Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Pavlov, Valentin A.; Ochani, Mahendar; Gallowitsch-Puerta, Margot; Ochani, Kanta; Huston, Jared M.; Czura, Christopher J.; Al‐Abed, Yousef; Tracey, Kevin J.

doi:10.1073/pnas.0600506103

Cited by 297 publications

(234 citation statements)

References 34 publications

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“…Choline generated in this mode may act to prolong α7nAChR activation selectively (36). While indicating a critical anti-inflammatory role for choline as an α7nAChR agonist, we cannot entirely exclude the contribution of other effects of choline to its anti-inflammatory activity in vivo, including the stimulation of cholinergic signaling in the central nervous system (CNS), which has been shown recently to play a role in controlling inflammation during endotoxemia (37). However, it is possible that these alternative pathways also culminate in α7nAChR-mediated signaling.…”

Section: Discussionmentioning

confidence: 90%

Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling

Parrish

Rosas-Ballina

Gallowitsch-Puerta

et al. 2008

Mol Med

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289

205

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The α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR) is an essential component in the vagus nerve-based cholinergic anti-inflammatory pathway that regulates the levels of TNF, high mobility group box 1 (HMGB1), and other cytokines during inflammation. Choline is an essential nutrient, a cell membrane constituent, a precursor in the biosynthesis of acetylcholine, and a selective natural α7nAChR agonist. Here, we studied the anti-inflammatory potential of choline in murine endotoxemia and sepsis, and the role of the α7nAChR in mediating the suppressive effect of choline on TNF release. Choline (0.1-50 mM) dosedependently suppressed TNF release from endotoxin-activated RAW macrophage-like cells, and this effect was associated with significant inhibition of NF-κB activation. Choline (50 mg/kg, intraperitoneally [i.p.]) treatment prior to endotoxin administration in mice significantly reduced systemic TNF levels. In contrast to its TNF suppressive effect in wild type mice, choline (50 mg/kg, i.p.) failed to inhibit systemic TNF levels in α7nAChR knockout mice during endotoxemia. Choline also failed to suppress TNF release from endotoxin-activated peritoneal macrophages isolated from α7nAChR knockout mice. Choline treatment prior to endotoxin resulted in a significantly improved survival rate as compared with saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo, and choline treatment initiated 24 h after cecal ligation and puncture (CLP)-induced polymicrobial sepsis significantly improved survival in mice. In addition, choline suppressed TNF release from endotoxin-activated human whole blood and macrophages. Collectively, these data characterize the anti-inflammatory efficacy of choline and demonstrate that the modulation of TNF release by choline requires α7nAChR-mediated signaling.

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Section: Discussionmentioning

confidence: 90%

Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling

Parrish

Rosas-Ballina

Gallowitsch-Puerta

et al. 2008

Mol Med

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289

205

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“…7,9 --11 Nicotinic receptors, most concentrated in the nervous system, but also found throughout the body, are the mediators of this 'cholinergic anti-inflammatory pathway'. 12 The a7-subtype acetylcholine cholinergic receptor (a7nAChR) is involved in cognitive processes 10,13 and is present in circulating macrophages and immune cells, where it regulates the release of inflammatory cytokines such as tumor necrosis factor alpha (TNFa), interleukin-1 (IL1) and IL18. 10 In rat adipocytes, longterm stimulation of a7nAChR has been shown to improve insulin sensitivity by modulating adipokine secretion, 14 and in a mouse model of diabetes, a specific a7nAChR agonist was shown to reduce body weight and improve metabolic parameters.…”

Section: Introductionmentioning

confidence: 99%

The nicotinic acetylcholine receptor α7 in subcutaneous mature adipocytes: downregulation in human obesity and modulation by diet-induced weight loss

et al. 2012

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BACKGROUND: It is known that cholinergic anti-inflammatory reflex regulates inflammation in peripheral tissues. Nicotinic acetylcholine receptors (nAChRs) are mediators of this anti-inflammatory pathway and also non-neuronal cells express functional nAChrs. A role for a7-subtype acetylcholine cholinergic receptor (a7nAChR) in insulin sensitivity improvement has already been shown in rodents both in vivo and in vitro. However, no data are available on a7nAChR expression in human adipocytes. OBJECTIVE: To investigate the expression and protein content of a7nAChR in human subcutaneous adipose tissue (SAT) and in isolated mature adipocytes. DESIGN: A total of 39 SAT biopsy specimens obtained from obese and normal-weight subjects were used to assess a7nAChR messenger RNA levels and to stimulate a7nAChR with a specific agonist and antagonist in vitro. Additional SATs from eight non-diabetic obese subjects were also studied, before and after a 3-month lifestyle intervention. RESULTS: a7nAChR expression was significantly lower in the SAT of obese subjects compared with that of normal-weight subjects. In mature adipocytes isolated from morbidly obese subjects (body mass index440 kg m À2 ), a7nAChR expression was 75% lower compared with adipocytes from normal-weight subjects. In adipocytes of obese subjects, a7nAChR was downregulated also at protein level. In eight non-diabetic obese subjects, a lifestyle intervention (3 months of diet and physical activity) induced a significant weight loss and an increase in a7nAChR SAT expression. In vitro stimulation of adipocytes with the specific a7nAChR agonist PNU282987 induced a significant anti-inflammatory effect. Furthermore, a similar downregulation of the inflammatory profile, associated with a significant increase in a7nAChR protein level, was observed after genistein stimulation. CONCLUSIONS: These results provide evidence that a7nAChR expression levels are significantly decreased in obese subjects, and that this receptor modulates inflammatory gene expression in human adipocytes. The upregulation of a7nAChR by genistein stimulation opens new insights for the management of low-grade inflammation linked to human obesity.

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“…We have described the ''cholinergic antiinflammatory pathway'' as a neural mechanism in which the efferent vagus nerve regulates systemic cytokine levels through a nicotinic acetylcholine receptor containing the ␣7 subunit (2)(3)(4). This pathway is controlled by brain muscarinic networks that depend on an intact vagus nerve to attenuate systemic cytokine production (5). Activation of the cholinergic antiinflammatory pathway, either by electrical stimulation of the vagus nerve or through pharmacological approaches, has been shown to significantly ameliorate cytokine-mediated disease models, including endotoxemia (2,6), sepsis (6,7), colitis (8), pancreatitis (9), and ischemia reperfusion (10,11).…”

mentioning

confidence: 99%

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia

Rosas-Ballina¹,

Ochani²,

Parrish³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The autonomic nervous system maintains homeostasis through its sympathetic and parasympathetic divisions. During infection, cells of the immune system release cytokines and other mediators that cause fever, hypotension, and tissue injury. Although the effect of cytokines on the nervous system has been known for decades, only recently has it become evident that the autonomic nervous system, in turn, regulates cytokine production through neural pathways. We have previously shown that efferent vagus nerve signals regulate cytokine production through the nicotinic acetylcholine receptor subunit ␣7, a mechanism termed ''the cholinergic antiinflammatory pathway.'' Here, we show that vagus nerve stimulation during endotoxemia specifically attenuates TNF production by spleen macrophages in the red pulp and the marginal zone. Administration of nicotine, a pharmacological agonist of ␣7, attenuated TNF immunoreactivity in these specific macrophage subpopulations. Synaptophysin-positive nerve endings were observed in close apposition to red pulp macrophages, but they do not express choline acetyltransferase or vesicular acetylcholine transporter. Surgical ablation of the splenic nerve and catecholamine depletion by reserpine indicate that these nerves are catecholaminergic and are required for functional inhibition of TNF production by vagus nerve stimulation. Thus, the cholinergic antiinflammatory pathway regulates TNF production in discrete macrophage populations via two serially connected neurons: one preganglionic, originating in the dorsal motor nucleus of the vagus nerve, and the second postganglionic, originating in the celiacsuperior mesenteric plexus, and projecting in the splenic nerve.brain ͉ cytokine ͉ innate ͉ spleen ͉ vagus T he autonomic nervous system is divided into two major branches based on anatomy and function. These divisions, sympathetic and parasympathetic, control organ function through a set of two serially connected neurons, the first of which is located in the CNS and the second in the peripheral ganglia. Typically, parasympathetic neurons originate in the brainstem medulla and sacral portion of the spinal cord, and the ganglia are located close to or within the innervated organ. Sympathetic neurons originate in the thoracic and lumbar portion of the spinal cord, and the ganglia are situated close to the spinal cord.

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Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia

Cited by 297 publications

References 34 publications

Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling

Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling

The nicotinic acetylcholine receptor α7 in subcutaneous mature adipocytes: downregulation in human obesity and modulation by diet-induced weight loss

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia

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