Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway

Jonge, Wouter J. de; Zanden, Esmerij P. van der; The, Frans O.; Bijlsma, Maarten F.; Westerloo, David J. van; Bennink, Roelof J.; Berthoud, Hans‐Rudolf; Uematsu, Satoshi; Akira, Shizuo; Wijngaard, René M. van den; Boeckxstaens, Guy E.

doi:10.1038/ni1229

Cited by 959 publications

(970 citation statements)

References 34 publications

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“…Because antigen presentation is a critical step in the generation of autoimmune responses, the failure of IL-10 in modulating this process might predispose to the generation of an autoimmune response. In addition, Stat-3 phosphorylation in macrophages is induced after vagus nerve stimulation through acetylcholine receptor signaling [32]. Thus, the impairment in the neuromodulatory activity of the parasympathic system in patients with MS [33,34] might prevent the activation of the IL-10 pathway in patients with MS.…”

Section: Discussionmentioning

confidence: 99%

IL‐10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis

et al. 2008

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T regulatory cells type 1 (Tr1 cells) are excellent candidates for cell therapy in multiple sclerosis (MS). The aim of our study was to assess the functional state of Tr1 cells and IL-10R signaling in patients with MS. Tr1 cells were induced in vitro by activation with anti-CD46 antibodies in controls and patients with MS. Cells were phenotyped by cytometry and suppression assays, and the expression of cytokines and transcription factors was evaluated by real-time PCR, ELISA, cytometry and Western blotting. We found that the activity of Tr1 cells and IL-10R signaling is impaired in MS patients since Tr1 cells isolated from MS patients produced less IL-10 than those obtained from controls. Indeed, the supernatants from Tr1 cells from controls did not suppress the proliferation of stimulated CD4 + cells from patients with MS. Furthermore, the IL-10R signaling pathway was not fully active in CD4 + cells from MS patients and these cells had higher baseline levels of SOCS3 transcripts than controls. Indeed, after in vitro IL-10 stimulation, the expression levels of the STAT1, STAT3 and IL-10RA genes were higher in MS patients than in controls. Moreover, Stat-3 phosphorylation was lower in controls than in patients after IL-10 stimulation. These results indicate that IL-10 regulatory function is impaired in patients with MS.

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Section: Discussionmentioning

confidence: 99%

IL‐10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis

et al. 2008

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“…10,14 The a7nAChR can be considered to be a peripheral 'immune' component of the cholinergic anti-inflammatory pathway. 18,19 Molecular mechanisms supporting these anti-inflammatory effects include nuclear factor kappa B pathway inhibition, 20 activation of Janus activated kinase --signal transducer and activator of transcription 21 and the consequent inhibition of TNFa production. 22 A functional role of nicotinic acetylcholine receptors (nAChRs) has already been demonstrated in rat adipocytes.…”

Section: Discussionmentioning

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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“…Since several articles recently described an immuno-regulatory role of nicotine, [25][26][27] we tested if nicotine might influence OPN-production by alveolar macrophages. Therefore, we stimulated BAL-cells from healthy, currently smoking and nonsmoking individuals with nicotine.…”

Section: Discussionmentioning

confidence: 99%

Essential Role of Osteopontin in Smoking-Related Interstitial Lung Diseases

Prasse

Stahl

Schulz

et al. 2009

The American Journal of Pathology

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Smoking-related interstitial lung diseases are characterized by the accumulation of macrophages and Langerhans cells, and fibrotic remodeling, which are linked to osteopontin (OPN) expression. Therefore, OPN levels were investigated in bronchoalveolar lavage (BAL) cells in 11 patients with pulmonary Langerhans cell histiocytosis (PLCH), 15 patients with desquamative interstitial pneumonitis (DIP), 10 patients with idiopathic pulmonary fibrosis, 5 patients with sarcoidosis, 13 otherwise healthy smokers, and 19 non-smoking controls. Furthermore, OPN overexpression was examined in rat lungs using adenoviral gene transfer. We found that BAL cells from patients with either PLCH or DIP spontaneously produced abundant amounts of OPN. BAL cells from healthy smokers produced 15-fold less OPN, and those cells from non-smoking healthy volunteers produced no OPN. BAL cells from patients with either idiopathic pulmonary fibrosis or sarcoidosis produced significantly less OPN, as compared with patients with PLCH. These data were confirmed by immunochemistry. Nicotine stimulation increased production of both OPN and granulocyte-macrophage colony stimulating factor by alveolar macrophages from smokers. Nicotinic acetylcholine receptor expression resembled the pattern of spontaneous OPN production and was dramatically increased in both PLCH and

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Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway

Cited by 959 publications

References 34 publications

IL‐10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis

IL‐10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis

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

Essential Role of Osteopontin in Smoking-Related Interstitial Lung Diseases

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