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Petracco G, Faimann I, Reichmann F. Inflammatory bowel disease and neuropsychiatric disorders: Mechanisms and emerging therapeutics targeting the microbiota-gut-brain axis. Pharmacol Ther 2025; 269:108831. [PMID: 40023320 DOI: 10.1016/j.pharmthera.2025.108831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 02/03/2025] [Accepted: 02/23/2025] [Indexed: 03/04/2025]
Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are the two major entities of inflammatory bowel disease (IBD). These disorders are known for their relapsing disease course and severe gastrointestinal symptoms including pain, diarrhoea and bloody stool. Accumulating evidence suggests that IBD is not only restricted to the gastrointestinal tract and that disease processes are able to reach distant organs including the brain. In fact, up to 35 % of IBD patients also suffer from neuropsychiatric disorders such as generalized anxiety disorder and major depressive disorder. Emerging research in this area indicates that in many cases these neuropsychiatric disorders are a secondary condition as a consequence of the disturbed communication between the gut and the brain via the microbiota-gut-brain axis. In this review, we summarise the current knowledge on IBD-associated neuropsychiatric disorders. We examine the role of different pathways of the microbiota-gut-brain axis in the development of CNS disorders highlighting altered neural, immunological, humoral and microbial communication. Finally, we discuss emerging therapies targeting the microbiota-gut-brain axis to alleviate IBD and neuropsychiatric symptoms including faecal microbiota transplantation, psychobiotics, microbial metabolites and vagus nerve stimulation.
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Affiliation(s)
- Giulia Petracco
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Isabella Faimann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Florian Reichmann
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria; BiotechMed-Graz, Austria.
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Wu HR, Zhang CN, Dou BQ, Chen NY, Gao DF, Zou PS, Pan CX, Gu JH, Mo DL, Su JC. Identification of O-arylated huperzinines as novel cholinergic anti-inflammatory pathway agonists against gout arthritis. Bioorg Chem 2024; 152:107716. [PMID: 39178707 DOI: 10.1016/j.bioorg.2024.107716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Revised: 08/05/2024] [Accepted: 08/10/2024] [Indexed: 08/26/2024]
Abstract
Lycodine alkaloids are important natural products with diverse biological effects. In this manuscript, we set out the first structural optimization of the 2-pyridone moiety of Lycodine alkaloid via selective O-arylation under metal-free conditions and obtained a series of potent bioactive molecules against monosodium urate (MSU)-induced IL-1β production. Further investigations demonstrated that these natural product derivatives could activate the neuro-immunomodulatory cholinergic anti-inflammatory pathway (CAP) to block the initial phase of NLRP3 inflammasome activation. Compared with the clinical drugs hydrocortisone and indomethacin, as well as commercially available CAP agonists GTS-21 and pnu282987, 3k and 3q possessed greater potency against MSU-induced IL-1β production. Meanwhile, these molecules possessed less cytotoxicity against promonocytic THP-1 macrophages when compared with colchicine. This work reports a concise strategy for direct modification of 2-pyridone moiety from natural Lycodine alkaloids, and provides novel frameworks for discovering CAP activators and drugs for gout arthritis.
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Affiliation(s)
- Hao-Ran Wu
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China
| | - Cai-Neng Zhang
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China
| | - Bo-Qiang Dou
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China
| | - Nan-Ying Chen
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China
| | - De-Feng Gao
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China
| | - Pei-Sen Zou
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China
| | - Cheng-Xue Pan
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China
| | - Ji-Hong Gu
- Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, China.
| | - Dong-Liang Mo
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
| | - Jun-Cheng Su
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin 541004, China.
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Abraham MN, Nedeljkovic-Kurepa A, Fernandes TD, Yaipen O, Brewer MR, Leisman DE, Taylor MD, Deutschman CS. M1 cholinergic signaling in the brain modulates cytokine levels and splenic cell sub-phenotypes following cecal ligation and puncture. Mol Med 2024; 30:22. [PMID: 38317082 PMCID: PMC10845657 DOI: 10.1186/s10020-024-00787-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 01/21/2024] [Indexed: 02/07/2024] Open
Abstract
BACKGROUND The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1 muscarinic acetylcholine (ACh) receptor (M1AChR) attenuated this endotoxin-mediated change. We hypothesize that decreased M1AChR-mediated activity contributes to inflammation following cecal ligation and puncture (CLP), a mouse model of sepsis. METHODS In male C57Bl/6 mice, we quantified basal forebrain cholinergic activity (immunostaining), hippocampal neuronal activity, serum cytokine/chemokine levels (ELISA) and splenic cell subtypes (flow cytometry) at baseline, following CLP and following CLP in mice also treated with the M1AChR agonist xanomeline. RESULTS At 48 h. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1β, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFα+ and ILβ+ neutrophils and ILβ+ monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4+ and CD8+ T cells were lower. When, following CLP, mice were treated with xanomeline activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1β, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomeline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα+ neutrophils also were lower in xanomeline-treated mice than in untreated animals. Percentages of IL-1β+ neutrophils, IL-1β+ monocytes, cDCs, CD4+ T cells and CD8+ T cells were similar in xanomeline-treated and untreated post-CLP mice. CONCLUSION Our findings indicate that M1AChR-mediated responses modulate CLP-induced alterations in serum levels of some, but not all, cytokines/chemokines and affected splenic immune response phenotypes.
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Affiliation(s)
- Mabel N Abraham
- Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA
- Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA
| | - Ana Nedeljkovic-Kurepa
- Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA
- Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA
| | - Tiago D Fernandes
- Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA
- Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA
| | - Omar Yaipen
- Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA
- Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA
| | - Mariana R Brewer
- Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA
- Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Daniel E Leisman
- Department of Medicine, Massachusetts General Hospital, Boston, USA
| | - Matthew D Taylor
- Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA
- Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Clifford S Deutschman
- Department of Pediatrics, Cohen Children's Medical Center, Northwell Health, New Hyde Park, New York, USA.
- Sepsis Research Laboratories, The Feinstein Institutes for Medical Research, Northwell Health, Room 3140, 350 Community Drive, Manhasset, NY, 11030, USA.
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
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Costa SO, Chaves WF, Lopes PKF, Silva IM, Burguer B, Ignácio-Souza LM, Torsoni AS, Milanski M, Rodrigues HG, Desai M, Ross MG, Torsoni MA. Maternal consumption of a high-fat diet modulates the inflammatory response in their offspring, mediated by the M1 muscarinic receptor. Front Immunol 2023; 14:1273556. [PMID: 38193079 PMCID: PMC10773672 DOI: 10.3389/fimmu.2023.1273556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 11/27/2023] [Indexed: 01/10/2024] Open
Abstract
Introduction High-fat diet (HFD) consumption is associated with various metabolic disorders and diseases. Both pre-pregnancy and maternal obesity can have long-term consequences on offspring health. Furthermore, consuming an HFD in adulthood significantly increases the risk of obesity and metabolic disorders. However, an intriguing phenomenon known as the obesity paradox suggests that obesity may confer a protective effect on mortality outcomes in sepsis. In sepsis, activation of the cholinergic anti-inflammatory pathway (CAP) can help mitigate systemic inflammation. We employed a metabolic programming model to explore the relationship between maternal HFD consumption and offspring response to sepsis. Methods We fed female mice either a standard diet (SC) or an HFD during the pre-pregnancy, pregnancy, and lactation periods. Subsequently, we evaluated 28-day-old male offspring. Results Notably, we discovered that offspring from HFD-fed dams (HFD-O) exhibited a higher survival rate compared with offspring from SC-fed dams (SC-O). Importantly, inhibition of the m1 muscarinic acetylcholine receptor (m1mAChR), involved in the CAP, in the hypothalamus abolished this protection. The expression of m1mAChR in the hypothalamus was higher in HFD-O at different ages, peaking on day 28. Treatment with an m1mAChR agonist could modulate the inflammatory response in peripheral tissues. Specifically, CAP activation was greater in the liver of HFD-O following agonist treatment. Interestingly, lipopolysaccharide (LPS) challenge failed to induce a more inflammatory state in HFD-O, in contrast to SC-O, and agonist treatment had no additional effect. Analysis of spleen immune cells revealed a distinct phenotype in HFD-O, characterized by elevated levels of CD4+ lymphocytes rather than CD8+ lymphocytes. Moreover, basal Il17 messenger RNA (mRNA) levels were lower while Il22 mRNA levels were higher in HFD-O, and we observed the same pattern after LPS challenge. Discussion Further examination of myeloid cells isolated from bone marrow and allowed to differentiate showed that HFD-O macrophages displayed an anti-inflammatory phenotype. Additionally, treatment with the m1mAChR agonist contributed to reducing inflammatory marker levels in both groups. In summary, our findings demonstrate that HFD-O are protected against LPS-induced sepsis, and this protection is mediated by the central m1mAChR. Moreover, the inflammatory response in the liver, spleen, and bone marrow-differentiated macrophages is diminished. However, more extensive analysis is necessary to elucidate the specific mechanisms by which m1mAChR modulates the immune response during sepsis.
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Affiliation(s)
- Suleyma Oliveira Costa
- Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Wenicios Ferreira Chaves
- Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | | | - Iracema M. Silva
- Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Beatriz Burguer
- Laboratory of Nutrients and Tissue Repair, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Leticia M. Ignácio-Souza
- Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira, Brazil
- Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - Adriana Souza Torsoni
- Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira, Brazil
- Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - Marciane Milanski
- Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira, Brazil
- Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
| | - Hosana Gomes Rodrigues
- Laboratory of Nutrients and Tissue Repair, School of Applied Sciences, University of Campinas, Limeira, Brazil
| | - Mina Desai
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles at Harbor-UCLA, Torrance, CA, United States
| | - Michael Glenn Ross
- Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles at Harbor-UCLA, Torrance, CA, United States
| | - Marcio Alberto Torsoni
- Laboratory of Metabolic Disorders, School of Applied Sciences, University of Campinas, Limeira, Brazil
- Obesity and Comorbidities Research Center, University of Campinas, Campinas, Brazil
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Fu S, Ni T, Zhang M, Ren D, Feng Y, Yao N, Zhang X, Wang R, Xu W, Yang N, Yang Y, He Y, Zhao Y, Liu J. Cholinergic Anti-inflammatory Pathway Attenuates Acute Liver Failure Through Inhibiting MAdCAM1/α4β7-mediated Gut-derived Proinflammatory Lymphocytes Accumulation. Cell Mol Gastroenterol Hepatol 2023; 17:199-217. [PMID: 37926366 PMCID: PMC10758884 DOI: 10.1016/j.jcmgh.2023.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 10/28/2023] [Accepted: 10/30/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND & AIMS The function of cholinergic anti-inflammatory pathway (CAP) in acute liver failure (ALF) with inflammatory storm remains indefinite. The liver-gut axis has been proved to be crucial for liver homeostasis. Investigation about CAP regulation on liver-gut axis would enrich our understanding over cholinergic anti-inflammatory mechanism. METHODS Co-injection of lipopolysaccharide and D-galactosamine was used to establish the model of ALF. PNU-282987 was used to activate the CAP. Histological staining, real-time polymerase chain reaction, Western blotting, RNA sequencing, and flow cytometry were conducted. Liver biopsy specimens and patients' serum from patients with liver failure were also analyzed. RESULTS We confirmed that activating the CAP alleviated hepatocyte destruction, accompanied by a significant decrease in hepatocyte apoptosis, pro-inflammatory cytokines, and NLRP3 inflammasome activation. Moreover, hepatic MAdCAM1 and serum MAdCAM1 levels were induced in ALF, and MAdCAM1 levels were positively correlated with the extent of liver damage and the expression of pro-inflammatory markers. Furthermore, activating the CAP mainly downregulated ectopic expression of MAdCAM1 on endothelial cells, and inhibition of NF-κB p65 nuclear translocation was partly attributed to the decreased MAdCAM1. Notably, in ALF, the aberrant hepatic expression of MAdCAM1 subsequently recruited gut-derived α4β7+ CD4+T cells to the liver, which exhibited an augmented IFN-γ-secreting and IL-17-producing phenotype. Finally, we revealed that the levels of serum and hepatic MAdCAM1 were elevated in patients with liver failure and closely correlated with clinical course. Increasing hepatic infiltration of β7+ cells were also confirmed in patients. CONCLUSIONS Activating the CAP attenuated liver injury by inhibiting MAdCAM1/α4β7 -mediated gut-derived proinflammatory lymphocytes infiltration, which provides a potential therapeutic target for ALF.
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Affiliation(s)
- Shan Fu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - TianZhi Ni
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - MengMeng Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, Shaanxi Province, China
| | - DanFeng Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, Shaanxi Province, China
| | - YaLi Feng
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - NaiJuan Yao
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Xiaoli Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - RuoJing Wang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - WeiCheng Xu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
| | - Nan Yang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, Shaanxi Province, China
| | - Yuan Yang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, Shaanxi Province, China
| | - Yingli He
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, Shaanxi Province, China
| | - YingRen Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, Shaanxi Province, China.
| | - JinFeng Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China; Shaanxi Clinical Medical Research Center of Infectious Diseases, Xi'an, Shaanxi Province, China.
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Abraham MN, Nedeljkovic-Kurepa A, Fernandes T, Yaipen O, Brewer MR, Taylor MD, Deutschman C. M1 Cholinergic Signaling Modulates Cytokine Levels and Splenocyte Sub-Phenotypes Following Cecal Ligation and Puncture. RESEARCH SQUARE 2023:rs.3.rs-3353062. [PMID: 37886474 PMCID: PMC10602092 DOI: 10.21203/rs.3.rs-3353062/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/28/2023]
Abstract
Background The contribution of the central nervous system to sepsis pathobiology is incompletely understood. In previous studies, administration of endotoxin to mice decreased activity of the vagus anti-inflammatory reflex. Treatment with the centrally-acting M1/M4 muscarinic acetylcholine (ACh) receptor (M1/M4AChR) attenuated this endotoxin-mediated change. We hypothesize that decreased M1/M4AChR-mediated activity contributes to inflammation following cecal ligation and puncture (CLP), a mouse model of sepsis. Methods Basal forebrain cholinergic activity (immunostaining), serum cytokine/chemokine levels (ELISA) and splenocyte subtypes (flow cytometry) were examined at baseline and following CLP in male C57BL/6 male mice. Rersults At 48hrs. post-CLP, activity in basal forebrain cells expressing choline acetyltransferase (ChAT) was half of that observed at baseline. Lower activity was also noted in the hippocampus, which contains projections from ChAT-expressing basal forebrain neurons. Serum levels of TNFα, IL-1β, MIP-1α, IL-6, KC and G-CSF were higher post-CLP than at baseline. Post-CLP numbers of splenic macrophages and inflammatory monocytes, TNFa+ and ILb+ neutrophils and ILb+ monocytes were higher than baseline while numbers of central Dendritic Cells (cDCs), CD4+ and CD8+ T cells were lower. When, following CLP, mice were treated with xanomeline, a central-acting M1AChR agonist, activity in basal forebrain ChAT-expressing neurons and in the hippocampus was significantly higher than in untreated animals. Post-CLP serum concentrations of TNFα, IL-1β, and MIP-1α, but not of IL-6, KC and G-CSF, were significantly lower in xanomline-treated mice than in untreated mice. Post-CLP numbers of splenic neutrophils, macrophages, inflammatory monocytes and TNFα+ neutrophils also were lower in xanomeline-treated mice than in untreated animals. The effects of CLP on percentages of IL-1β+ neutrophils, IL-1β+ monocytes, cDCs, CD4+ T cells and CD8+ T cells were similar in xanomeline - treated and untreated post-CLP mice. Conclusion Our findings indicate that M1/M4AChR-mediated responses modulate CLP-induced alterations in the distribution of some, but not all, leukocyte phenotypes and certain cytokines and chemokines.
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Affiliation(s)
| | | | | | - Omar Yaipen
- Northwell Health Feinstein Institutes for Medical Research
| | | | | | - Clifford Deutschman
- Hofstra Northwell School of Medicine at Hofstra University: Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
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Keever KR, Yakubenko VP, Hoover DB. Neuroimmune nexus in the pathophysiology and therapy of inflammatory disorders: role of α7 nicotinic acetylcholine receptors. Pharmacol Res 2023; 191:106758. [PMID: 37028776 DOI: 10.1016/j.phrs.2023.106758] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/30/2023] [Accepted: 04/02/2023] [Indexed: 04/08/2023]
Abstract
The α7-nicotinic acetylcholine receptor (α7nAChR) is a key protein in the cholinergic anti-inflammatory pathway (CAP) that links the nervous and immune systems. Initially, the pathway was discovered based on the observation that vagal nerve stimulation (VNS) reduced the systemic inflammatory response in septic animals. Subsequent studies form a foundation for the leading hypothesis about the central role of the spleen in CAP activation. VNS evokes noradrenergic stimulation of ACh release from T cells in the spleen, which in turn activates α7nAChRs on the surface of macrophages. α7nAChR-mediated signaling in macrophages reduces inflammatory cytokine secretion and modifies apoptosis, proliferation, and macrophage polarization, eventually reducing the systemic inflammatory response. A protective role of the CAP has been demonstrated in preclinical studies for multiple diseases including sepsis, metabolic disease, cardiovascular diseases, arthritis, Crohn's disease, ulcerative colitis, endometriosis, and potentially COVID-19, sparking interest in using bioelectronic and pharmacological approaches to target α7nAChRs for treating inflammatory conditions in patients. Despite a keen interest, many aspects of the cholinergic pathway are still unknown. α7nAChRs are expressed on many other subsets of immune cells that can affect the development of inflammation differently. There are also other sources of ACh that modify immune cell functions. How the interplay of ACh and α7nAChR on different cells and in various tissues contributes to the anti-inflammatory responses requires additional study. This review provides an update on basic and translational studies of the CAP in inflammatory diseases, the relevant pharmacology of α7nAChR-activated drugs and raises some questions that require further investigation.
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Alvarez MR, Alarcon JM, Roman CA, Lazaro D, Bobrowski-Khoury N, Baena-Caldas GP, Esber GR. Can a basic solution activate the inflammatory reflex? A review of potential mechanisms, opportunities, and challenges. Pharmacol Res 2023; 187:106525. [PMID: 36441036 DOI: 10.1016/j.phrs.2022.106525] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 10/09/2022] [Accepted: 10/25/2022] [Indexed: 11/24/2022]
Abstract
Stimulation of the inflammatory reflex (IR) is a promising strategy to treat systemic inflammatory disorders. However, this strategy is hindered by the cost and side effects of traditional IR activators. Recently, oral intake of sodium bicarbonate (NaHCO3) has been suggested to activate the IR, providing a safe and inexpensive alternative. Critically, the mechanisms whereby NaHCO3 might achieve this effect and more broadly the pathways underlying the IR remain poorly understood. Here, we argue that the recognition of NaHCO3 as a potential IR activator presents exciting clinical and research opportunities. To aid this quest, we provide an integrative review of our current knowledge of the neural and cellular pathways mediating the IR and discuss the status of physiological models of IR activation. From this vantage point, we derive testable hypotheses on potential mechanisms whereby NaHCO3 might stimulate the IR and compare NaHCO3 with classic IR activators. Elucidation of these mechanisms will help determine the therapeutic value of NaHCO3 as an IR activator and provide new insights into the IR circuitry.
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Affiliation(s)
- Milena Rodriguez Alvarez
- Department of Internal Medicine, Division of Rheumatology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA.
| | - Juan Marcos Alarcon
- Department of Pathology, The Robert F. Furchgott Center for Neural and Behavioral Science, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA
| | - Christopher A Roman
- Department of Cell Biology, State University of New York (SUNY) Downstate Health Sciences University, Brooklyn, NY 11203, USA
| | - Deana Lazaro
- Division of Rheumatology, Department of Internal Medicine, Veterans Affairs New York Harbor Healthcare System, Brooklyn, NY, USA
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Oshaghi M, Kourosh-Arami M, Roozbehkia M. Role of neurotransmitters in immune-mediated inflammatory disorders: a crosstalk between the nervous and immune systems. Neurol Sci 2023; 44:99-113. [PMID: 36169755 DOI: 10.1007/s10072-022-06413-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 09/14/2022] [Indexed: 02/07/2023]
Abstract
Immune-mediated inflammatory diseases (IMIDs) are a group of common heterogeneous disorders, characterized by an alteration of cellular homeostasis. Primarily, it has been shown that the release and diffusion of neurotransmitters from nervous tissue could result in signaling through lymphocyte cell-surface receptors and the modulation of immune function. This finding led to the idea that the neurotransmitters could serve as immunomodulators. It is now manifested that neurotransmitters can also be released from leukocytes and act as autocrine or paracrine modulators. Increasing data indicate that there is a crosstalk between inflammation and alterations in neurotransmission. The primary goal of this review is to demonstrate how these two pathways may converge at the level of the neuron and glia to involve in IMID. We review the role of neurotransmitters in IMID. The different effects that these compounds exert on a variety of immune cells are also reviewed. Current and future developments in understanding the cross-talk between the immune and nervous systems will undoubtedly identify new ways for treating immune-mediated diseases utilizing agonists or antagonists of neurotransmitter receptors.
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Affiliation(s)
- Mojgan Oshaghi
- Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Kourosh-Arami
- Department of Neuroscience, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Maryam Roozbehkia
- Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
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10
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Pavlov VA, Tracey KJ. Bioelectronic medicine: Preclinical insights and clinical advances. Neuron 2022; 110:3627-3644. [PMID: 36174571 PMCID: PMC10155266 DOI: 10.1016/j.neuron.2022.09.003] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 07/28/2022] [Accepted: 09/02/2022] [Indexed: 11/17/2022]
Abstract
The nervous system maintains homeostasis and health. Homeostatic disruptions underlying the pathobiology of many diseases can be controlled by bioelectronic devices targeting CNS and peripheral neural circuits. New insights into the regulatory functions of the nervous system and technological developments in bioelectronics drive progress in the emerging field of bioelectronic medicine. Here, we provide an overview of key aspects of preclinical research, translation, and clinical advances in bioelectronic medicine.
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Affiliation(s)
- Valentin A Pavlov
- Institute of Bioelectronic Medicine, the Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Elmezzi Graduate School of Molecular Medicine, Northwell Health, Manhasset, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
| | - Kevin J Tracey
- Institute of Bioelectronic Medicine, the Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA; Elmezzi Graduate School of Molecular Medicine, Northwell Health, Manhasset, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
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11
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Parasympathetic-macrophages-ductal epithelial cells axis promotes female rat submandibular gland regeneration after excretory duct ligation/deligation. Arch Oral Biol 2022; 145:105586. [DOI: 10.1016/j.archoralbio.2022.105586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 11/06/2022] [Accepted: 11/09/2022] [Indexed: 11/13/2022]
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12
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Mota CMD, Madden CJ. Neural control of the spleen as an effector of immune responses to inflammation: mechanisms and treatments. Am J Physiol Regul Integr Comp Physiol 2022; 323:R375-R384. [PMID: 35993560 PMCID: PMC9485006 DOI: 10.1152/ajpregu.00151.2022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/29/2022] [Accepted: 08/11/2022] [Indexed: 11/22/2022]
Abstract
Immune system responses are a vital defense mechanism against pathogens. Inflammatory mediators finely regulate complex inflammatory responses from initiation to resolution. However, in certain conditions, the inflammation is initiated and amplified, but not resolved. Understanding the biological mechanisms underlying the regulation of the immune response is critical for developing therapeutic alternatives, including pharmaceuticals and bioelectronic tools. The spleen is an important immune effector organ since it orchestrates innate and adaptive immune responses such as pathogen clearance, cytokine production, and differentiation of cells, therefore playing a modulatory role that balances pro- and anti-inflammatory responses. However, modulation of splenic immune activity is a largely unexplored potential therapeutic tool that could be used for the treatment of inflammatory and life-threatening conditions. This review discusses some of the mechanisms controlling neuroimmune communication and the brain-spleen axis.
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Affiliation(s)
- Clarissa M D Mota
- Department of Neurological Surgery, Oregon Health and Science University, Portland, Oregon
| | - Christopher J Madden
- Department of Neurological Surgery, Oregon Health and Science University, Portland, Oregon
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13
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Yasmin F, Sahito AM, Mir SL, Khatri G, Shaikh S, Gul A, Hassan SA, Koritala T, Surani S. Electrical neuromodulation therapy for inflammatory bowel disease. World J Gastrointest Pathophysiol 2022; 13:128-142. [PMID: 36187600 PMCID: PMC9516456 DOI: 10.4291/wjgp.v13.i5.128] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 02/19/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal (GI) tract. It has financial and quality of life impact on patients. Although there has been a significant advancement in treatments, a considerable number of patients do not respond to it or have severe side effects. Therapeutic approaches such as electrical neuromodulation are being investigated to provide alternate options. Although bioelectric neuromodulation technology has evolved significantly in the last decade, sacral nerve stimulation (SNS) for fecal incontinence remains the only neuromodulation protocol commonly utilized use for GI disease. For IBD treatment, several electrical neuromodulation techniques have been studied, such as vagus NS, SNS, and tibial NS. Several animal and clinical experiments were conducted to study the effectiveness, with encouraging results. The precise underlying mechanisms of action for electrical neuromodulation are unclear, but this modality appears to be promising. Randomized control trials are required to investigate the efficacy of intrinsic processes. In this review, we will discuss the electrical modulation therapy for the IBD and the data pertaining to it.
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Affiliation(s)
- Farah Yasmin
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Abdul Moiz Sahito
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Syeda Lamiya Mir
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Govinda Khatri
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Somina Shaikh
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Ambresha Gul
- Department of Medicine, People’s University of Medical and Health Sciences, Nawabshah 67480, Pakistan
| | - Syed Adeel Hassan
- Department of Medicine, University of Louisville, Louiseville, KY 40292, United States
| | - Thoyaja Koritala
- Department of Medicine, Mayo Clinic, Rochester, NY 55902, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, College Station, TX 77843, United States
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55902, United States
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14
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Brinkman DJ, Simon T, Ten Hove AS, Zafeiropoulou K, Welting O, van Hamersveld PHP, Willemze RA, Yim AYFL, Verseijden C, Hakvoort TBM, Luyer MD, Vervoordeldonk MJ, Blancou P, de Jonge WJ. Electrical stimulation of the splenic nerve bundle ameliorates dextran sulfate sodium-induced colitis in mice. J Neuroinflammation 2022; 19:155. [PMID: 35715845 PMCID: PMC9204975 DOI: 10.1186/s12974-022-02504-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 06/01/2022] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Vagus nerve stimulation has been suggested to affect immune responses, partly through a neuronal circuit requiring sympathetic innervation of the splenic nerve bundle and norepinephrine (NE) release. Molecular and cellular mechanisms of action remain elusive. Here, we investigated the therapeutic value of this neuromodulation in inflammatory bowel disease (IBD) by applying electrical splenic nerve bundle stimulation (SpNS) in mice with dextran sulfate sodium (DSS)-induced colitis. METHODS Cuff electrodes were implanted around the splenic nerve bundle in mice, whereupon mice received SpNS or sham stimulation. Stimulation was applied 6 times daily for 12 days during DSS-induced colitis. Colonic and splenic tissues were collected for transcriptional analyses by qPCR and RNA-sequencing (RNA-seq). In addition, murine and human splenocytes were stimulated with lipopolysaccharide (LPS) in the absence or presence of NE. Single-cell RNA-seq data from publicly available data sets were analyzed for expression of β-adrenergic receptors (β-ARs). RESULTS Colitic mice undergoing SpNS displayed reduced colon weight/length ratios and showed improved Disease Activity Index scores with reduced Tumor Necrosis Factor α mRNA expression in the colon compared with sham stimulated mice. Analyses of splenocytes from SpNS mice using RNA-seq demonstrated specific immune metabolism transcriptome profile changes in myeloid cells. Splenocytes showed expression of β-ARs in myeloid and T cells. Cytokine production was reduced by NE in mouse and human LPS-stimulated splenocytes. CONCLUSIONS Together, our results demonstrate that SpNS reduces clinical features of colonic inflammation in mice with DSS-induced colitis possibly by inhibiting splenic myeloid cell activation. Our data further support exploration of the clinical use of SpNS for patients with IBD.
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Affiliation(s)
- David J Brinkman
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands.
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands.
| | - Thomas Simon
- Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, CNRS, Nice, France
| | - Anne S Ten Hove
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Konstantina Zafeiropoulou
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
- Department of Pediatric Surgery, Emma Children's Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands
| | - Olaf Welting
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Patricia H P van Hamersveld
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Rose A Willemze
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Andrew Y F Li Yim
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
- Department of Clinical Genetics, Genome Diagnostics Laboratory, Amsterdam Reproduction and Development, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Caroline Verseijden
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Theodorus B M Hakvoort
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
| | - Misha D Luyer
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
| | - Margriet J Vervoordeldonk
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
- Galvani Bioelectronics, Stevenage, UK
| | - Philippe Blancou
- Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d'Azur, CNRS, Nice, France
| | - Wouter J de Jonge
- Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Room S2-162, Meibergdreef 69, 1105 BK, Amsterdam, The Netherlands
- Department of Surgery, University of Bonn, Bonn, Germany
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15
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Ahmed U, Chang YC, Zafeiropoulos S, Nassrallah Z, Miller L, Zanos S. Strategies for precision vagus neuromodulation. Bioelectron Med 2022; 8:9. [PMID: 35637543 PMCID: PMC9150383 DOI: 10.1186/s42234-022-00091-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 05/05/2022] [Indexed: 12/21/2022] Open
Abstract
The vagus nerve is involved in the autonomic regulation of physiological homeostasis, through vast innervation of cervical, thoracic and abdominal visceral organs. Stimulation of the vagus with bioelectronic devices represents a therapeutic opportunity for several disorders implicating the autonomic nervous system and affecting different organs. During clinical translation, vagus stimulation therapies may benefit from a precision medicine approach, in which stimulation accommodates individual variability due to nerve anatomy, nerve-electrode interface or disease state and aims at eliciting therapeutic effects in targeted organs, while minimally affecting non-targeted organs. In this review, we discuss the anatomical and physiological basis for precision neuromodulation of the vagus at the level of nerve fibers, fascicles, branches and innervated organs. We then discuss different strategies for precision vagus neuromodulation, including fascicle- or fiber-selective cervical vagus nerve stimulation, stimulation of vagal branches near the end-organs, and ultrasound stimulation of vagus terminals at the end-organs themselves. Finally, we summarize targets for vagus neuromodulation in neurological, cardiovascular and gastrointestinal disorders and suggest potential precision neuromodulation strategies that could form the basis for effective and safe therapies.
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Affiliation(s)
- Umair Ahmed
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Yao-Chuan Chang
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Stefanos Zafeiropoulos
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Zeinab Nassrallah
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Larry Miller
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Stavros Zanos
- Institute of Bioelectronic Medicine, Feinstein Institutes for Medical Research, Manhasset, New York, USA.
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA.
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16
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Serafini MA, Paz AH, Nunes NS. Cholinergic immunomodulation in inflammatory bowel diseases. Brain Behav Immun Health 2022; 19:100401. [PMID: 34977822 PMCID: PMC8683952 DOI: 10.1016/j.bbih.2021.100401] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 11/29/2021] [Accepted: 12/04/2021] [Indexed: 12/28/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic intestinal disorders characterized by dysregulated immune responses to resident microbiota in genetically susceptible hosts. The activation of the cholinergic system has been proposed for the treatment of IBD patients according to its potential anti-inflammatory effect in vivo. The α-7-nicotinic-acetylcholine receptor (α7nAChR) is involved in the inhibition of inflammatory processes, modulating the production of cytokines, suppressing dendritic cells and macrophage activity, leading to the suppression of T cells. In this review, we address the most recent studies and clinical trials concerning cholinergic signaling and its therapeutic potential for inflammatory bowel diseases.
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Affiliation(s)
- Michele A. Serafini
- Biological Sciences, Physiology Graduate Program, Federal University of Rio Grande do Sul, 90050170, Porto Alegre, Brazil
- Cells, Tissue and Genes Laboratory, Experimental Research Center, Hospital de Clinicas de Porto Alegre, 90035903, Porto Alegre, Brazil
| | - Ana H. Paz
- Morphological Sciences Department, Basic Health Sciences Institute, Federal University of Rio Grande do Sul, 90050170, Porto Alegre, Brazil
- Cells, Tissue and Genes Laboratory, Experimental Research Center, Hospital de Clinicas de Porto Alegre, 90035903, Porto Alegre, Brazil
| | - Natalia S. Nunes
- Experimental Transplantation Immunotherapy Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 20852, Bethesda, MD, USA
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17
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Muscarinic receptors control markers of inflammation in the small intestine of BALB/c mice. J Neuroimmunol 2022; 362:577764. [PMID: 34823118 DOI: 10.1016/j.jneuroim.2021.577764] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 09/22/2021] [Accepted: 11/03/2021] [Indexed: 11/24/2022]
Abstract
Muscarinic-acetylcholine-receptors (mAChRs) modulate intestinal homeostasis, but their role in inflammation is unclear; thus, this issue was the focus of this study. BALB/c mice were treated for 7 days with muscarine (mAChR/agonist), atropine (mAChR/antagonist) or saline. Small-intestine samples were collected for histology and cytofluorometric assays in Peyer's patches (PP) and lamina propria (LP) cell-suspensions. In LP, goblet-cells/leukocytes/neutrophils/MPO+ cells and MPO/activity were increased in the muscarine group. In PP, IFN-γ+/CD4+ T or IL-6+/CD4+ T cell numbers were higher in the muscarine or atropine groups, respectively. In LP, TNF-α+/CD4+ T cell number was higher in the muscarine group and lower in the atropine.
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18
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The Regulation Effect of α7nAChRs and M1AChRs on Inflammation and Immunity in Sepsis. Mediators Inflamm 2021; 2021:9059601. [PMID: 34776789 PMCID: PMC8580654 DOI: 10.1155/2021/9059601] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 09/14/2021] [Accepted: 10/25/2021] [Indexed: 02/07/2023] Open
Abstract
The inflammatory storm in the early stage and immunosuppression in the late stage are responsible for the high mortality rates and multiple organ dysfunction in sepsis. In recent years, studies have found that the body's cholinergic system can spontaneously and dynamically regulate inflammation and immunity in sepsis according to the needs of the body. Firstly, the vagus nerve senses and regulates local or systemic inflammation by means of the Cholinergic Anti-inflammatory Pathway (CAP) and activation of α7-nicotinic acetylcholine receptors (α7nAChRs); thus, α7nAChRs play important roles for the central nervous system (CNS) to modulate peripheral inflammation; secondly, the activation of muscarinic acetylcholine receptors 1 (M1AChRs) in the forebrain can affect the neurons of the Medullary Visceral Zone (MVZ), the core of CAP, to regulate systemic inflammation and immunity. Based on the critical role of these two cholinergic receptor systems in sepsis, it is necessary to collect and analyze the related findings in recent years to provide ideas for further research studies and clinical applications. By consulting the related literature, we draw some conclusions: MVZ is the primary center for the nervous system to regulate inflammation and immunity. It coordinates not only the sympathetic system and vagus system but also the autonomic nervous system and neuroendocrine system to regulate inflammation and immunity; α7nAChRs are widely expressed in immune cells, neurons, and muscle cells; the activation of α7nAChRs can suppress local and systemic inflammation; the expression of α7nAChRs represents the acute or chronic inflammatory state to a certain extent; M1AChRs are mainly expressed in the advanced centers of the brain and regulate systemic inflammation; neuroinflammation of the MVZ, hypothalamus, and forebrain induced by sepsis not only leads to their dysfunctions but also underlies the regulatory dysfunction on systemic inflammation and immunity. Correcting the neuroinflammation of these regulatory centers and adjusting the function of α7nAChRs and M1AChRs may be two key strategies for the treatment of sepsis in the future.
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19
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Metz CN, Pavlov VA. Treating disorders across the lifespan by modulating cholinergic signaling with galantamine. J Neurochem 2021; 158:1359-1380. [PMID: 33219523 PMCID: PMC10049459 DOI: 10.1111/jnc.15243] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/15/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023]
Abstract
Advances in understanding the regulatory functions of the nervous system have revealed neural cholinergic signaling as a key regulator of cytokine responses and inflammation. Cholinergic drugs, including the centrally acting acetylcholinesterase inhibitor, galantamine, which are in clinical use for the treatment of Alzheimer's disease and other neurodegenerative and neuropsychiatric disorders, have been rediscovered as anti-inflammatory agents. Here, we provide a timely update on this active research and clinical developments. We summarize the involvement of cholinergic mechanisms and inflammation in the pathobiology of Alzheimer's disease, Parkinson's disease, and schizophrenia, and the effectiveness of galantamine treatment. We also highlight recent findings demonstrating the effects of galantamine in preclinical and clinical settings of numerous conditions and diseases across the lifespan that are characterized by immunological, neurological, and metabolic dysfunction.
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Affiliation(s)
- Christine N. Metz
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Valentin A. Pavlov
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
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20
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Mikami Y, Tsunoda J, Kiyohara H, Taniki N, Teratani T, Kanai T. Vagus nerve-mediated intestinal immune regulation: therapeutic implications for inflammatory bowel diseases. Int Immunol 2021; 34:97-106. [PMID: 34240133 DOI: 10.1093/intimm/dxab039] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 07/07/2021] [Indexed: 12/13/2022] Open
Abstract
The pathophysiology of inflammatory bowel disease (IBD) involves immunological, genetic and environmental factors. Through its ability to sense environmental stimuli, the autonomic nervous system plays a key role in the development and persistence of IBD. The vagus nerve (VN), which contains sensory and motor neurons, travels throughout the body to innervate the gut and other visceral organs in the thoracic and abdominopelvic cavities. Recent studies show that the VN has anti-inflammatory effects via the release of acetylcholine, in what is known as the cholinergic anti-inflammatory pathway (CAIP). In the gut immune system, the CAIP is proposed to be activated directly by signals from the gut and indirectly by signals from the liver, which receives gut-derived bioactive substances via the portal vein and senses the status of the gut. The gut-brain axis and liver-brain-gut reflex arc regulate a wide variety of peripheral immune cells to maintain homeostasis in the gut. Therefore, targeting the neural reflex by methods such as VN stimulation is now under investigation for suppressing intestinal inflammation associated with IBD. In this review, we describe the role of the VN in the regulation of intestinal immunity, and we discuss novel therapeutic approaches for IBD that target neuroimmune interactions.
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Affiliation(s)
- Yohei Mikami
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Junya Tsunoda
- Department of Surgery, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan
| | - Hiroki Kiyohara
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Nobuhito Taniki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Toshiaki Teratani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine.,AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan
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21
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Meroni E, Stakenborg N, Gomez-Pinilla PJ, Stakenborg M, Aguilera-Lizarraga J, Florens M, Delfini M, de Simone V, De Hertogh G, Goverse G, Matteoli G, Boeckxstaens GE. Vagus Nerve Stimulation Promotes Epithelial Proliferation and Controls Colon Monocyte Infiltration During DSS-Induced Colitis. Front Med (Lausanne) 2021; 8:694268. [PMID: 34307422 PMCID: PMC8292675 DOI: 10.3389/fmed.2021.694268] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022] Open
Abstract
Background: We previously showed increased susceptibility to dextran sulfate sodium (DSS)-induced colitis in vagotomized mice. Here, we evaluated whether vagus nerve stimulation (VNS) is able to reduce the severity of DSS colitis and aimed to unravel the mechanism involved. Methods: Colitis was induced in wild type mice by 2.5% DSS administration in drinking water for 5 days. VNS (5 Hz, 1 ms, 1 mA) was applied 1 day prior to and after 4 days of DSS administration to evaluate changes in epithelial integrity and inflammatory response, respectively. Epithelial integrity was assessed using TUNEL and Ki67 staining. Monocytes, immature and mature macrophages were sorted from colonic samples and gene expression levels of pro-inflammatory cytokines were studied. Results: VNS applied prior to DSS administration (i.e., prophylactic VNS) reduced disease activity index (VNS 0.8 ± 0.6 vs. sham 2.8 ± 0.7, p < 0.001, n = 5) and tended to improve histology score. Prophylactic VNS significantly increased epithelial cell proliferation and diminished apoptosis compared to sham stimulation. VNS applied at day 4 during DSS administration (i.e., therapeutic VNS) decreased the influx of monocytes, monocyte-derived macrophages and neutrophils, and significantly reduced pro-inflammatory cytokine expression (i.e., Tnfα and Cxcl1) in immature macrophages compared to sham stimulation. Conclusions: A single period of VNS applied prior to DSS exposure reduced DSS-induced colitis by an improvement in epithelial integrity. On the other hand, VNS applied during the inflammatory phase of DSS colitis reduced cytokine expression in immature macrophages. Our data further underscores the potential of VNS as novel therapeutic approach for inflammatory bowel diseases.
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Affiliation(s)
- Elisa Meroni
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Nathalie Stakenborg
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Pedro J Gomez-Pinilla
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Michelle Stakenborg
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Mucosal Immunology, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Javier Aguilera-Lizarraga
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Morgane Florens
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Marcello Delfini
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Veronica de Simone
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Mucosal Immunology, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Gert De Hertogh
- Department of Pathology, Universitair Ziekenhuis Leuven, Leuven, Belgium
| | - Gera Goverse
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Mucosal Immunology, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Gianluca Matteoli
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Mucosal Immunology, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
| | - Guy E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), Lab for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases, Metabolism and Ageing, Katholieke Universiteit Leuven - University of Leuven, Leuven, Belgium
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22
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Stakenborg N, Boeckxstaens GE. Bioelectronics in the brain-gut axis: focus on inflammatory bowel disease (IBD). Int Immunol 2021; 33:337-348. [PMID: 33788920 PMCID: PMC8183669 DOI: 10.1093/intimm/dxab014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/30/2021] [Indexed: 12/17/2022] Open
Abstract
Accumulating evidence shows that intestinal homeostasis is mediated by cross-talk between the nervous system, enteric neurons and immune cells, together forming specialized neuroimmune units at distinct anatomical locations within the gut. In this review, we will particularly discuss how the intrinsic and extrinsic neuronal circuitry regulates macrophage function and phenotype in the gut during homeostasis and aberrant inflammation, such as observed in inflammatory bowel disease (IBD). Furthermore, we will provide an overview of basic and translational IBD research using these neuronal circuits as a novel therapeutic tool. Finally, we will highlight the different challenges ahead to make bioelectronic neuromodulation a standard treatment for intestinal immune-mediated diseases.
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Affiliation(s)
- Nathalie Stakenborg
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Herestraat 49, O&N1 bus 701, Leuven 3000, Belgium
| | - Guy E Boeckxstaens
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Herestraat 49, O&N1 bus 701, Leuven 3000, Belgium
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23
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Halder N, Lal G. Cholinergic System and Its Therapeutic Importance in Inflammation and Autoimmunity. Front Immunol 2021; 12:660342. [PMID: 33936095 PMCID: PMC8082108 DOI: 10.3389/fimmu.2021.660342] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/26/2021] [Indexed: 12/11/2022] Open
Abstract
Neurological and immunological signals constitute an extensive regulatory network in our body that maintains physiology and homeostasis. The cholinergic system plays a significant role in neuroimmune communication, transmitting information regarding the peripheral immune status to the central nervous system (CNS) and vice versa. The cholinergic system includes the neurotransmitter\ molecule, acetylcholine (ACh), cholinergic receptors (AChRs), choline acetyltransferase (ChAT) enzyme, and acetylcholinesterase (AChE) enzyme. These molecules are involved in regulating immune response and playing a crucial role in maintaining homeostasis. Most innate and adaptive immune cells respond to neuronal inputs by releasing or expressing these molecules on their surfaces. Dysregulation of this neuroimmune communication may lead to several inflammatory and autoimmune diseases. Several agonists, antagonists, and inhibitors have been developed to target the cholinergic system to control inflammation in different tissues. This review discusses how various molecules of the neuronal and non-neuronal cholinergic system (NNCS) interact with the immune cells. What are the agonists and antagonists that alter the cholinergic system, and how are these molecules modulate inflammation and immunity. Understanding the various functions of pharmacological molecules could help in designing better strategies to control inflammation and autoimmunity.
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Affiliation(s)
- Namrita Halder
- Laboratory of Autoimmunity and Tolerance, National Centre for Cell Science, Ganeshkhind, Pune, India
| | - Girdhari Lal
- Laboratory of Autoimmunity and Tolerance, National Centre for Cell Science, Ganeshkhind, Pune, India
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24
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Sangaleti CT, Katayama KY, De Angelis K, Lemos de Moraes T, Araújo AA, Lopes HF, Camacho C, Bortolotto LA, Michelini LC, Irigoyen MC, Olofsson PS, Barnaby DP, Tracey KJ, Pavlov VA, Consolim Colombo FM. The Cholinergic Drug Galantamine Alleviates Oxidative Stress Alongside Anti-inflammatory and Cardio-Metabolic Effects in Subjects With the Metabolic Syndrome in a Randomized Trial. Front Immunol 2021; 12:613979. [PMID: 33776997 PMCID: PMC7991724 DOI: 10.3389/fimmu.2021.613979] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/08/2021] [Indexed: 12/13/2022] Open
Abstract
Background: The metabolic syndrome (MetS) is an obesity-associated disorder of pandemic proportions and limited treatment options. Oxidative stress, low-grade inflammation and altered neural autonomic regulation, are important components and drivers of pathogenesis. Galantamine, an acetylcholinesterase inhibitor and a cholinergic drug that is clinically-approved (for Alzheimer's disease) has been implicated in neural cholinergic regulation of inflammation in several conditions characterized with immune and metabolic derangements. Here we examined the effects of galantamine on oxidative stress in parallel with inflammatory and cardio-metabolic parameters in subjects with MetS. Trial Design and Methods: The effects of galantamine treatment, 8 mg daily for 4 weeks or placebo, followed by 16 mg daily for 8 weeks or placebo were studied in randomly assigned subjects with MetS (n = 22 per group) of both genders. Oxidative stress, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities, lipid and protein peroxidation, and nitrite levels were analyzed before and at the end of the treatment. In addition, plasma cytokine and adipokine levels, insulin resistance (HOMA-IR) and other relevant cardio-metabolic indices were analyzed. Autonomic regulation was also examined by heart rate variability (HRV) before treatment, and at every 4 weeks of treatment. Results: Galantamine treatment significantly increased antioxidant enzyme activities, including SOD [+1.65 USOD/mg protein, [95% CI 0.39-2.92], P = 0.004] and CAT [+0.93 nmol/mg, [95% CI 0.34-1.51], P = 0.01], decreased lipid peroxidation [thiobarbituric acid reactive substances [log scale 0.72 pmol/mg, [95% CI 0.46-1.07], P = 0.05], and systemic nitrite levels [log scale 0.83 μmol/mg protein, [95% CI 0.57-1.20], P = 0.04] compared with placebo. In addition, galantamine significantly alleviated the inflammatory state and insulin resistance, and decreased the low frequency/high frequency ratio of HRV, following 8 and 12 weeks of drug treatment. Conclusion: Low-dose galantamine alleviates oxidative stress, alongside beneficial anti-inflammatory, and metabolic effects, and modulates neural autonomic regulation in subjects with MetS. These findings are of considerable interest for further studies with the cholinergic drug galantamine to ameliorate MetS.
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Affiliation(s)
- Carine Teles Sangaleti
- Hypertension Unit, University of São Paulo (USP), São Paulo, Brazil
- Postgraduate Program in Health Science, Midwestern State University (UNICENTRO), Paraná, Brazil
| | - Keyla Yukari Katayama
- Nursing Department Graduate Program in Nanosciences and Biosciences, Nove de Julho University (UNINOVE), São Paulo, Brazil
| | - Kátia De Angelis
- Nursing Department Graduate Program in Nanosciences and Biosciences, Nove de Julho University (UNINOVE), São Paulo, Brazil
- Department of Physiology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Tércio Lemos de Moraes
- Nursing Department Graduate Program in Nanosciences and Biosciences, Nove de Julho University (UNINOVE), São Paulo, Brazil
| | | | - Heno F. Lopes
- Hypertension Unit, University of São Paulo (USP), São Paulo, Brazil
- Nursing Department Graduate Program in Nanosciences and Biosciences, Nove de Julho University (UNINOVE), São Paulo, Brazil
| | - Cleber Camacho
- Nursing Department Graduate Program in Nanosciences and Biosciences, Nove de Julho University (UNINOVE), São Paulo, Brazil
| | | | - Lisete Compagno Michelini
- Biomedical Sciences Institute Department of Physiology and Biophysics, University of São Paulo (USP), São Paulo, Brazil
| | | | - Peder S. Olofsson
- Laboratory of Immunobiology, Department of Medicine, Center for Bioelectronic Medicine, Karolinska Institutet, Stockholm, Sweden
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Douglas P. Barnaby
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Kevin J. Tracey
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Valentin A. Pavlov
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Fernanda Marciano Consolim Colombo
- Hypertension Unit, University of São Paulo (USP), São Paulo, Brazil
- Nursing Department Graduate Program in Nanosciences and Biosciences, Nove de Julho University (UNINOVE), São Paulo, Brazil
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25
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Magalhães DDA, Batista JA, Sousa SG, Ferreira JDS, da Rocha Rodrigues L, Pereira CMC, do Nascimento Lima JV, de Albuquerque IF, Bezerra NLSD, Monteiro CEDS, Franco AX, da Costa Filho HB, Ferreira FCS, Havt A, Di Lenardo D, Vasconcelos DFP, de Oliveira JS, Soares PMG, Barbosa ALDR. McN-A-343, a muscarinic agonist, reduces inflammation and oxidative stress in an experimental model of ulcerative colitis. Life Sci 2021; 272:119194. [PMID: 33609541 DOI: 10.1016/j.lfs.2021.119194] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 01/24/2021] [Accepted: 02/01/2021] [Indexed: 11/30/2022]
Abstract
AIM The aim of the present study was to investigate the anti-inflammatory response mediated of the M1 muscarinic acetylcholine receptor (mAChR) during experimental colitis. MATERIAL AND METHODS After the induction of 6% acetic acid colitis, mice were treated with McN-A-343 0.5, 1.0, and 1.5 mg/kg or dexamethasone (DEXA, 2.0 mg/kg) or pirenzepine (PIR, 10 mg/kg; M1 mAChR antagonist). Colonic inflammation was assessed by macroscopic and microscopic lesion scores, colonic wet weight, myeloperoxidase (MPO) activity, interleukin-1 beta (IL1-β) levels and tumor necrosis factor alpha (TNF-α), glutathione (GSH), malondialdehyde (MDA) and nitrate and nitrite (NO3/NO2), mRNA expression of IKKα, nuclear factor kappa beta (NF-kB) and cyclooxygenase-2 (COX-2), as well protein expression of NF-kB and COX-2. RESULTS Treatment with McN-A-343 at a concentration of 1.5 mg/kg showed a significant reduction in intestinal damage as well as a decrease in wet weight, MPO activity, pro-inflammatory cytokine concentration, markers of oxidative stress and expression of inflammatory mediators. The action of the M1 agonist by the administration of pirenzepine, which promoted the blocking of the mAChR M1-mediated anti-inflammatory response, has also been proven. CONCLUSION The results suggest that peripheral colonic M1 mAChR is involved in reversing the pro-inflammatory effect of experimentally induced colitis, which may represent a promising therapeutic alternative for patients with ulcerative colitis.
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Affiliation(s)
- Diva de Aguiar Magalhães
- Laboratory of Experimental Physiopharmacology, LAFFEX, Federal University of Piauí, Parnaíba, Brazil; The Northeast Biotechnology Network, Federal University of Piauí, Teresina, Brazil
| | - Jalles Arruda Batista
- Laboratory of Experimental Physiopharmacology, LAFFEX, Federal University of Piauí, Parnaíba, Brazil; The Northeast Biotechnology Network, Federal University of Piauí, Teresina, Brazil
| | - Stefany Guimarães Sousa
- Laboratory of Experimental Physiopharmacology, LAFFEX, Federal University of Piauí, Parnaíba, Brazil; The Northeast Biotechnology Network, Federal University of Piauí, Teresina, Brazil
| | - Jayro Dos Santos Ferreira
- Laboratory of Experimental Physiopharmacology, LAFFEX, Federal University of Piauí, Parnaíba, Brazil
| | | | | | | | | | | | | | - Alvaro Xavier Franco
- Laboratory of Physiopharmacology Study of Gastrointestinal Tract, LEFFAG, Federal University of Ceará, Fortaleza, Brazil
| | | | | | - Alexandre Havt
- Laboratory of Molecular Toxinology, LTM, Federal University of Ceará, Fortaleza, CE, Brazil
| | - David Di Lenardo
- Laboratory of Analysis and Histological Processing, LAPHIS, Department of Biomedicine, Federal University of Piauí, Parnaíba, Brazil
| | - Daniel Fernando Pereira Vasconcelos
- The Northeast Biotechnology Network, Federal University of Piauí, Teresina, Brazil; Laboratory of Analysis and Histological Processing, LAPHIS, Department of Biomedicine, Federal University of Piauí, Parnaíba, Brazil
| | - Jefferson Soares de Oliveira
- The Northeast Biotechnology Network, Federal University of Piauí, Teresina, Brazil; Biochemistry Laboratory of Laticifers Plants (LABPL), Department of Biomedicine, Federal University of Piauí, Parnaíba, Brazil
| | - Pedro Marcos Gomes Soares
- Laboratory of Physiopharmacology Study of Gastrointestinal Tract, LEFFAG, Federal University of Ceará, Fortaleza, Brazil
| | - André Luiz Dos Reis Barbosa
- Laboratory of Experimental Physiopharmacology, LAFFEX, Federal University of Piauí, Parnaíba, Brazil; The Northeast Biotechnology Network, Federal University of Piauí, Teresina, Brazil.
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26
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Hanscom M, Loane DJ, Aubretch T, Leser J, Molesworth K, Hedgekar N, Ritzel RM, Abulwerdi G, Shea-Donohue T, Faden AI. Acute colitis during chronic experimental traumatic brain injury in mice induces dysautonomia and persistent extraintestinal, systemic, and CNS inflammation with exacerbated neurological deficits. J Neuroinflammation 2021; 18:24. [PMID: 33461596 PMCID: PMC7814749 DOI: 10.1186/s12974-020-02067-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 12/21/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Disruptions of brain-gut axis have been implicated in the progression of a variety of gastrointestinal (GI) disorders and central nervous system (CNS) diseases and injuries, including traumatic brain injury (TBI). TBI is a chronic disease process characterized by persistent secondary injury processes which can be exacerbated by subsequent challenges. Enteric pathogen infection during chronic TBI worsened cortical lesion volume; however, the pathophysiological mechanisms underlying the damaging effects of enteric challenge during chronic TBI remain unknown. This preclinical study examined the effect of intestinal inflammation during chronic TBI on associated neurobehavioral and neuropathological outcomes, systemic inflammation, and dysautonomia. METHODS Dextran sodium sulfate (DSS) was administered to adult male C57BL/6NCrl mice 28 days following craniotomy (Sham) or TBI for 7 days to induce intestinal inflammation, followed by a return to normal drinking water for an additional 7 to 28 days for recovery; uninjured animals (Naïve) served as an additional control group. Behavioral testing was carried out prior to, during, and following DSS administration to assess changes in motor and cognitive function, social behavior, and mood. Electrocardiography was performed to examine autonomic balance. Brains were collected for histological and molecular analyses of injury lesion, neurodegeneration, and neuroinflammation. Blood, colons, spleens, mesenteric lymph nodes (mLNs), and thymus were collected for morphometric analyses and/or immune characterization by flow cytometry. RESULTS Intestinal inflammation 28 days after craniotomy or TBI persistently induced, or exacerbated, respectively, deficits in fine motor coordination, cognition, social behavior, and anxiety-like behavior. Behavioral changes were associated with an induction, or exacerbation, of hippocampal neuronal cell loss and microglial activation in Sham and TBI mice administered DSS, respectively. Acute DSS administration resulted in a sustained systemic immune response with increases in myeloid cells in blood and spleen, as well as myeloid cells and lymphocytes in mesenteric lymph nodes. Dysautonomia was also induced in Sham and TBI mice administered DSS, with increased sympathetic tone beginning during DSS administration and persisting through the first recovery week. CONCLUSION Intestinal inflammation during chronic experimental TBI causes a sustained systemic immune response and altered autonomic balance that are associated with microglial activation, increased neurodegeneration, and persistent neurological deficits.
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Affiliation(s)
- Marie Hanscom
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA.
| | - David J Loane
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
| | - Taryn Aubretch
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Jenna Leser
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Kara Molesworth
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Nivedita Hedgekar
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Rodney M Ritzel
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Gelareh Abulwerdi
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
| | - Terez Shea-Donohue
- Division of Translational Radiation Sciences (DTRS), Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alan I Faden
- Department of Anesthesiology and Shock, Trauma and Anesthesiology Research (STAR) Center, University of Maryland School of Medicine, 685 West Baltimore Street, MSTF #6-016, Baltimore, MD, 21201, USA
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27
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Wu YJ, Wang L, Ji CF, Gu SF, Yin Q, Zuo J. The Role of α7nAChR-Mediated Cholinergic Anti-inflammatory Pathway in Immune Cells. Inflammation 2021; 44:821-834. [PMID: 33405021 DOI: 10.1007/s10753-020-01396-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 11/05/2020] [Accepted: 12/07/2020] [Indexed: 12/14/2022]
Abstract
Alpha 7 nicotinic acetylcholine receptor (α7nAChR) is widely distributed in the nervous and non-cholinergic immune systems. It is necessary for the cholinergic transmitter to participate in the regulation of inflammatory response and is the key element of cholinergic anti-inflammatory pathway (CAP). Because of the profound impact of CAP on the immune system, α7nAChR is considered as a potential therapeutic target for the treatment of inflammatory diseases. Available evidences confirmed that manipulation of CAP by activating α7nAChR with either endogenous acetylcholine (ACh) or cholinergic agonists can substantially alleviate inflammatory responses both in vivo and in vitro. However, the mechanism through which CAP curbs the excessive pro-inflammatory responses and maintains immune homeostasis is not fully understood. Obtained clues suggest that the crosstalk between CAP and classical inflammatory pathways is the key to elucidate the anti-inflammatory mechanism, and the impacts of CAP activation in α7nAChR-expressing immune cells are the foundation of the immunoregulatory property. In this article, we review and update the knowledge concerning the progresses of α7nAChR-based CAP, including α7nAChR properties, signal transductions, interactions with classic immune pathways, and immunoregulatory functions in different immune cells. Certain critical issues to be addressed are also highlighted. By providing a panoramic view of α7nAChR, the summarized evidences will pave the way for the development of novel anti-inflammatory reagents and strategy and inspire further researches.
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Affiliation(s)
- Yi-Jin Wu
- The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China
| | - Li Wang
- Department of Pharmacy, Wuhu Medicine and Health School, Wuhu, 241000, China
| | - Chao-Fan Ji
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
| | - Shao-Fei Gu
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China
| | - Qin Yin
- The Second Affiliated Hospital of Wannan Medical College, Wuhu, 241000, China.
- School of Pharmacy, Wannan Medical College, Wuhu, 241000, China.
| | - Jian Zuo
- Department of Traditional Chinese Medicine, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), Wuhu, 241000, China.
- Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241000, China.
- Research Center of Integrated Traditional and Western Medicine, Wannan Medical College, 241000, Wuhu, China.
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28
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Eckol protects against acute experimental colitis in mice: Possible involvement of Reg3g. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104088] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
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Zeng Z, Mukherjee A, Varghese AP, Yang XL, Chen S, Zhang H. Roles of G protein-coupled receptors in inflammatory bowel disease. World J Gastroenterol 2020; 26:1242-1261. [PMID: 32256014 PMCID: PMC7109274 DOI: 10.3748/wjg.v26.i12.1242] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/18/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a complex disease with multiple pathogenic factors. Although the pathogenesis of IBD is still unclear, a current hypothesis suggests that genetic susceptibility, environmental factors, a dysfunctional immune system, the microbiome, and the interactions of these factors substantially contribute to the occurrence and development of IBD. Although existing and emerging drugs have been proven to be effective in treating IBD, none can cure IBD permanently. G protein-coupled receptors (GPCRs) are critical signaling molecules implicated in the immune response, cell proliferation, inflammation regulation and intestinal barrier maintenance. Breakthroughs in the understanding of the structures and functions of GPCRs have provided a driving force for exploring the roles of GPCRs in the pathogenesis of diseases, thereby leading to the development of GPCR-targeted medication. To date, a number of GPCRs have been shown to be associated with IBD, significantly advancing the drug discovery process for IBD. The associations between GPCRs and disease activity, disease severity, and disease phenotypes have also paved new avenues for the precise management of patients with IBD. In this review, we mainly focus on the roles of the most studied proton-sensing GPCRs, cannabinoid receptors, and estrogen-related GPCRs in the pathogenesis of IBD and their potential clinical values in IBD and some other diseases.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Arjudeb Mukherjee
- West China School of Medicine, Sichuan University, Chengdu 410061, Sichuan Province, China
| | | | - Xiao-Li Yang
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Sha Chen
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Hu Zhang
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
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Pavlov VA, Chavan SS, Tracey KJ. Bioelectronic Medicine: From Preclinical Studies on the Inflammatory Reflex to New Approaches in Disease Diagnosis and Treatment. Cold Spring Harb Perspect Med 2020; 10:a034140. [PMID: 31138538 PMCID: PMC7050582 DOI: 10.1101/cshperspect.a034140] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Bioelectronic medicine is an evolving field in which new insights into the regulatory role of the nervous system and new developments in bioelectronic technology result in novel approaches in disease diagnosis and treatment. Studies on the immunoregulatory function of the vagus nerve and the inflammatory reflex have a specific place in bioelectronic medicine. These studies recently led to clinical trials with bioelectronic vagus nerve stimulation in inflammatory diseases and other conditions. Here, we outline key findings from this preclinical and clinical research. We also point to other aspects and pillars of interdisciplinary research and technological developments in bioelectronic medicine.
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Affiliation(s)
- Valentin A Pavlov
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York 11030
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York 11550
| | - Sangeeta S Chavan
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York 11030
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York 11550
| | - Kevin J Tracey
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York 11030
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York 11550
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Cox MA, Bassi C, Saunders ME, Nechanitzky R, Morgado-Palacin I, Zheng C, Mak TW. Beyond neurotransmission: acetylcholine in immunity and inflammation. J Intern Med 2020; 287:120-133. [PMID: 31710126 DOI: 10.1111/joim.13006] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 08/24/2019] [Accepted: 09/10/2019] [Indexed: 12/21/2022]
Abstract
Acetylcholine (ACh) is best known as a neurotransmitter and was the first such molecule identified. ACh signalling in the neuronal cholinergic system has long been known to regulate numerous biological processes (reviewed by Beckmann and Lips). In actuality, ACh is a ubiquitous signalling molecule that is produced by numerous non-neuronal cell types and even by some single-celled organisms. Within multicellular organisms, a non-neuronal cholinergic system that includes the immune system functions in parallel with the neuronal cholinergic system. Several immune cell types both respond to ACh signals and can directly produce ACh. Recent work from our laboratory has demonstrated that the capacity to produce ACh is an intrinsic property of T cells responding to viral infection, and that this ability to produce ACh is dependent upon IL-21 signalling to the T cells. Furthermore, during infection this immune-derived ACh is necessary for the T cells to migrate into infected tissues. In this review, we will discuss the various sources of ACh that are relevant during immune responses and describe how ACh acts on immune cells to influence their functions. We will also address the clinical implications of this fascinating aspect of immunity, focusing on ACh's role in the migration of T cells during infection and cancer.
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Affiliation(s)
- M A Cox
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - C Bassi
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - M E Saunders
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - R Nechanitzky
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - I Morgado-Palacin
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - C Zheng
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - T W Mak
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.,Ontario Institute for Cancer Research, Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.,Department of Immunology, University of Toronto, Toronto, ON, Canada.,Department of Pathology, University of Hong Kong, Hong Kong, Hong Kong
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32
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Murray K, Barboza M, Rude KM, Brust-Mascher I, Reardon C. Functional circuitry of neuro-immune communication in the mesenteric lymph node and spleen. Brain Behav Immun 2019; 82:214-223. [PMID: 31445965 PMCID: PMC6800652 DOI: 10.1016/j.bbi.2019.08.188] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/20/2019] [Accepted: 08/21/2019] [Indexed: 12/23/2022] Open
Abstract
The peripheral nervous system is an active participant in immune responses capable of blocking aberrant activation of a variety of immune cells. As one of these neuro-immune circuits, the cholinergic anti-inflammatory pathway has been well established to reduce the severity of several immunopathologies. While the activation of this pathway by vagal nerve stimulation requires sympathetic innervation of the spleen, the neuro-immune circuitry remains highly controversial. Neuro-immune pathways in other lymphoid tissues such as mesenteric lymph nodes (MLN) that are critical to the surveillance of the small intestine and proximal colon have not been assessed. Using conditionally expressed Channelrhodopsin, selective stimulation of sympathetic post-ganglionic neurons in the superior mesenteric ganglion (SMG) prevented macrophage activation and LPS-induced TNFα production in the spleen and MLN, but not in the inguinal LN. Site selective stimulation of the SMG induced the release of norepinephrine, resulting in β2AR dependent acetylcholine release in the MLN and spleen. VNS-evoked release of norepinephrine and acetylcholine in the MLN and spleen was significantly reduced using selective optogenetic blockade applied at the SMG. Additionally, this optogenetic blockade restored LPS-induced TNFα production, despite VNS. These studies identify the superior mesenteric ganglion as a critical node in a neuro-immune circuit that can inhibit immune function in the MLN and the spleen.
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Affiliation(s)
- Kaitlin Murray
- Department. of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America
| | - Mariana Barboza
- Department. of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America
| | - Kavi M. Rude
- Department. of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America
| | - Ingrid Brust-Mascher
- Department. of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America
| | - Colin Reardon
- Department of Anatomy, Physiology, and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA, USA.
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Willemze RA, Brinkman DJ, Welting O, van Hamersveld PHP, Verseijden C, Luyer MD, Wildenberg ME, Seppen J, de Jonge WJ. Acetylcholine-producing T cells augment innate immune-driven colitis but are redundant in T cell-driven colitis. Am J Physiol Gastrointest Liver Physiol 2019; 317:G557-G568. [PMID: 31322912 DOI: 10.1152/ajpgi.00067.2019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Clinical trials suggest that vagus nerve stimulation presents an alternative approach to classical immune suppression in Crohn's disease. T cells capable of producing acetylcholine (ChAT+ T cells) in the spleen are essential mediators of the anti-inflammatory effect of vagus nerve stimulation. Besides the spleen, ChAT+ T cells are found abundantly in Peyer's patches of the small intestine. However, the role of ChAT+ T cells in colitis pathogenesis is unknown. Here, we made use of CD4creChATfl/fl mice (CD4ChAT-/- mice) lacking ChAT expression specifically in CD4+ T cells. Littermates (ChATfl/fl mice) served as controls. In acute dextran sulfate sodium (DSS)-induced colitis (7 days of 2% DSS in drinking water), CD4ChAT-/- mice showed attenuated colitis and lower intestinal inflammatory cytokine levels compared with ChATfl/fl mice. In contrast, in a resolution model of DSS-induced colitis (5 days of 2% DSS followed by 7 days without DSS), CD4ChAT-/- mice demonstrated a worsened colitis recovery and augmented colonic histological inflammation scores and inflammatory cytokine levels as compared with ChATfl/fl mice. In a transfer colitis model using CD4+CD45RBhigh T cells, T cells from CD4ChAT-/- mice induced a similar level of colitis compared with ChATfl/fl T cells. Together, our results indicate that ChAT+ T cells aggravate the acute innate immune response upon mucosal barrier disruption in an acute DSS-induced colitis model, whereas they are supporting the later resolution process of this innate immune-driven colitis. Surprisingly, ChAT expression in T cells seems redundant in the context of T cell-driven colitis.NEW & NOTEWORTHY By using different mouse models of experimental colitis, we provide evidence that in dextran sulfate sodium-induced colitis, ChAT+ T cells capable of producing acetylcholine worsen the acute immune response, whereas they support the later healing phase of this innate immune-driven colitis.
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Affiliation(s)
- Rose A Willemze
- Amsterdam University Medical Center, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef, Amsterdam, The Netherlands
| | - David J Brinkman
- Amsterdam University Medical Center, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef, Amsterdam, The Netherlands
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
| | - Olaf Welting
- Amsterdam University Medical Center, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef, Amsterdam, The Netherlands
| | - Patricia H P van Hamersveld
- Amsterdam University Medical Center, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef, Amsterdam, The Netherlands
| | - Caroline Verseijden
- Amsterdam University Medical Center, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef, Amsterdam, The Netherlands
| | - Misha D Luyer
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
| | - Manon E Wildenberg
- Amsterdam University Medical Center, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef, Amsterdam, The Netherlands
| | - Jurgen Seppen
- Amsterdam University Medical Center, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef, Amsterdam, The Netherlands
| | - Wouter J de Jonge
- Amsterdam University Medical Center, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Meibergdreef, Amsterdam, The Netherlands
- Department of Surgery, University of Bonn, Bonn, Germany
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Mogilevski T, Burgell R, Aziz Q, Gibson PR. Review article: the role of the autonomic nervous system in the pathogenesis and therapy of IBD. Aliment Pharmacol Ther 2019; 50:720-737. [PMID: 31418887 DOI: 10.1111/apt.15433] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 04/25/2019] [Accepted: 07/01/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND There is a growing body of evidence implicating a role for the brain-gut axis in the pathogenesis of inflammation in patients with IBD. AIMS To perform a narrative review of published literature regarding the association of the autonomic nervous system and intestinal inflammation and to describe the rationale for and emerging use of autonomic manipulation as a therapeutic agent METHODS: Current relevant literature was summarised and critically examined. RESULTS There is substantial pre-clinical and clinical evidence for a multifaceted anti-inflammatory effect of the vagus at both systemic and local intestinal levels. It acts via acetylcholine-mediated activation of α-7-acetylcholine receptors involving multiple cell types in innate and adaptive immunity and the enteric nervous system with subsequent protective influences on the intestinal barrier, inflammatory mechanisms and the microbiome. In patients with IBD, there is evidence for a sympatho-vagal imbalance, functional enteric neuronal depletion and hyporeactivity of the hypothalamic-pituitary-adrenal axis. Direct or transcutaneous vagal neuromodulation up-regulates the cholinergic anti-inflammatory pathway in pre-clinical and clinical models with down-regulation of systemic and local intestinal inflammation. This is supported by two small studies in Crohn's disease although remains to be investigated in ulcerative colitis. CONCLUSIONS Modulating the cholinergic anti-inflammatory pathway influences inflammation both systemically and at a local intestinal level. It represents a potentially underutilised anti-inflammatory therapeutic strategy. Given the likely pathogenic role of the autonomic nervous system in patients with IBD, vagal neuromodulation, an apparently safe and successful means of increasing vagal tone, warrants further clinical exploration.
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Affiliation(s)
- Tamara Mogilevski
- Centre for Neuroscience, Surgery and Trauma, Barts and the London School of Medicine and Dentistry, Blizard Institute, Wingate Institute of Neurogastroenterology, London, UK.,Barts Health NHS Trust, London, UK.,Department of Gastroenterology, Monash University and Alfred Health, Melbourne, Australia
| | - Rebecca Burgell
- Department of Gastroenterology, Monash University and Alfred Health, Melbourne, Australia
| | - Qasim Aziz
- Centre for Neuroscience, Surgery and Trauma, Barts and the London School of Medicine and Dentistry, Blizard Institute, Wingate Institute of Neurogastroenterology, London, UK.,Barts Health NHS Trust, London, UK
| | - Peter R Gibson
- Department of Gastroenterology, Monash University and Alfred Health, Melbourne, Australia
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35
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36
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Bonaz B, Sinniger V, Pellissier S. Vagus Nerve Stimulation at the Interface of Brain-Gut Interactions. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a034199. [PMID: 30201788 DOI: 10.1101/cshperspect.a034199] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The vagus nerve, a key component of the cross-communication between the gut and the brain, is a major element of homeostasis sensing the "milieu intérieur" and boosting the nervous and endocrine responses to maintain the gastrointestinal health status. This nerve has anti-inflammatory properties regulating the gut through the activation of the hypothalamic-pituitary-adrenal axis and the release of cortisol and through a vagovagal reflex, which has an anti-tumor necrosis factor (TNF) effect called the cholinergic anti-inflammatory pathway. Stimulating this nerve is an interesting tool as a nondrug therapy for the treatment of gastrointestinal diseases in which brain-gut communication is dysfunctional, such as inflammatory bowel disorders and others. This review presents the rationale of vagal gastrointestinal physiology and diseases and the most recent advances in vagus nerve stimulation. It also highlights the main issues to be addressed in the future to improve this bioelectronic therapy for gastrointestinal disorders.
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Affiliation(s)
- Bruno Bonaz
- Division of Hepato-Gastroenterology, Grenoble University Hospital, 38043 Grenoble Cedex 09, France.,U1216, INSERM, GIN, Grenoble Institute of Neurosciences, University Grenoble Alpes, Grenoble, France
| | - Valérie Sinniger
- Division of Hepato-Gastroenterology, Grenoble University Hospital, 38043 Grenoble Cedex 09, France.,U1216, INSERM, GIN, Grenoble Institute of Neurosciences, University Grenoble Alpes, Grenoble, France
| | - Sonia Pellissier
- University Grenoble Alpes, University Savoie Mont Blanc, 38000 Grenoble, France
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Brinkman DJ, Ten Hove AS, Vervoordeldonk MJ, Luyer MD, de Jonge WJ. Neuroimmune Interactions in the Gut and Their Significance for Intestinal Immunity. Cells 2019; 8:670. [PMID: 31269754 PMCID: PMC6679154 DOI: 10.3390/cells8070670] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Revised: 06/24/2019] [Accepted: 06/28/2019] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD) have a complex, multifactorial pathophysiology with an unmet need for effective treatment. This calls for novel strategies to improve disease outcome and quality of life for patients. Increasing evidence suggests that autonomic nerves and neurotransmitters, as well as neuropeptides, modulate the intestinal immune system, and thereby regulate the intestinal inflammatory processes. Although the autonomic nervous system is classically divided in a sympathetic and parasympathetic branch, both play a pivotal role in the crosstalk with the immune system, with the enteric nervous system acting as a potential interface. Pilot clinical trials that employ vagus nerve stimulation to reduce inflammation are met with promising results. In this paper, we review current knowledge on the innervation of the gut, the potential of cholinergic and adrenergic systems to modulate intestinal immunity, and comment on ongoing developments in clinical trials.
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Affiliation(s)
- David J Brinkman
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
- Department of Surgery, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands
| | - Anne S Ten Hove
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
| | - Margriet J Vervoordeldonk
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands
- Galvani Bioelectronics, Stevenage SG1 2NY, UK
| | - Misha D Luyer
- Department of Surgery, Catharina Hospital, 5623 EJ Eindhoven, The Netherlands
| | - Wouter J de Jonge
- Tytgat Institute for Intestinal and Liver Research, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 BK, The Netherlands.
- Department of General, Visceral-, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany.
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38
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Pavlov VA. Collateral benefits of studying the vagus nerve in bioelectronic medicine. Bioelectron Med 2019; 5:5. [PMID: 32232096 PMCID: PMC7098239 DOI: 10.1186/s42234-019-0021-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Accepted: 04/24/2019] [Indexed: 12/20/2022] Open
Abstract
Studies on the role of the vagus nerve in the regulation of immunity and inflammation have contributed to current preclinical and clinical efforts in bioelectronic medicine. In parallel, this research has generated new insights into the cellular and molecular mechanisms underlying the immunoregulatory functions of the vagus nerve within the inflammatory reflex. The vagus nerve and other cellular components of the inflammatory reflex are implicated in the regulation of bleeding, cancer, obesity, blood pressure, viral infections and other conditions. This collateral benefit broadens scientific horizons and provides new rationale for technological advances and therapeutic implications.
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Affiliation(s)
- Valentin A. Pavlov
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health System, Manhasset, NY 11030 USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11550 USA
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Kermarrec L, Eissa N, Wang H, Kapoor K, Diarra A, Gounni AS, Bernstein CN, Ghia J. Semaphorin-3E attenuates intestinal inflammation through the regulation of the communication between splenic CD11C + and CD4 + CD25 - T-cells. Br J Pharmacol 2019; 176:1235-1250. [PMID: 30736100 PMCID: PMC6468259 DOI: 10.1111/bph.14614] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 01/02/2019] [Accepted: 01/15/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND PURPOSE An alteration in the communication between the innate and adaptive immune cells is a hallmark of ulcerative colitis (UC). Semaphorin-3E (SEMA3E), a secreted guidance protein, regulates various immune responses. EXPERIMENTAL APPROACH We investigated the expression of SEMA3E in colonic biopsies of active UC patients and its mechanisms in Sema3e-/- mice using an experimental model of UC. KEY RESULTS SEMA3E level was decreased in active UC patients and negatively correlated with pro-inflammatory mediators. Colonic expression of SEMA3E was reduced in colitic Sema3e+/+ mice, and recombinant (rec-) Plexin-D1 treatment exacerbated disease severity. In vivo rec-SEMA3E treatment restored SEMA3E level in colitic Sema3e+/+ mice. In Sema3e-/- mice, disease severity was increased, and rec-SEMA3E ameliorated these effects. Lack of Sema3e increased the expression of CD11c and CD86 markers. Colitic Sema3e-/- splenocytes and splenic CD11c+ cells produced more IL-12/23 and IFN-γ compared to Sema3e+/+ , and rec-SEMA3E reduced their release as much as NF-κB inhibitors, whereas an NF-κB activator increased their production and attenuated the effect of rec-SEMA3E. Colitic Sema3e-/- splenic CD11c+ /CD4+ CD25- T-cell co-cultures produced higher concentrations of IFN-γ and IL-17 when compared to colitic Sema3e+/+ splenic cell co-cultures, and rec-SEMA3E decreased these effects. In vitro, anti-IL-12p19 and -12p35 antibodies and rec-IL-12 and -23 treatment confirmed the crosstalk between CD11c+ and CD4+ CD25- T-cells. CONCLUSION AND IMPLICATIONS SEMA3E is reduced in colitis and modulates colonic inflammation by regulating the interaction between CD11c+ and CD4+ CD25- T-cells via an NF-κB-dependent mechanism. Thus, SEMA3E could be a potential therapeutic target for UC patients.
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Affiliation(s)
| | - Nour Eissa
- Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
- Children Research Hospital Research Institute of ManitobaUniversity of ManitobaWinnipegManitobaCanada
- Department of Internal Medicine Section of Gastroenterology, IBD Clinical and Research CentreUniversity of ManitobaWinnipegManitobaCanada
| | - Hongxing Wang
- Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
| | - Kunal Kapoor
- Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
| | - Abdoulaye Diarra
- Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
| | | | - Charles N. Bernstein
- Department of Internal Medicine Section of Gastroenterology, IBD Clinical and Research CentreUniversity of ManitobaWinnipegManitobaCanada
| | - Jean‐Eric Ghia
- Department of ImmunologyUniversity of ManitobaWinnipegManitobaCanada
- Children Research Hospital Research Institute of ManitobaUniversity of ManitobaWinnipegManitobaCanada
- Department of Internal Medicine Section of Gastroenterology, IBD Clinical and Research CentreUniversity of ManitobaWinnipegManitobaCanada
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40
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Chang EH, Chavan SS, Pavlov VA. Cholinergic Control of Inflammation, Metabolic Dysfunction, and Cognitive Impairment in Obesity-Associated Disorders: Mechanisms and Novel Therapeutic Opportunities. Front Neurosci 2019; 13:263. [PMID: 31024226 PMCID: PMC6460483 DOI: 10.3389/fnins.2019.00263] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Accepted: 03/06/2019] [Indexed: 12/26/2022] Open
Abstract
Obesity and obesity-associated disorders have become world-wide epidemics, substantially increasing the risk of debilitating morbidity and mortality. A characteristic feature of these disorders, which include the metabolic syndrome (MetS) and type 2 diabetes, is chronic low-grade inflammation stemming from metabolic and immune dysregulation. Inflammation in the CNS (neuroinflammation) and cognitive impairment have also been associated with obesity-driven disorders. The nervous system has a documented role in the regulation of metabolic homeostasis and immune function, and recent studies have indicated the important role of vagus nerve and brain cholinergic signaling in this context. In this review, we outline relevant aspects of this regulation with a specific focus on obesity-associated conditions. We outline accumulating preclinical evidence for the therapeutic efficacy of cholinergic stimulation in alleviating obesity-associated inflammation, neuroinflammation, and metabolic derangements. Recently demonstrated beneficial effects of galantamine, a centrally acting cholinergic drug and cognitive enhancer, in patients with MetS are also summarized. These studies provide a rationale for further therapeutic developments using pharmacological and bioelectronic cholinergic modulation for clinical benefit in obesity-associated disorders.
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Affiliation(s)
- Eric H. Chang
- Center for Bioelectronic Medicine and Biomedical Sciences, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Sangeeta S. Chavan
- Center for Bioelectronic Medicine and Biomedical Sciences, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Valentin A. Pavlov
- Center for Bioelectronic Medicine and Biomedical Sciences, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
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41
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Lehner KR, Silverman HA, Addorisio ME, Roy A, Al-Onaizi MA, Levine Y, Olofsson PS, Chavan SS, Gros R, Nathanson NM, Al-Abed Y, Metz CN, Prado VF, Prado MAM, Tracey KJ, Pavlov VA. Forebrain Cholinergic Signaling Regulates Innate Immune Responses and Inflammation. Front Immunol 2019; 10:585. [PMID: 31024522 PMCID: PMC6455130 DOI: 10.3389/fimmu.2019.00585] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 03/05/2019] [Indexed: 01/04/2023] Open
Abstract
The brain regulates physiological functions integral to survival. However, the insight into brain neuronal regulation of peripheral immune function and the neuromediator systems and pathways involved remains limited. Here, utilizing selective genetic and pharmacological approaches, we studied the role of forebrain cholinergic signaling in the regulation of peripheral immune function and inflammation. Forebrain-selective genetic ablation of acetylcholine release and vagotomy abolished the suppression of serum TNF by the centrally-acting cholinergic drug galantamine in murine endotoxemia. Selective stimulation of acetylcholine action on the M1 muscarinic acetylcholine receptor (M1 mAChR) by central administration of the positive allosteric modulator benzyl quinolone carboxylic acid (BQCA) suppressed serum TNF (TNFα) levels in murine endotoxemia. This effect was recapitulated by peripheral administration of the compound. BQCA also improved survival in murine endotoxemia and these effects were abolished in M1 mAChR knockout (KO) mice. Selective optogenetic stimulation of basal forebrain cholinergic neurons innervating brain regions with abundant M1 mAChR localization reduced serum TNF in endotoxemic mice. These findings reveal that forebrain cholinergic neurons regulate innate immune responses and inflammation, suggesting the possibility that in diseases associated with cholinergic dysfunction, including Alzheimer's disease this anti-inflammatory regulation can be impaired. These results also suggest novel anti-inflammatory approaches based on targeting forebrain cholinergic signaling in sepsis and other disorders characterized by immune dysregulation.
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Affiliation(s)
- Kurt R. Lehner
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
| | - Harold A. Silverman
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Meghan E. Addorisio
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Ashbeel Roy
- Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Mohammed A. Al-Onaizi
- Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada
- Department of Anatomy, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait
| | - Yaakov Levine
- SetPoint Medical Corporation, Valencia, CA, United States
| | - Peder S. Olofsson
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Department of Medicine, Center for Bioelectronic Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Sangeeta S. Chavan
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Robert Gros
- Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Neil M. Nathanson
- Department of Pharmacology, University of Washington, Seattle, WA, United States
| | - Yousef Al-Abed
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
- Department of Medicinal Chemistry, Center for Molecular Innovation, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Christine N. Metz
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Vania F. Prado
- Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Graduate Program in Neuroscience, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Marco A. M. Prado
- Schulich School of Medicine and Dentistry, Robarts Research Institute, University of Western Ontario, London, ON, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
- Graduate Program in Neuroscience, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada
| | - Kevin J. Tracey
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Valentin A. Pavlov
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
- Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, United States
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Meroni E, Stakenborg N, Viola MF, Boeckxstaens GE. Intestinal macrophages and their interaction with the enteric nervous system in health and inflammatory bowel disease. Acta Physiol (Oxf) 2019; 225:e13163. [PMID: 29998613 PMCID: PMC6519157 DOI: 10.1111/apha.13163] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 07/07/2018] [Accepted: 07/09/2018] [Indexed: 12/19/2022]
Abstract
Over the past decades, there has been an increasing understanding of cellular and molecular mechanisms that mediate modulation of the immune system by the autonomic nervous system. The discovery that vagal nerve stimulation (VNS) attenuates endotoxin-induced experimental sepsis paved the way for further studies investigating neuro-immune interaction. In particular, great attention is now given to intestinal macrophages: several studies report the existence of both intrinsic and extrinsic neural mechanisms by which intestinal immune homoeostasis can be regulated in different layers of the intestine, mainly by affecting macrophage activation through neurotransmitter release. Given the important role of inflammation in numerous disease processes, such as inflammatory bowel disease (IBD), cholinergic anti-inflammatory mechanisms are under intense investigation both from a basic and clinical science perspective in immune-mediated diseases such as IBD. This review discusses recent insights on the cross-talk between enteric neurons and the immune system, especially focusing on macrophages, and provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response as therapeutic alternative to reinstall immune homoeostasis in intestinal chronic inflammation.
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Affiliation(s)
- Elisa Meroni
- Department of Chronic Diseases, Metabolism and AgeingTranslational Research Center for Gastrointestinal Disorders (TARGID)KU Leuven—University of LeuvenLeuvenBelgium
| | - Nathalie Stakenborg
- Department of Chronic Diseases, Metabolism and AgeingTranslational Research Center for Gastrointestinal Disorders (TARGID)KU Leuven—University of LeuvenLeuvenBelgium
| | - Maria Francesca Viola
- Department of Chronic Diseases, Metabolism and AgeingTranslational Research Center for Gastrointestinal Disorders (TARGID)KU Leuven—University of LeuvenLeuvenBelgium
| | - Guy E. Boeckxstaens
- Department of Chronic Diseases, Metabolism and AgeingTranslational Research Center for Gastrointestinal Disorders (TARGID)KU Leuven—University of LeuvenLeuvenBelgium
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In Vivo Effects of Neostigmine and Physostigmine on Neutrophil Functions and Evaluation of Acetylcholinesterase and Butyrylcholinesterase as Inflammatory Markers during Experimental Sepsis in Rats. Mediators Inflamm 2019; 2019:8274903. [PMID: 30804708 PMCID: PMC6360579 DOI: 10.1155/2019/8274903] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 09/27/2018] [Accepted: 11/26/2018] [Indexed: 12/17/2022] Open
Abstract
Introduction Recent studies have shown that acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) may serve as important diagnostic and therapeutic targets in sepsis. Since polymorphonuclear neutrophils (PMNs) play a pivotal role in the early phase of sepsis, we evaluated the potential therapeutic effects of cholinesterase inhibitors on PMN functions during cecal ligation and puncture- (CLP-) induced sepsis and investigated the roles of AChE and BChE as inflammatory markers under standardized experimental conditions. Methods Sham surgery or CLP was performed in male Wistar rats (n = 60). Animals were randomized into four groups: physostigmine, 100 μg/kg; neostigmine, 75 μg/kg; 0.9% saline (control group); and sham group, each applied four times over 24 h. The levels of reactive oxygen species (ROS) production and CD11b/CD62l expression were quantified by flow cytometry at t = 0, 6, 15, 20, and 24 h. Blood gas analysis as well as AChE and BChE activity levels was measured by validated point-of-care measurements. Clinical scores and survival times were determined. Results CLP induced a significant increase in ROS production and CD11b upregulation by rat PMNs. Treatment with physostigmine or neostigmine significantly reduced ROS production and CD11b upregulation by PMNs 20 h after CLP induction. In physostigmine-treated animals, survival times were significantly improved compared to the control animals, but not in neostigmine-treated animals. While AChE activity significantly decreased in the control animals at t > 6 h, AChE activity did not change in the sham group. BChE activity decreased at t > 20 h in the control animals. Conclusion While AChE activity may serve as an acute inflammatory marker, BChE activity shows a delayed decrease. Administration of centrally acting physostigmine in CLP-induced sepsis in rats has protective effects on PMN functions and improves survival times, which may be of interest in clinical practice.
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Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation. Nat Commun 2018; 9:5300. [PMID: 30546054 PMCID: PMC6294142 DOI: 10.1038/s41467-018-07747-0] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 11/23/2018] [Indexed: 12/18/2022] Open
Abstract
The liver possesses a high regenerative capacity. Liver regeneration is a compensatory response overcoming disturbances of whole-body homeostasis provoked by organ defects. Here we show that a vagus-macrophage-hepatocyte link regulates acute liver regeneration after liver injury and that this system is critical for promoting survival. Hepatic Foxm1 is rapidly upregulated after partial hepatectomy (PHx). Hepatic branch vagotomy (HV) suppresses this upregulation and hepatocyte proliferation, thereby increasing mortality. In addition, hepatic FoxM1 supplementation in vagotomized mice reverses the suppression of liver regeneration and blocks the increase in post-PHx mortality. Hepatic macrophage depletion suppresses both post-PHx Foxm1 upregulation and remnant liver regeneration, and increases mortality. Hepatic Il-6 rises rapidly after PHx and this is suppressed by HV, muscarinic blockade or resident macrophage depletion. Furthermore, IL-6 neutralization suppresses post-PHx Foxm1 upregulation and remnant liver regeneration. Collectively, vagal signal-mediated IL-6 production in hepatic macrophages upregulates hepatocyte FoxM1, leading to liver regeneration and assures survival. The mechanisms underlying the regenerative capacity of the liver are not fully understood. Here, the authors show that the acute regenerative response to liver injury in mice is regulated by the communication involving the vagus nerve, macrophages, and hepatocytes, leading to hepatic FoxM1 activation and promotion of overall survival.
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Liu D, Li T, Luo H, Zuo X, Liu S, Wu S. The effect of the cholinergic anti-inflammatory pathway on collagen-induced arthritis involves the modulation of dendritic cell differentiation. Arthritis Res Ther 2018; 20:263. [PMID: 30486874 PMCID: PMC6262974 DOI: 10.1186/s13075-018-1759-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 10/31/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The cholinergic anti-inflammatory pathway (CAP) has a strong anti-inflammatory effect on collagen-induced arthritis (CIA), a classic animal model of rheumatoid arthritis (RA). However, the underlying immune regulatory mechanism remains unclear. Here, we investigated the effect of the CAP on arthritis development and the involvement of dendritic cells (DCs). METHODS Forty DBA/1 mice were randomly divided into five groups: a control group (sham vagotomy+ phosphate-buffered saline; shamVGX+PBS), a CIA group (shamVGX+CIA + PBS), a vagotomy group (VGX + CIA + PBS), a GTS-21 (4 mg/kg) group (shamVGX+CIA + GTS-4), and a GTS-21 (8 mg/kg) group (shamVGX+CIA + GTS-8). The vagotomy group underwent left cervical vagotomy 4 days before arthritis induction, whereas the sham-vagotomy group underwent vagus nerve exposure. Mice were pretreated with GTS-21 by intraperitoneal injection on the day of surgery. The degree of arthritis was measured by using the arthritis score, hematoxylin and eosin staining, and TRAP (tartrate-resistant acid phosphatase) staining. Flow cytometry was used to detect the expression of CD80 and major histocompatibility complex II (MHC II) on CD11c+ DCs in the spleen. Luminex was used to detect the serum concentration of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), and IL-10. Immunohistochemistry was used to detect CD11c expression in the synovium. The effects of GTS-21 on DC differentiation and maturation were examined in vitro by treating bone marrow-derived DCs with GTS-21 and assessing differentiation and maturation. Flow cytometry was used to analyze CD80 and MHC II expression on the surface of DCs. RESULTS GTS-21 treatment ameliorated clinical arthritis in a mouse model of CIA in vivo, decreasing the secretion of pro-inflammatory cytokines in the serum and downregulating CD80 and MHC II expression on DCs in the spleen of CIA mice. GTS-21 treatment strongly suppressed the infiltration of DCs into the synovium. Vagotomy itself did not exacerbate the severity of arthritis in CIA mice. In vitro, GTS-21 (10 μmol/L) significantly downregulated CD80 and MHC II in bone marrow-derived immature DCs and this effect was blocked by the α7-nicotinic acetylcholine receptor antagonist methyllycaconitine (MLA). However, GTS-21 had no effects on mature DCs. CONCLUSIONS The present study provides new insight into the mechanism underlying the effects of the CAP on RA and indicates that the immunosuppressive effect of GTS-21 may be mediated by the inhibition of DC differentiation.
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Affiliation(s)
- Di Liu
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Hunan Province, Changsha, 410008, People's Republic of China
| | - Tong Li
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Hunan Province, Changsha, 410008, People's Republic of China
| | - Hui Luo
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Hunan Province, Changsha, 410008, People's Republic of China
| | - Xiaoxia Zuo
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Hunan Province, Changsha, 410008, People's Republic of China
| | - Sijia Liu
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Hunan Province, Changsha, 410008, People's Republic of China.
| | - Shiyao Wu
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Hunan Province, Changsha, 410008, People's Republic of China.
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Metz CN, Pavlov VA. Vagus nerve cholinergic circuitry to the liver and the gastrointestinal tract in the neuroimmune communicatome. Am J Physiol Gastrointest Liver Physiol 2018; 315:G651-G658. [PMID: 30001146 PMCID: PMC6293249 DOI: 10.1152/ajpgi.00195.2018] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Improved understanding of neuroimmune communication and the neural regulation of immunity and inflammation has recently led to proposing the concept of the "neuroimmune communicatome." This advance is based on experimental evidence for an organized and brain-integrated reflex-like relationship and dialogue between the nervous and the immune systems. A key circuitry in this communicatome is provided by efferent vagus nerve fibers and cholinergic signaling. Inflammation and metabolic alterations coexist in many disorders affecting the liver and the gastrointestinal (GI) tract, including obesity, metabolic syndrome, fatty liver disease, liver injury, and liver failure, as well as inflammatory bowel disease. Here, we outline mechanistic insights regarding the role of the vagus nerve and cholinergic signaling in the regulation of inflammation linked to metabolic derangements and the pathogenesis of these disorders in preclinical settings. Recent clinical advances using this knowledge in novel therapeutic neuromodulatory approaches within the field of bioelectronic medicine are also briefly summarized.
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Affiliation(s)
- Christine N. Metz
- 1Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York,2Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
| | - Valentin A. Pavlov
- 1Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York,2Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
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Abstract
The interplay between the immune and nervous systems has been acknowledged in the past, but only more recent studies have started to unravel the cellular and molecular players of such interactions. Mounting evidence indicates that environmental signals are sensed by discrete neuro-immune cell units (NICUs), which represent defined anatomical locations in which immune and neuronal cells colocalize and functionally interact to steer tissue physiology and protection. These units have now been described in multiple tissues throughout the body, including lymphoid organs, adipose tissue, and mucosal barriers. As such, NICUs are emerging as important orchestrators of multiple physiological processes, including hematopoiesis, organogenesis, inflammation, tissue repair, and thermogenesis. In this review we focus on the impact of NICUs in tissue physiology and how this fast-evolving field is driving a paradigm shift in our understanding of immunoregulation and organismal physiology.
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Affiliation(s)
- Cristina Godinho-Silva
- Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisboa, Portugal; , ,
| | - Filipa Cardoso
- Champalimaud Research, Champalimaud Centre for the Unknown, 1400-038 Lisboa, Portugal; , ,
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Weiberg D, Basic M, Smoczek M, Bode U, Bornemann M, Buettner M. Participation of the spleen in the IgA immune response in the gut. PLoS One 2018; 13:e0205247. [PMID: 30286198 PMCID: PMC6171922 DOI: 10.1371/journal.pone.0205247] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 09/23/2018] [Indexed: 11/18/2022] Open
Abstract
The role of the spleen in the induction of an immune response to orally administered antigens is still under discussion. Although it is well known that after oral antigen administration specific germinal centres are not only formed in the Peyers patches (PP) and the mesenteric lymph nodes (mLN) but also in the spleen, there is still a lack of functional data showing a direct involvement of splenic B cells in an IgA immune response in the gut. In addition, after removal of mLN a high level of IgA+ B cells was observed in the gut. Therefore, in this study we analysed the role of the spleen in the induction of IgA+ B cells in the gut after mice were orally challenged with antigens. Here we have shown that antigen specific splenic IgM+ B cells after in vitro antigen stimulation as well as oral immunisation of donor mice were able to migrate into the gut of recipient mice, where they predominantly switch to IgA+ plasma cells. Furthermore, stimulation of recipient mice by orally administered antigens enhanced the migration of the splenic B cells into the gut as well as their switch to IgA+ plasma cells. Removal of the mLN led to a higher activation level of the splenic B cells. Altogether, our results imply that splenic IgM+ B cells migrate in the intestinal lamina propria, where they differentiate into IgA+ plasma cells and subsequently proliferate. In conclusion, we demonstrated that the spleen plays a major role in the gut immune response serving as a reservoir of immune cells that migrate to the site of antigen entrance.
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Affiliation(s)
- Desiree Weiberg
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
- Department of Nuclear Medicine, Hannover Medical School, Hannover, Germany
| | - Marijana Basic
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Margarethe Smoczek
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - Ulrike Bode
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
| | - Melanie Bornemann
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
| | - Manuela Buettner
- Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
- * E-mail:
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Reardon C, Murray K, Lomax AE. Neuroimmune Communication in Health and Disease. Physiol Rev 2018; 98:2287-2316. [PMID: 30109819 PMCID: PMC6170975 DOI: 10.1152/physrev.00035.2017] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 04/09/2018] [Accepted: 04/09/2018] [Indexed: 12/14/2022] Open
Abstract
The immune and nervous systems are tightly integrated, with each system capable of influencing the other to respond to infectious or inflammatory perturbations of homeostasis. Recent studies demonstrating the ability of neural stimulation to significantly reduce the severity of immunopathology and consequently reduce mortality have led to a resurgence in the field of neuroimmunology. Highlighting the tight integration of the nervous and immune systems, afferent neurons can be activated by a diverse range of substances from bacterial-derived products to cytokines released by host cells. While activation of vagal afferents by these substances dominates the literature, additional sensory neurons are responsive as well. It is becoming increasingly clear that although the cholinergic anti-inflammatory pathway has become the predominant model, a multitude of functional circuits exist through which neuronal messengers can influence immunological outcomes. These include pathways whereby efferent signaling occurs independent of the vagus nerve through sympathetic neurons. To receive input from the nervous system, immune cells including B and T cells, macrophages, and professional antigen presenting cells express specific neurotransmitter receptors that affect immune cell function. Specialized immune cell populations not only express neurotransmitter receptors, but express the enzymatic machinery required to produce neurotransmitters, such as acetylcholine, allowing them to act as signaling intermediaries. Although elegant experiments have begun to decipher some of these interactions, integration of these molecules, cells, and anatomy into defined neuroimmune circuits in health and disease is in its infancy. This review describes these circuits and highlights continued challenges and opportunities for the field.
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Affiliation(s)
- Colin Reardon
- Department of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, UC Davis, Davis, California ; and Department of Biomedical and Molecular Sciences and Department of Medicine, Queen's University , Kingston, Ontario , Canada
| | - Kaitlin Murray
- Department of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, UC Davis, Davis, California ; and Department of Biomedical and Molecular Sciences and Department of Medicine, Queen's University , Kingston, Ontario , Canada
| | - Alan E Lomax
- Department of Anatomy, Physiology, and Cell Biology, UC Davis School of Veterinary Medicine, UC Davis, Davis, California ; and Department of Biomedical and Molecular Sciences and Department of Medicine, Queen's University , Kingston, Ontario , Canada
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Seyedabadi M, Rahimian R, Ghia JE. The role of alpha7 nicotinic acetylcholine receptors in inflammatory bowel disease: involvement of different cellular pathways. Expert Opin Ther Targets 2018; 22:161-176. [PMID: 29298542 DOI: 10.1080/14728222.2018.1420166] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Autonomic imbalance plays a pivotal role in the pathophysiology of inflammatory bowel diseases (IBD). The central nervous system (CNS) cooperates dynamically with the immune system to regulate inflammation through humoral and neural pathways. In particular, acetylcholine (Ach), the main neurotransmitter in the vagus nerve, decreases the production of pro-inflammatory cytokines through a mechanism dependent on the α7 nicotinic Ach receptors (α7nAChRs). Areas covered: Here, we review the evidence for involvement of the cholinergic anti-inflammatory pathway (CAP) in IBD. We also elaborate the role of α7nAChRs and subsequent cellular pathways in CAP. Finally, we review potential therapeutic implications of modulators of these receptors. Expert opinion: Alpha7nAChR modulators possess both cognitive improving and anti-inflammatory properties. Although, these agents demonstrated therapeutic benefits in experimental models, their efficacy has not always been translated in clinical trials. Thus, development of more specific α7nAChR ligands as well as more experimental studies and better controlled trials, especially in the field of IBD, are encouraged for a progress in this field.
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Affiliation(s)
- Mohammad Seyedabadi
- a Department of Pharmacology, School of Medicine , Bushehr University of Medical Sciences , Bushehr , Iran.,b The Persian Gulf Biomedical Sciences Research Institute , Bushehr University of Medical Sciences , Bushehr , Iran.,c Education Development Center , Bushehr University of Medical Sciences , Bushehr , Iran
| | - Reza Rahimian
- d Department of Psychiatry and Neuroscience, Faculty of Medicine , CERVO Brain Research Center, Laval University , Quebec , Quebec , Canada
| | - Jean-Eric Ghia
- e Department of Immunology , University of Manitoba , Winnipeg , Manitoba , Canada.,f Department of Internal Medicine Section of Gastroenterology, and Inflammatory Bowel Disease Clinical & Research Center , University of Manitoba , Winnipeg , Manitoba , Canada
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