGF‐induced migration of vascular smooth muscle cells by activating mitochondrial deacetylase sirtuin 3

Tong

Zeng

et al. 2018

British J Pharmacology

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Background and Purpose PDGF‐BB is an angiogenic factor involved in cardiovascular diseases. Here, we investigated the possible effects of activation of the nicotinic ACh receptor α7 subtype (α7nAChR) on PDGF‐BB‐induced proliferation and migration in vascular smooth muscle cells (VSMCs). Experimental Approach PNU‐282987, a selective α7nAChR pharmacological agonist, was used to activate α7nAChR. The influences of α7nAChR activation on PDGF‐BB‐induced proliferation and migration, as well as the phosphorylation of focal adhesion kinase (FAK)/Src, a pro‐migration signalling pathway, were determined in VSMCs. A variety of biochemical assays were applied to explore the underlying molecular mechanisms. Key Results PDGF‐BB induced pronounced migration and proliferation of VSMCs. Activation of α7nAChRs by PNU‐282987 blocked PDGF‐BB‐induced migration but not proliferation in wild‐type (WT) VSMCs, whereas this effect was absent in α7nAChR‐knockout VSMCs. Accordingly, PNU‐282987 attenuated PDGF‐BB‐induced phosphorylation of FAKTyr397 and SrcTyr416 in WT VSMCs. Mechanistically, PNU‐282987 suppressed PDGF‐BB‐induced oxidative stress, as demonstrated by the alterations in ROS, H2O2 content, superoxide anion and total antioxidant activity. A sirtuin 3 (SIRT3) inhibitor 3‐(1H‐1,2,3‐triazol‐4‐yl) pyridine or shRNA‐mediated SIRT3 knockdown abolished the inhibitory effect of PNU‐282987. PNU‐282987 did not modulate SIRT3 protein expression but enhanced mitochondrial SIRT3 deacetylase activity. In line with this action, PNU‐282987 enhanced the deacetylation of mitochondrial FoxO3. Lastly, PNU‐282987 corrected the PDGF‐BB‐induced mitochondrial dysfunction by increasing mitochondrial citrate synthase activity, ATP content and nicotinamide adenine dinucleotide pool. Conclusions Pharmacological activation of α7nAChRs inhibits PDGF‐BB‐induced VSMC migration by activating the mitochondrial deacetylase SIRT3, implying an important role for α7nAChRs in mitochondria biology and PDGF‐related diseases. Linked Articles This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc

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“…It has been shown that extramedullary production of CD11b + cells continues for at least 24 days after challenge (33). Conversely, therapeutic stimulation of the nicotinic acetylcholine receptor alpha 7 reduces splenic monocyte mobilization and antagonizes atherogenesis (49).…”

Section: Establishment Of Hspcs In Hematopoietic Sitesmentioning

confidence: 99%

Contribution of Extramedullary Hematopoiesis to Atherosclerosis. The Spleen as a Neglected Hub of Inflammatory Cells

et al. 2020

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Cardiovascular diseases (CVDs) incidence is becoming higher. This fact is promoted by metabolic disorders such as obesity, and aging. Atherosclerosis is the underlying cause of most of these pathologies. It is a chronic inflammatory disease that begins with the progressive accumulation of lipids and fibrotic materials in the blood-vessel wall, which leads to massive leukocyte recruitment. Rupture of the fibrous cap of the atherogenic cusps is responsible for tissue ischemic events, among them myocardial infarction. Extramedullary hematopoiesis (EMH), or blood cell production outside the bone marrow (BM), occurs when the normal production of these cells is impaired (chronic hematological and genetic disorders, leukemia, etc.) or is altered by metabolic disorders, such as hypercholesterolemia, or after myocardial infarction. Recent studies indicate that the main EMH tissues (spleen, liver, adipose and lymph nodes) complement the hematopoietic function of the BM, producing circulating inflammatory cells that infiltrate into the atheroma. Indeed, the spleen, which is a secondary lymphopoietic organ with high metabolic activity, contains a reservoir of myeloid progenitors and monocytes, constituting an important source of inflammatory cells to the atherosclerotic lesion. Furthermore, the spleen also plays an important role in lipid homeostasis and immunecell selection. Interestingly, clinical evidence from splenectomized subjects shows that they are more susceptible to developing pathologies, such as dyslipidemia and atherosclerosis due to the loss of immune selection. Although CVDs represent the leading cause of death worldwide, the mechanisms involving the spleenatherosclerosis-heart axis cross-talk remain poorly characterized.

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Nicotinic acetylcholine receptor alpha 7 stimulation dampens splenic myelopoiesis and inhibits atherogenesis in Apoe −/− mice

Cited by 19 publications

References 24 publications

Glycolysis Is Required for LPS-Induced Activation and Adhesion of Human CD14+CD16− Monocytes

Glycolysis Is Required for LPS-Induced Activation and Adhesion of Human CD14+CD16− Monocytes

Nicotinic ACh receptor α7 inhibits PDGF‐induced migration of vascular smooth muscle cells by activating mitochondrial deacetylase sirtuin 3

Contribution of Extramedullary Hematopoiesis to Atherosclerosis. The Spleen as a Neglected Hub of Inflammatory Cells

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