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Annette Bruchfeld - One of the best experts on this subject based on the ideXlab platform.

  • The Cholinergic Anti-Inflammatory Pathway in chronic kidney disease-review and vagus nerve stimulation clinical pilot study.
    Nephrology dialysis transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 2020
    Co-Authors: Marie Hilderman, Annette Bruchfeld
    Abstract:

    Inflammation and autonomic dysfunction are common findings in chronic and end-stage kidney disease and contribute to a markedly increased risk of mortality in this patient population. The Cholinergic Anti-Inflammatory Pathway (CAP) is a vagal neuro-immune circuit that upholds the homoeostatic balance of inflammatory activity in response to cell injury and pathogens. CAP models have been examined in preclinical studies to investigate its significance in a range of clinical inflammatory conditions and diseases. More recently, cervical vagus nerve stimulation (VNS) implants have been shown to be of potential benefit for patients with chronic autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. We have previously shown that dialysis patients have a functional CAP ex vivo. Here we review the field and the potential role of the CAP in acute kidney injury and chronic kidney disease (CKD) as well as in hypertension. We also present a VNS pilot study in haemodialysis patients. Controlling inflammation by neuroimmune modulation may lead to new therapeutic modalities for improved treatment, outcome, prognosis and quality of life for patients with CKD.

  • The Cholinergic Anti-Inflammatory Pathway in chronic kidney disease—review and vagus nerve stimulation clinical pilot study
    Nephrology Dialysis Transplantation, 2020
    Co-Authors: Marie Hilderman, Annette Bruchfeld
    Abstract:

    Abstract Inflammation and autonomic dysfunction are common findings in chronic and end-stage kidney disease and contribute to a markedly increased risk of mortality in this patient population. The Cholinergic Anti-Inflammatory Pathway (CAP) is a vagal neuro-immune circuit that upholds the homoeostatic balance of inflammatory activity in response to cell injury and pathogens. CAP models have been examined in preclinical studies to investigate its significance in a range of clinical inflammatory conditions and diseases. More recently, cervical vagus nerve stimulation (VNS) implants have been shown to be of potential benefit for patients with chronic autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease. We have previously shown that dialysis patients have a functional CAP ex vivo. Here we review the field and the potential role of the CAP in acute kidney injury and chronic kidney disease (CKD) as well as in hypertension. We also present a VNS pilot study in haemodialysis patients. Controlling inflammation by neuroimmune modulation may lead to new therapeutic modalities for improved treatment, outcome, prognosis and quality of life for patients with CKD.

  • The Cholinergic Anti-Inflammatory Pathway in resistant hypertension treated with renal denervation
    Molecular Medicine, 2019
    Co-Authors: Marie Hilderman, Abdul Rashid Qureshi, Farhad Abtahi, Kaj Lindecrantz, Nils Witt, Christina Jägren, Joakim Olbers, Martin Delle, Annette Bruchfeld
    Abstract:

    Background Renal denervation (RDN) reduces sympathetic tone and may alter the sympathetic-parasympathetic balance. The autonomic nervous system is partly a regulator of innate immunity via the Cholinergic Anti-Inflammatory Pathway (CAP) which inhibits inflammation via the vagus nerve. Placental Growth Factor (PlGF) influences a neuro-immunological Pathway in the spleen which may contribute to hypertension. The aim of this study was to investigate if modulation of renal sympathetic nerve activity affects CAP in terms of cytokine release as well as levels of PlGF.

  • Cholinergic Anti-Inflammatory Pathway activity in dialysis patients: a role for neuroimmunomodulation?
    Clinical Kidney Journal, 2015
    Co-Authors: Marie Hilderman, Abdul Rashid Qureshi, Yousef Al-abed, Farhad Abtahi, Kaj Lindecrantz, Björn Anderstam, Annette Bruchfeld
    Abstract:

    BACKGROUND: The Cholinergic Anti-Inflammatory Pathway (CAP) modulates inflammatory responses through the vagus nerve and the α-7-nicotinic acetylcholine receptor (α7nAChR) on macrophages and immune ...

  • Cholinergic Anti-Inflammatory Pathway activity and High Mobility Group Box-1 (HMGB1) serum levels in patients with rheumatoid arthritis.
    Molecular Medicine, 2007
    Co-Authors: Richard S. Goldstein, Margot Gallowitsch-puerta, Abdul Rashid Qureshi, Annette Bruchfeld, Mauricio Rosas-ballina, Sangeeta S. Chavan, Lihong Yang, Nirav Patel, Brett J. Huston, Peter K. Gregersen
    Abstract:

    High Mobility Group Box-1 (HMGB1) is a cytokine implicated in the pathogenesis of rheumatoid arthritis (RA) and other inflammatory diseases. The Cholinergic Anti-Inflammatory Pathway, a vagus nerve-dependent mechanism, inhibits HMGB1 release in experimental disease models. Here, we examine the relationship between vagus nerve activity and HMGB1 in patients with RA. We compared RR interval variability, an index of cardiac vagal modulation, HMGB1 and hsCRP serum levels, and disease activity scores in thirteen RA patients and eleven age- and sex-matched controls. In RA patients, serum levels of HMGB1 and hsCRP were elevated as compared with controls (HMGB1 = 71 ng/mL [45–99] vs. 18 ng/mL [0–40], P < 0.0001; hsCRP = 14.5 mg/L [0.7–59] vs. 1 mg/L [0.4–2.9], P < 0.001). RR interval variability in RA patients was significantly decreased as compared with controls (HF = 38 msec2 [14–80] vs. 288 msec2 [38–364], P < 0.0001; rMSSD = 20.9 ± 9.79 msec, 52.6 ± 35.3 msec, P < 0.01). HMGB1 levels and RR interval variability were significantly related (rho = −0.49, P < 0.01). HMGB1 serum levels significantly correlated with disease activity scores (DAS-28) in patients with RA (P = 0.004). The study design does not enable a determination of causality, but the results are consistent with the hypothesis that decreased Cholinergic Anti-Inflammatory Pathway activity is associated with increased HMGB1 levels in patients with RA.

Didier Clarençon - One of the best experts on this subject based on the ideXlab platform.

  • Vagus nerve stimulation: from epilepsy to the Cholinergic Anti-Inflammatory Pathway.
    Neurogastroenterology & Motility, 2013
    Co-Authors: Bruno Bonaz, Chloé Picq, Valérie Sinniger, Jean-françois Mayol, Didier Clarençon
    Abstract:

    BACKGROUND: The brain and the gut communicate bidirectionally through the autonomic nervous system (ANS). The vagus nerve (VN), a major component of the ANS, plays a key role in the neuro-endocrine-immune axis to maintain homeostasia through its afferents (through the activation of the hypothalamic pituitary adrenal axis and the central ANS) and through its efferents (i.e. the Cholinergic Anti-Inflammatory Pathway; CAP). The CAP has an anti-TNF effect both through the release of acetylcholine at the distal VN acting on macrophages and through the connection of the VN with the spleen through the splenic sympathetic nerve. Vagus nerve stimulation (VNS) of vagal afferents at high frequency (20-30 Hz) is used for the treatment of drug-resistant epilepsy and depression. Low-frequency (5 Hz) VNS of vagal efferents activates the CAP for an Anti-Inflammatory effect that is as an anti-TNF therapy in inflammatory diseases were TNF is a key cytokine as represented by experimental sepsis, postoperative ileus, burn-induced intestinal barrier injury, colitis. However, both vagal afferents and efferents are activated by VNS. PURPOSE: The objective of this review was to explore the following: (i) the supporting evidence for the importance of VNS in epilepsy (and depression) and its mechanisms of action, (ii) the Anti-Inflammatory characteristics of the VN, (iii) the experimental evidence that VNS impact on inflammatory disorders focusing on the digestive tract, and (iv) how VNS could potentially be harnessed therapeutically in human inflammatory disorders such as inflammatory bowel diseases, irritable bowel syndrome, postoperative ileus, rheumatoid arthritis as an Anti-Inflammatory therapy.

Bruno Bonaz - One of the best experts on this subject based on the ideXlab platform.

  • Targeting the Cholinergic Anti-Inflammatory Pathway with vagus nerve stimulation in patients with Covid-19?
    Bioelectronic Medicine, 2020
    Co-Authors: Bruno Bonaz, Valérie Sinniger, Sonia Pellissier
    Abstract:

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), at the origin of the worldwide COVID-19 pandemic, is characterized by a dramatic cytokine storm in some critical patients with COVID-19. This storm is due to the release of high levels of pro-inflammatory cytokines such as interleukin (IL)-1 β, IL-6, tumor necrosis factor (TNF), and chemokines by respiratory epithelial and dendritic cells, and macrophages. We hypothesize that this cytokine storm and the worsening of patients' health status can be dampened or even prevented by specifically targeting the vagal-driven Cholinergic Anti-Inflammatory Pathway (CAP). The CAP is a concept that involves an Anti-Inflammatory effect of vagal efferents by the release of acetylcholine (ACh). Nicotinic acetylcholine receptor alpha7 subunit (α7nAChRs) is required for ACh inhibition of macrophage-TNF release and cytokine modulation. Hence, targeting the α7nAChRs through vagus nerve stimulation (VNS) could be of interest in the management of patients with SARS-CoV-2 infection. Indeed, through the wide innervation of the organism by the vagus nerve, especially the lungs and gastrointestinal tract, VNS appears as a serious candidate for a few side effect treatment that could dampen or prevent the cytokine storm observed in COVID-19 patients with severe symptoms. Finally, a continuous vagal tone monitoring in patients with COVID-19 could be used as a predictive marker of COVID-19 illness course but also as a predictive marker of response to COVID-19 treatment such as VNS or others.

  • Vagus nerve stimulation: from epilepsy to the Cholinergic Anti-Inflammatory Pathway.
    Neurogastroenterology & Motility, 2013
    Co-Authors: Bruno Bonaz, Chloé Picq, Valérie Sinniger, Jean-françois Mayol, Didier Clarençon
    Abstract:

    BACKGROUND: The brain and the gut communicate bidirectionally through the autonomic nervous system (ANS). The vagus nerve (VN), a major component of the ANS, plays a key role in the neuro-endocrine-immune axis to maintain homeostasia through its afferents (through the activation of the hypothalamic pituitary adrenal axis and the central ANS) and through its efferents (i.e. the Cholinergic Anti-Inflammatory Pathway; CAP). The CAP has an anti-TNF effect both through the release of acetylcholine at the distal VN acting on macrophages and through the connection of the VN with the spleen through the splenic sympathetic nerve. Vagus nerve stimulation (VNS) of vagal afferents at high frequency (20-30 Hz) is used for the treatment of drug-resistant epilepsy and depression. Low-frequency (5 Hz) VNS of vagal efferents activates the CAP for an Anti-Inflammatory effect that is as an anti-TNF therapy in inflammatory diseases were TNF is a key cytokine as represented by experimental sepsis, postoperative ileus, burn-induced intestinal barrier injury, colitis. However, both vagal afferents and efferents are activated by VNS. PURPOSE: The objective of this review was to explore the following: (i) the supporting evidence for the importance of VNS in epilepsy (and depression) and its mechanisms of action, (ii) the Anti-Inflammatory characteristics of the VN, (iii) the experimental evidence that VNS impact on inflammatory disorders focusing on the digestive tract, and (iv) how VNS could potentially be harnessed therapeutically in human inflammatory disorders such as inflammatory bowel diseases, irritable bowel syndrome, postoperative ileus, rheumatoid arthritis as an Anti-Inflammatory therapy.

Kevin J. Tracey - One of the best experts on this subject based on the ideXlab platform.

  • The pulse of inflammation: heart rate variability, the Cholinergic anti‐inflammatory Pathway and implications for therapy
    Journal of Internal Medicine, 2010
    Co-Authors: Jared M. Huston, Kevin J. Tracey
    Abstract:

    Biological therapeutics targeting TNF, IL-1 and IL-6 are widely used for treatment of rheumatoid arthritis, inflammatory bowel disease and a growing list of other syndromes, often with remarkable success. Now advances in neuroscience have collided with this therapeutic approach, perhaps rendering possible the development of nerve stimulators to inhibit cytokines. Action potentials transmitted in the vagus nerve culminate in the release of acetylcholine that blocks cytokine production by cells expressing acetylcholine receptors. The molecular mechanism of this Cholinergic Anti-Inflammatory Pathway is attributable to signal transduction by the nicotinic alpha 7 acetylcholine receptor subunit, a regulator of the intracellular signals that control cytokine transcription and translation. Favourable preclinical data support the possibility that nerve stimulators may be added to the future therapeutic armamentarium, possibly replacing some drugs to inhibit cytokines.

  • Brain acetylcholinesterase activity controls systemic cytokine levels through the Cholinergic Anti-Inflammatory Pathway.
    Brain Behavior and Immunity, 2009
    Co-Authors: Valentin A. Pavlov, Yousef Al-abed, William R. Parrish, Mauricio Rosas-ballina, Mahendar Ochani, Margot Gallowitsch Puerta, Kanta Ochani, Sangeeta S. Chavan, Kevin J. Tracey
    Abstract:

    Abstract The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “Cholinergic Anti-Inflammatory Pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the α7 subunit-containing nicotinic acetylcholine receptor (α7nAChR). Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks, but despite considerable importance, little is known about the molecular basis for central regulation of the vagus nerve-based Cholinergic Anti-Inflammatory Pathway. Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF production during endotoxemia. Peripheral administration of the acetylcholinesterase inhibitor galantamine significantly reduced serum TNF levels through vagus nerve signaling, and protected against lethality during murine endotoxemia. Administration of a centrally-acting muscarinic receptor antagonist abolished the suppression of TNF by galantamine, indicating that suppressing acetylcholinesterase activity, coupled with central muscarinic receptors, controls peripheral cytokine responses. Administration of galantamine to α7nAChR knockout mice failed to suppress TNF levels, indicating that the α7nAChR-mediated Cholinergic Anti-Inflammatory Pathway is required for the Anti-Inflammatory effect of galantamine. These findings show that inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal- and α7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor can be utilized to suppress abnormal inflammation to therapeutic advantage.

  • Controlling inflammation: the Cholinergic Anti-Inflammatory Pathway
    Biochemical Society Transactions, 2006
    Co-Authors: Valentin A. Pavlov, Kevin J. Tracey
    Abstract:

    Innate immune responses and inflammation are regulated in part by neural mechanisms. In the present paper, we summarize experimental evidence that reveals that innate immunity and inflammation are controlled by the vagus nerve, previously known as a regulator of other vital physiological functions. Activation of vagus nerve Cholinergic signalling inhibits TNF (tumour necrosis factor) and other pro-inflammatory cytokine overproduction through ‘immune’ α7 nicotinic receptor-mediated mechanisms. This efferent vagus nerve-based ‘Cholinergic Anti-Inflammatory Pathway’ has been elucidated as a critical regulator of inflammation in several experimental models of diseases. Our recent observations have shown that activation of central (brain) Cholinergic transmission by selective muscarinic receptor ligands results in lower systemic TNF levels in rodents and indicate that the efferent vagus nerve may provide a functional brain-to-immune connection. Thus central Cholinergic signalling is implicated in the activation of the Cholinergic Anti-Inflammatory Pathway. Electrical vagus nerve stimulation is clinically approved for the treatment of epilepsy and depression and current knowledge suggests that it could be utilized to control inflammation. Advances in understanding the receptor and molecular mechanisms of Cholinergic Anti-Inflammatory signalling indicate that selective α7 nicotinic receptor agonists and centrally acting Cholinergic enhancers can be used in the treatment of pathological conditions characterized by cytokine overproduction.

  • Immunologic Role of the Cholinergic Anti‐Inflammatory Pathway and the Nicotinic Acetylcholine α7 Receptor
    Annals of the New York Academy of Sciences, 2005
    Co-Authors: Margot Gallowitsch-puerta, Kevin J. Tracey
    Abstract:

    Cytokines are small protein molecules that facilitate communication between cells of the immune system and other tissues. Their messenger function elicits responses in other cells, ranging from DNA binding and tissue remodeling to coordinating the local cellular response to inflammation. The magnitude of the cytokine response is regulated closely, because an over- or underabundance of cytokine activity can impair organ function and cause shock and tissue injury. Counterregulatory molecular and humoral mechanisms protect the host from cytokine excess, including the pituitary-adrenal-glucocorticoid system, and the Anti-Inflammatory cytokine system. These humoral systems are protective, but they are relatively slow-acting, concentration-gradient dependent, and not integrated. We recently discovered that the "Cholinergic Anti-Inflammatory Pathway," a nervous system-based, rapid, and locally acting mechanism, can inhibit the cytokine response. Signals transmitted via the vagus nerve converge on cytokine-producing cells that express the nicotinic acetylcholine receptor alpha 7 (nAChR alpha7). The alpha7 receptor is an essential component of the Cholinergic Anti-Inflammatory Pathway, because activation of this receptor prevents cytokine release. Advances in understanding the molecular structure and function of alpha7 have begun to provide a better understanding of potential mechanisms regarding its assembly, expression, and cytokine-inhibiting functions. It may be possible to exploit this Pathway to therapeutic advantage for diseases caused by excessive cytokine activity.

  • The Cholinergic Anti-Inflammatory Pathway regulates the host response during septic peritonitis
    The Journal of Infectious Diseases, 2005
    Co-Authors: David J. Van Westerloo, Kevin J. Tracey, I. A. J. Giebelen, Sandrine Florquin, Joost Daalhuisen, Marco J. Bruno, Alex F. De Vos, Tom Van Der Poll
    Abstract:

    Background The nervous system, through the vagus nerve, can down-regulate inflammation in vivo by decreasing the release of tumor necrosis factor- alpha by endotoxin-stimulated macrophages. This Anti-Inflammatory effect is mediated by an interaction between acetylcholine, the principal neurotransmitter of the vagus nerve, and Cholinergic nicotinic acetylcholine receptors on macrophages. Methods We determined the role of this "Cholinergic Anti-Inflammatory Pathway" during septic peritonitis induced in mice by intraperitoneal injection of live Escherichia coli. Septic peritonitis was preceded by inhibition of the Cholinergic Anti-Inflammatory Pathway by unilateral cervical vagotomy, by stimulation of this Pathway by pretreatment of mice with nicotine, or by a combination of both interventions. Results Initial cytokine release during septic peritonitis was enhanced after previous vagotomy and was decreased after nicotine pretreatment, independently of the integrity of the vagus nerve. Further study established that vagotomy before septic peritonitis resulted in an enhanced influx of neutrophils and a marked increase in proinflammatory cytokine levels and liver damage. Conversely, nicotine pretreatment strongly decreased cell influx, proinflammatory cytokine levels, and liver damage, whereas bacterial clearance and survival were impaired. Discussion These data provide the first evidence, to our knowledge, of an important role of the vagus nerve in regulating the innate immune response to a severe bacterial infection.

Diane L. Rosin - One of the best experts on this subject based on the ideXlab platform.

  • non canonical Cholinergic anti inflammatory Pathway mediated activation of peritoneal macrophages induces hes1 and blocks ischemia reperfusion injury in the kidney
    Kidney International, 2019
    Co-Authors: Tsuyoshi Inoue, Liping Huang, Diane L. Rosin, Takahide Kohro, Shinji Tanaka, Shuqiu Zheng, Hong Ye, Reiko Inagi, Ruth L Stornetta, Masaomi Nangaku
    Abstract:

    The Cholinergic Anti-Inflammatory Pathway (CAP) links the nervous and immune systems and modulates innate and adaptive immunity. Activation of the CAP by vagus nerve stimulation exerts protective effects in a wide variety of clinical disorders including rheumatoid arthritis and Crohn's disease, and in murine models of acute kidney injury including ischemia/reperfusion injury (IRI). The canonical CAP Pathway involves activation of splenic alpha7-nicotinic acetylcholine receptor (α7nAChR)-positive macrophages by splenic β2-adrenergic receptor-positive CD4+ T cells. Here we demonstrate that ultrasound or vagus nerve stimulation also activated α7nAChR-positive peritoneal macrophages, and that adoptive transfer of these activated peritoneal macrophages reduced IRI in recipient mice. The protective effect required α7nAChR, and did not occur in splenectomized mice or in mice lacking T and B cells, suggesting a bidirectional interaction between α7nAChR-positive peritoneal macrophages and other immune cells including β2-adrenergic receptor-positive CD4+ T cells. We also found that expression of hairy and enhancer of split-1 (Hes1), a basic helix-loop-helix DNA-binding protein, is induced in peritoneal macrophages by ultrasound or vagus nerve stimulation. Adoptive transfer of Hes1-overexpressing peritoneal macrophages reduced kidney IRI. Our data suggest that Hes1 is downstream of α7nAChR and is important to fully activate the CAP. Taken together, these results suggest that peritoneal macrophages play a previously unrecognized role in mediating the protective effect of CAP activation in kidney injury, and that Hes1 is a new candidate pharmacological target to activate the CAP.

  • Ultrasound Prevents Renal Ischemia-Reperfusion Injury by Stimulating the Splenic Cholinergic Anti-Inflammatory Pathway
    Journal of the American Society of Nephrology, 2013
    Co-Authors: Joseph C. Gigliotti, Liping Huang, Amandeep Bajwa, Kryt Chattrabhuti, Sangju Lee, Alexander L. Klibanov, Kambiz Kalantari, Diane L. Rosin, Mark D. Okusa
    Abstract:

    AKI affects both quality of life and health care costs and is an independent risk factor for mortality. At present, there are few effective treatment options for AKI. Here, we describe a nonpharmacologic, noninvasive, ultrasound-based method to prevent renal ischemia-reperfusion injury in mice, which is a model for human AKI. We exposed anesthetized mice to an ultrasound protocol 24 hours before renal ischemia. After 24 hours of reperfusion, ultrasound-treated mice exhibited preserved kidney morphology and function compared with sham-treated mice. Ultrasound exposure before renal ischemia reduced the accumulation of CD11b+Ly6Ghigh neutrophils and CD11b+F4/80high myeloid cells in kidney tissue. Furthermore, splenectomy and adoptive transfer studies revealed that the spleen and CD4+ T cells mediated the protective effects of ultrasound. Last, blockade or genetic deficiency of the α7 nicotinic acetylcholine receptor abrogated the protective effect of ultrasound, suggesting the involvement of the Cholinergic Anti-Inflammatory Pathway. Taken together, these results suggest that an ultrasound-based treatment could have therapeutic potential for the prevention of AKI, possibly by stimulating a splenic Anti-Inflammatory Pathway.