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Role of the nicotinic acetylcholine receptor ?3 subtype in vascular inflammation.

ABSTRACT: BACKGROUND AND PURPOSE:Vascular inflammation is a major factor contributing to the development of vascular diseases. The aim of this study was to investigate the role of the nicotinic acetylcholine receptor ?3 subtype (?3-nAChR) in vascular inflammation. EXPERIMENTAL APPROACH:Vascular inflammation was studied in apolipoprotein E knockout (ApoE-/- ) mice fed a high-fat diet. Inflammatory markers were measured in mouse aortic endothelial cells (MAECs) and macrophages after ?3-nAChRs were antagonized pharmacologically, or after the gene of ?3-nAChRs was silenced. KEY RESULTS:Treatment with ?-conotoxin MII (MII; an ?3-nAChR antagonist) increased the number of inflammatory cells infiltrating the aortic walls and further impaired the endothelium-dependent vasodilatations in the aorta of ApoE-/- mice. MII also increased the plasma levels of inflammatory cytokines. Furthermore, the infiltration of classical activated macrophages into the arterial wall of ApoE-/- mice was markedly elevated by MII but that of alternative activated macrophages was reduced. In MAECs, the lipopolysaccharide-stimulated secretion of adhesion molecules and inflammatory cytokines was enhanced by MII, or by silencing the gene of ?3-nAChRs. This effect was reversed by inhibitors of the PI3K-Akt-I?K?/?-I?B?-NF?B pathways. In macrophages, the classical activation was enhanced, but the alternative activation was reduced when the gene of ?3-nACh receptors was silenced. These effects were prevented by inhibitors of the I?K?/?-I?B?-NF?B and JAK2-STAT6-PPAR? pathways respectively. CONCLUSIONS AND IMPLICATIONS:?3-nAChRs play a pivotal role in regulating the inflammatory responses in endothelial cells and macrophages. The mechanisms involve the modulations of multiple cell signalling pathways.

SUBMITTER: Yang C

PROVIDER: S-EPMC5071564 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Role of the nicotinic acetylcholine receptor α3 subtype in vascular inflammation.

Yang Cui C Li Zhengtao Z Yan Saimei S He Yonghui Y Dai Rong R Leung George Pek-Heng GP Pan Shitian S Yang Jinyan J Yan Rong R Du Guanhua G

British journal of pharmacology 20160929 22

<h4>Background and purpose</h4>Vascular inflammation is a major factor contributing to the development of vascular diseases. The aim of this study was to investigate the role of the nicotinic acetylcholine receptor α3 subtype (α3-nAChR) in vascular inflammation.<h4>Experimental approach</h4>Vascular inflammation was studied in apolipoprotein E knockout (ApoE<sup>-/-</sup> ) mice fed a high-fat diet. Inflammatory markers were measured in mouse aortic endothelial cells (MAECs) and macrophages afte ...[more]

PMID: 27572927

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Project description:Inflammatory responses to stimuli are essential body defenses against foreign threats. However, uncontrolled inflammation may result in serious health problems, which can be life-threatening. The ?7 nicotinic acetylcholine receptor, a ligand-gated ion channel expressed in the nervous and immune systems, has an essential role in the control of inflammation. Activation of the macrophage ?7 receptor by acetylcholine, nicotine, or other agonists, selectively inhibits production of pro-inflammatory cytokines while leaving anti-inflammatory cytokines undisturbed. The neural control of this regulation pathway was discovered recently and it was named the cholinergic anti-inflammatory pathway (CAP). When afferent vagus nerve terminals are activated by cytokines or other pro-inflammatory stimuli, the message travels through the afferent vagus nerve, resulting in action potentials traveling down efferent vagus nerve fibers in a process that eventually leads to macrophage ?7 activation by acetylcholine and inhibition of pro-inflammatory cytokines production. The mechanism by which activation of ?7 in macrophages regulates pro-inflammatory responses is subject of intense research, and important insights have thus been made. The results suggest that activation of the macrophage ?7 controls inflammation by inhibiting NF-?B nuclear translocation, and activating the JAK2/STAT3 pathway among other suggested pathways. While the ?7 is well characterized as a ligand-gated ion channel in neurons, whole-cell patch clamp experiments suggest that ?7's ion channel activity, defined as the translocation of ions across the membrane in response to ligands, is absent in leukocytes, and therefore, ion channel activity is generally assumed not to be required for the operation of the CAP. In this perspective, we briefly review macrophage ?7 activation as it relates to the control of inflammation, and broaden the current view by providing single-channel currents as evidence that the ?7 expressed in macrophages retains its ion translocation activity despite the absence of whole-cell currents. Whether this ion-translocating activity is relevant for the proper operation of the CAP or other important physiological processes remains obscure.

Project description:The nicotinic acetylcholine receptor α1 (nAChRα1) was investigated as a potential proinflammatory molecule in the kidney, given a recent report that it is an alternative urokinase plasminogen activator (uPA) receptor, in addition to the classical receptor uPAR. Two animal models and in vitro monocyte studies were involved: (1) In an ApoE(-/-) mouse model of chronic kidney disease, glomerular-resident cells and monocytes/macrophages were identified as the primary cell types that express nAChRα1 during hypercholesterolemia/uninephrectomy-induced nephropathy. Silencing of the nAChRα1 gene for 4 months (6 months on Western diet) prevented the increases in renal monocyte chemoattractant protein-1 and osteopontin expression levels and F4/80+ macrophage infiltration compared with the nonsilenced mice. These changes were associated with significantly reduced transforming growth factor-β1 mRNA (50% decrease) and α smooth muscle actin-positive (αSMA+) myofibroblasts (90% decrease), better glomerular and tubular basement membranes (GBM/TBM) preservation (threefold less disintegration), and better renal function preservation (serum creatinine 40% lower) in the nAChRα1-silenced mice. The nAChRα1 silencing was also associated with significantly reduced renal tissue calcium deposition (78% decrease) and calpain-1 (but not calpain-2) activation (70% decrease). (2) The nAChRα1 was expressed in vitro by mouse monocyte cell line WEHI-274.1. The silencing of nAChRα1 significantly reduced both calpain-1 and -2 activities, and reduced the degradation of the calpain substrate talin. (3) To further explore the role of calpain-1 activity in hypercholesterolemic nephropathy, disease severities were compared in CAST(-/-)ApoE(-/-) (calpain overactive) mice and ApoE(-/-) mice fed with Western diet for 10 months (n=12). Macrophages were the main cell type of renal calpain-1 production in the model. The number of renal F4/80+ macrophages was 10-fold higher in the CAST(-/-)ApoE(-/-) mice (P<0.05), and was associated with a significantly higher level of αSMA+ cells, increased GBM/TBM destruction, and higher serum creatinine levels. Our studies suggest that the receptor nAChRα1 is an important regulator of calpain-1 activation and inflammation in the chronic hypercholesterolemic nephropathy. This new proinflammatory pathway may also be relevant to other disorders beyond hyperlipidemic nephropathy.

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Role of the nicotinic acetylcholine receptor ?3 subtype in vascular inflammation.

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Role of the nicotinic acetylcholine receptor α3 subtype in vascular inflammation.

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