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Reduced size and macrophage content of advanced atherosclerotic lesions in mice with bone marrow specific deficiency of alpha 7 nicotinic acetylcholine receptor.

ABSTRACT: In macrophages the ?7 nicotinic acetylcholine receptor (?7nAChR) modulates production of inflammatory cytokines, cholesterol accumulation and lipoprotein uptake. Recently, our laboratory showed that selective stimulation of the ?7nAChR protects macrophages from apoptosis, an effect that is absent in ?7nAChR-deficient macrophages. All these observations are suggestive of a potential role of macrophage ?7nAChR in atherosclerosis. Mouse models of the disease with bone marrow deletion of ?7nAChR represent an attractive approach to address the in vivo relevance of these in vitro findings. However, recent studies that focused on the impact of hematopoietic deficiency of ?7nAChR on early atherosclerotic lesions of low density lipoprotein receptor knockout (LDLRKO) mice, yielded controversial results. The question also remained whether macrophage ?7nAChR modulates the characteristics of advanced lesions. Here we used LDLR knockout mice transplanted with bone marrow from wild-type or ?7nAChR knockout animals to revisit the effect of hematopoietic deficiency of ?7nAChR on early lesions and to examine, for the first time, its impact on advanced plaques. Aortic sinus atherosclerotic lesions were analyzed following 8 and 14 weeks on a high fat diet. Early lesions in mice with ?7nAChR deficient bone marrow were not different from those in control animals. However, advanced lesions of mice with bone marrow deletion of ?7nAChR exhibited reduction in size, macrophage content and cell proliferation. These studies are the first in examining the impact of hematopoietic deficiency of ?7nAChR on the characteristics of advanced atherosclerotic lesions in a mouse model of the disease and provide novel evidence underscoring a potential pro-atherogenic role of macrophage ?7nAChR.

SUBMITTER: Lee RH

PROVIDER: S-EPMC4380454 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Reduced size and macrophage content of advanced atherosclerotic lesions in mice with bone marrow specific deficiency of alpha 7 nicotinic acetylcholine receptor.

Lee Robert H RH Vazquez Guillermo G

PloS one 20150331 3

In macrophages the α7 nicotinic acetylcholine receptor (α7nAChR) modulates production of inflammatory cytokines, cholesterol accumulation and lipoprotein uptake. Recently, our laboratory showed that selective stimulation of the α7nAChR protects macrophages from apoptosis, an effect that is absent in α7nAChR-deficient macrophages. All these observations are suggestive of a potential role of macrophage α7nAChR in atherosclerosis. Mouse models of the disease with bone marrow deletion of α7nAChR rep ...[more]

PMID: 25826262

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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.

Dataset Information

Reduced size and macrophage content of advanced atherosclerotic lesions in mice with bone marrow specific deficiency of alpha 7 nicotinic acetylcholine receptor.

Publications

Reduced size and macrophage content of advanced atherosclerotic lesions in mice with bone marrow specific deficiency of alpha 7 nicotinic acetylcholine receptor.

Similar Datasets

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