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1
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Shute L, Fry M. Neuropeptide Y modulates the electrical activity of subfornical organ neurons. CURRENT RESEARCH IN NEUROBIOLOGY 2025; 8:100149. [PMID: 40308261 PMCID: PMC12041781 DOI: 10.1016/j.crneur.2025.100149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 02/16/2025] [Accepted: 03/16/2025] [Indexed: 05/02/2025] Open
Abstract
The subfornical organ (SFO) is a sensory circumventricular organ, lacking a blood-brain barrier. It is well-recognized as a key center for detection and integration of osmotic, ionic and hormonal signals for maintenance of hydromineral balance and cardiovascular regulation. Recently, the SFO has also been recognized as a center for the detection and integration of circulating satiety signals for regulation of energy balance. Neuropeptide Y (NPY) is a multifunctional neuropeptide, with effects on energy balance, cardiovascular tone and other aspects of homeostasis. Interestingly, despite the overlap of function between SFO and NPY, and observations that SFO expresses several subtypes of Y receptors, NPY regulation of SFO neurons has never been investigated. In this study, we examined the effects of NPY on dissociated rat SFO neurons using patch clamp electrophysiology. We observed that 300 nM NPY caused depolarization of 16 % of SFO neurons tested, and hyperpolarization of 26 %, while the remaining neurons were insensitive to NPY (n = 31). These effects were dose-dependent with an apparent EC50 of 3.9 nM for depolarizing neurons and 3.5 nM for hyperpolarizing neurons. Activation of Y5 receptors alone led to predominately hyperpolarizing effects, while activation of Y1 or Y2 receptors alone led to mixed responses. Voltage-clamp experiments demonstrated that NPY caused increases in voltage-gated K+ current amplitude as well as hyperpolarizing shifts in persistent Na+ current, mediating the hyperpolarizing and depolarizing effects, respectively. These findings indicate that NPY elicits direct electrophysiological effects on SFO neurons, suggesting that NPY acts via the SFO to regulate energy homeostatic function.
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Affiliation(s)
| | - Mark Fry
- Department of Biological Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
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2
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Hesampour F, Bernstein CN, Ghia JE. Investigating the effect of neuro-immune communication on immune responses in health and disease: Exploring immunological disorders. Cell Immunol 2025; 413:104963. [PMID: 40378510 DOI: 10.1016/j.cellimm.2025.104963] [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: 01/30/2025] [Revised: 05/02/2025] [Accepted: 05/06/2025] [Indexed: 05/19/2025]
Abstract
Recent recognition of the intricate nervous-immune system interplay has prompted research into the specific cellular components involved in these interactions. Emerging evidence suggests that immune and neural cells collaborate within distinct units and act in concert to regulate tissue function and provide protection. These specialized neuro-immune cell units have been identified in diverse body tissues, ranging from lymphoid organs to the bone marrow and mucosal barriers. Their significance has become increasingly apparent as they are recognized as pivotal regulators influencing a broad spectrum of physiological and pathological processes. This recognition extends to critical roles in hematopoiesis, organ function, inflammatory responses, and intricate tissue repair processes. This review explores the bidirectional communication between the nervous and immune systems. The focus is on understanding the profound impact of this communication on immune cells within key anatomical sites, such as the bone marrow, gastrointestinal tract, and lymphoid organs. By examining these interactions, this review aims to shed light on how this intricate network operates under normal and pathological conditions, offering insights into the mechanisms underlying health and disease.
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Affiliation(s)
| | - Charles N Bernstein
- Internal Medicine, University of Manitoba, Winnipeg, Canada; Inflammatory Bowel Disease Clinical & Research Centre, University of Manitoba, Winnipeg, Canada
| | - Jean-Eric Ghia
- Immunology, University of Manitoba, Winnipeg, Canada; Internal Medicine, University of Manitoba, Winnipeg, Canada; Inflammatory Bowel Disease Clinical & Research Centre, University of Manitoba, Winnipeg, Canada; Children's Hospital Research Institute of Manitoba, Winnipeg, Canada.
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3
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Mihaylova A, Doncheva N, Vlasheva M, Katsarova M, Gardjeva P, Dimitrova S, Kostadinov I. Investigation of the Immunomodulatory and Neuroprotective Properties of Nigella sativa Oil in Experimental Systemic and Neuroinflammation. Int J Mol Sci 2025; 26:2235. [PMID: 40076857 PMCID: PMC11900984 DOI: 10.3390/ijms26052235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2025] [Revised: 02/27/2025] [Accepted: 02/28/2025] [Indexed: 03/14/2025] Open
Abstract
Nigella sativa (NS) is a promising medicinal plant with diverse therapeutic properties. This study aimed to investigate the impact of NS oil (NSO) on memory functions in rats with LPS (lipopolysaccharide)-induced neuroinflammation, as well as its effect on serum levels of inflammatory cytokines, neuropeptide Y (NPY) and brain-derived neurotrophic factor (BDNF). Male rats were divided into four groups: control, LPS-control, LPS+NSO 3 and 5 mL/kg. Neuroinflammation was induced by a single intraperitoneal LPS injection (2 mg/kg). The novel object recognition test (NORT) and Y-maze were used for the evaluation of memory processes. Recognition index (RI) and % spontaneous alteration (%SA) were registered, respectively. Blood samples for TNF-α, IL-1β, IL-10, BDNF, and NPY serum levels were taken. Thymoquinone, the active compound of the oil, was detected by high-performance liquid chromatography. NSO administration resulted in an improvement in spatial and episodic memory, as evidenced by increased % SA and RI compared to LPS-control. Treatment with NSO led to a significant reduction in pro-inflammatory cytokines and NPY, along with an increase in IL-10 and BDNF levels, when compared to LPS-control. In conclusion, NSO enhances BDNF production and regulates pro- and anti-inflammatory cytokines release, which probably contributes to the observed cognitive improvement in animals with experimental neuroinflammation.
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Affiliation(s)
- Anita Mihaylova
- Department of Pharmacology, Toxicology and Pharmacotherapy, Faculty of Pharmacy, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria;
- Research Institute, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria;
| | - Nina Doncheva
- Department of Pharmacology, Toxicology and Pharmacotherapy, Faculty of Pharmacy, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria;
- Research Institute, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria;
| | - Maria Vlasheva
- Department of Bioorganic Chemistry, Faculty of Pharmacy, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria; (M.V.); (M.K.)
| | - Mariana Katsarova
- Department of Bioorganic Chemistry, Faculty of Pharmacy, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria; (M.V.); (M.K.)
| | - Petya Gardjeva
- Department of Medical Microbiology and Immunology “Prof. Dr. Elissay Yanev”, Faculty of Medicine, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria;
| | - Stela Dimitrova
- Research Institute, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria;
- Department of Bioorganic Chemistry, Faculty of Pharmacy, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria; (M.V.); (M.K.)
| | - Ilia Kostadinov
- Research Institute, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria;
- Department of Pharmacology and Clinical Pharmacology, Faculty of Medicine, Medical University of Plovdiv, 15A Vasil Aprilov Blvd., 4002 Plovdiv, Bulgaria
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Chen K, Wu X, Li X, Pan H, Zhang W, Shang J, Di Y, Liu R, Zheng Z, Hou X. Antimicrobial Neuropeptides and Their Receptors: Immunoregulator and Therapeutic Targets for Immune Disorders. Molecules 2025; 30:568. [PMID: 39942672 PMCID: PMC11820534 DOI: 10.3390/molecules30030568] [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: 12/22/2024] [Revised: 01/23/2025] [Accepted: 01/24/2025] [Indexed: 02/16/2025] Open
Abstract
The interaction between the neuroendocrine system and the immune system plays a key role in the onset and progression of various diseases. Neuropeptides, recognized as common biochemical mediators of communication between these systems, are receiving increasing attention because of their potential therapeutic applications in immune-related disorders. Additionally, many neuropeptides share significant similarities with antimicrobial peptides (AMPs), and evidence shows that these antimicrobial neuropeptides are directly involved in innate immunity. This review examines 10 antimicrobial neuropeptides, including pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), α-melanocyte stimulating hormone (α-MSH), ghrelin, adrenomedullin (AM), neuropeptide Y (NPY), urocortin II (UCN II), calcitonin gene-related peptide (CGRP), substance P (SP), and catestatin (CST). Their expression characteristics and the immunomodulatory mechanisms mediated by their specific receptors are summarized, along with potential drugs targeting these receptors. Future studies should focus on further investigating antimicrobial neuropeptides and advancing the development of related drugs in preclinical and/or clinical studies to improve the treatment of immune-related diseases.
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Affiliation(s)
- Kaiqi Chen
- College of Medical Imaging and Laboratory, Jining Medical University, Jining 272067, China; (K.C.); (X.L.); (H.P.); (W.Z.); (J.S.); (Y.D.)
| | - Xiaojun Wu
- College of Medical Engineering, Jining Medical University, Jining 272067, China; (X.W.); (R.L.)
| | - Xiaoke Li
- College of Medical Imaging and Laboratory, Jining Medical University, Jining 272067, China; (K.C.); (X.L.); (H.P.); (W.Z.); (J.S.); (Y.D.)
| | - Haoxuan Pan
- College of Medical Imaging and Laboratory, Jining Medical University, Jining 272067, China; (K.C.); (X.L.); (H.P.); (W.Z.); (J.S.); (Y.D.)
| | - Wenhui Zhang
- College of Medical Imaging and Laboratory, Jining Medical University, Jining 272067, China; (K.C.); (X.L.); (H.P.); (W.Z.); (J.S.); (Y.D.)
| | - Jinxi Shang
- College of Medical Imaging and Laboratory, Jining Medical University, Jining 272067, China; (K.C.); (X.L.); (H.P.); (W.Z.); (J.S.); (Y.D.)
| | - Yinuo Di
- College of Medical Imaging and Laboratory, Jining Medical University, Jining 272067, China; (K.C.); (X.L.); (H.P.); (W.Z.); (J.S.); (Y.D.)
| | - Ruonan Liu
- College of Medical Engineering, Jining Medical University, Jining 272067, China; (X.W.); (R.L.)
| | - Zhaodi Zheng
- College of Medical Imaging and Laboratory, Jining Medical University, Jining 272067, China; (K.C.); (X.L.); (H.P.); (W.Z.); (J.S.); (Y.D.)
| | - Xitan Hou
- College of Medical Imaging and Laboratory, Jining Medical University, Jining 272067, China; (K.C.); (X.L.); (H.P.); (W.Z.); (J.S.); (Y.D.)
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Beeraka NM, Basappa B, Nikolenko VN, Mahesh PA. Role of Neurotransmitters in Steady State Hematopoiesis, Aging, and Leukemia. Stem Cell Rev Rep 2025; 21:2-27. [PMID: 38976142 DOI: 10.1007/s12015-024-10761-z] [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] [Accepted: 07/02/2024] [Indexed: 07/09/2024]
Abstract
Haematopoiesis within the bone marrow (BM) represents a complex and dynamic process intricately regulated by neural signaling pathways. This delicate orchestration is susceptible to disruption by factors such as aging, diabetes, and obesity, which can impair the BM niche and consequently affect haematopoiesis. Genetic mutations in Tet2, Dnmt3a, Asxl1, and Jak2 are known to give rise to clonal haematopoiesis of intermediate potential (CHIP), a condition linked to age-related haematological malignancies. Despite these insights, the exact roles of circadian rhythms, sphingosine-1-phosphate (S1P), stromal cell-derived factor-1 (SDF-1), sterile inflammation, and the complement cascade on various BM niche cells remain inadequately understood. Further research is needed to elucidate how BM niche cells contribute to these malignancies through neural regulation and their potential in the development of gene-corrected stem cells. This literature review describes the updated functional aspects of BM niche cells in haematopoiesis within the context of haematological malignancies, with a particular focus on neural signaling and the potential of radiomitigators in acute radiation syndrome. Additionally, it underscores the pressing need for technological advancements in stem cell-based therapies to alleviate the impacts of immunological stressors. Recent studies have illuminated the microheterogeneity and temporal stochasticity of niche cells within the BM during haematopoiesis, emphasizing the updated roles of neural signaling and immunosurveillance. The development of gene-corrected stem cells capable of producing blood, immune cells, and tissue-resident progeny is essential for combating age-related haematological malignancies and overcoming immunological challenges. This review aims to provide a comprehensive overview of these evolving insights and their implications for future therapeutic strategies.
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Affiliation(s)
- Narasimha M Beeraka
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, 1044 W. Walnut Street, R4-168, Indianapolis, IN, 46202, USA.
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow, 119991, Russia.
- Raghavendra Institute of Pharmaceutical Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh, 515721, India.
| | - Basappa Basappa
- Department of Studies in Organic Chemistry, Laboratory of Chemical Biology, University of Mysore, Mysore, Karnataka, 570006, India
| | - Vladimir N Nikolenko
- Department of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow, 119991, Russia
| | - P A Mahesh
- Department of Pulmonary Medicine, JSS Medical College, JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India
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6
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Russjan E. The Role of Peptides in Asthma-Obesity Phenotype. Int J Mol Sci 2024; 25:3213. [PMID: 38542187 PMCID: PMC10970696 DOI: 10.3390/ijms25063213] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 03/08/2024] [Accepted: 03/10/2024] [Indexed: 01/04/2025] Open
Abstract
The co-occurrence of asthma and obesity is becoming an increasingly common health problem. It became clear that both diseases are closely related, since overweight/obesity are associated with an increased risk of asthma development, and more than half of the subjects with severe or difficult-to-treat asthma are obese. Currently, there are no specific guidelines for the treatment of this group of patients. The mechanisms involved in the asthma-obesity phenotype include low-grade chronic inflammation and changes in pulmonary physiology. However, genetic predispositions, gender differences, comorbid conditions, and gut microbiota also seem to be important. Regulatory peptides affect many processes related to the functioning of the respiratory tract and adipose tissue. Adipokines such as leptin, adiponectin, resistin, and the less studied omentin, chemerin, and visfatin, as well as the gastrointestinal hormones ghrelin, cholecystokinin, glucagon-like peptide-1, and neuropeptides, including substance P or neuropeptide Y, can play a significant role in asthma with obesity. The aim of this article is to provide a concise review of the contribution of particular peptides in inflammatory reactions, obesity, asthma, and a combination of both diseases, as well as emphasize their potential role in the effective treatment of the asthma-obesity phenotype in the future.
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Affiliation(s)
- Ewelina Russjan
- Department of Respiration Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5 St., 02-106 Warsaw, Poland
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Liao X, Gao S, Xie F, Wang K, Wu X, Wu Y, Gao W, Wang M, Sun J, Liu D, Xu W, Li Q. An underlying mechanism behind interventional pulmonology techniques for refractory asthma treatment: Neuro-immunity crosstalk. Heliyon 2023; 9:e20797. [PMID: 37867902 PMCID: PMC10585236 DOI: 10.1016/j.heliyon.2023.e20797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 09/11/2023] [Accepted: 10/06/2023] [Indexed: 10/24/2023] Open
Abstract
Asthma is a common disease that seriously threatens public health. With significant developments in bronchoscopy, different interventional pulmonology techniques for refractory asthma treatment have been developed. These technologies achieve therapeutic purposes by targeting diverse aspects of asthma pathophysiology. However, even though these newer techniques have shown appreciable clinical effects, their differences in mechanisms and mutual commonalities still deserve to be carefully explored. Therefore, in this review, we summarized the potential mechanisms of bronchial thermoplasty, targeted lung denervation, and cryoablation, and analyzed the relationship between these different methods. Based on available evidence, we speculated that the main pathway of chronic airway inflammation and other pathophysiologic processes in asthma is sensory nerve-related neurotransmitter release that forms a "neuro-immunity crosstalk" and amplifies airway neurogenic inflammation. The mechanism of completely blocking neuro-immunity crosstalk through dual-ablation of both efferent and afferent fibers may have a leading role in the clinical efficacy of interventional pulmonology in the treatment of asthma and deserves further investigation.
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Affiliation(s)
- Ximing Liao
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Shaoyong Gao
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Fengyang Xie
- Department of Hematology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Kun Wang
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiaodong Wu
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yin Wu
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wei Gao
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Muyun Wang
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jiaxing Sun
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Dongchen Liu
- Department of Cardiovascular Medicine, The Second Affiliated Hospital of Shantou University Medical College, Shantou, 515000, China
| | - Wujian Xu
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qiang Li
- Department of Respiratory and Critical Care Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
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Yu Y, Li R, Yu X, Hu Y, Liao Z, Li W. Immuno-protective effect of neuropeptide Y immersion on the juvenile tilapia infected by Streptococcus agalactiae. FISH & SHELLFISH IMMUNOLOGY 2023; 141:109072. [PMID: 37709180 DOI: 10.1016/j.fsi.2023.109072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 08/29/2023] [Accepted: 09/09/2023] [Indexed: 09/16/2023]
Abstract
Neuropeptide Y (NPY), an important neurotransmitter, is widely distributed in the nervous systems of vertebrates. Multiple functions of NPY in mammals include the regulation of brain activity, emotion, stress response, feeding, digestion, metabolism and immune function. In the present study, we used synthetic NPY to immerse juvenile tilapia, thus firstly exploring the dose and time effect of this immersion. The results showed that the expression level of y8b and serum glucose increased after NPY immersion. When juvenile tilapia was challenged with Streptococcus agalactiae (S. agalactiae), no matter before or after the administration of NPY-immersion, it was found that NPY immersion could inhibit the expression of il-1β induced by S. agalactiae in telencephalon, hypothalamus, spleen and head kidney, and then promote the expression of il-10. In addition, NPY-immersion could reduce the activity of serum SOD but increase that of lysozyme, and ameliorate tissue damage in the head kidney and spleen of juvenile tilapia caused by S. agalactiae infection. This study firstly proposes the potential of NPY to be an immune protect factor in juvenile fish, and the results can provide a reference for the application of immersion administration in the immune protection of juvenile fish.
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Affiliation(s)
- Yang Yu
- State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Aquatic Economic Animals, Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
| | - Ruoyun Li
- State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Aquatic Economic Animals, Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
| | - Xiaozheng Yu
- State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Aquatic Economic Animals, Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
| | - Yongqi Hu
- State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Aquatic Economic Animals, Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
| | - Zongzhen Liao
- State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Aquatic Economic Animals, Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
| | - Wensheng Li
- State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory for Aquatic Economic Animals, Guangdong Provincial Engineering Technology Research Center for Healthy Breeding of Important Economic Fish, School of Life Sciences, Sun Yat-Sen University, Guangzhou, 510275, China.
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Bubeck M, Becker C, Patankar JV. Guardians of the gut: influence of the enteric nervous system on the intestinal epithelial barrier. Front Med (Lausanne) 2023; 10:1228938. [PMID: 37692784 PMCID: PMC10485265 DOI: 10.3389/fmed.2023.1228938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/24/2023] [Indexed: 09/12/2023] Open
Abstract
The intestinal mucosal surface forms one of the largest areas of the body, which is in direct contact with the environment. Co-ordinated sensory functions of immune, epithelial, and neuronal cells ensure the timely detection of noxious queues and potential pathogens and elicit proportional responses to mitigate the threats and maintain homeostasis. Such tuning and maintenance of the epithelial barrier is constantly ongoing during homeostasis and its derangement can become a gateway for systemic consequences. Although efforts in understanding the gatekeeping functions of immune cells have led the way, increasing number of studies point to a crucial role of the enteric nervous system in fine-tuning and maintaining this delicate homeostasis. The identification of immune regulatory functions of enteric neuropeptides and glial-derived factors is still in its infancy, but has already yielded several intriguing insights into their important contribution to the tight control of the mucosal barrier. In this review, we will first introduce the reader to the current understanding of the architecture of the enteric nervous system and the epithelial barrier. Next, we discuss the key discoveries and cellular pathways and mediators that have emerged as links between the enteric nervous, immune, and epithelial systems and how their coordinated actions defend against intestinal infectious and inflammatory diseases. Through this review, the readers will gain a sound understanding of the current neuro-immune-epithelial mechanisms ensuring intestinal barrier integrity and maintenance of intestinal homeostasis.
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Affiliation(s)
- Marvin Bubeck
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Christoph Becker
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Jay V. Patankar
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
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10
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Sohn R, Jenei-Lanzl Z. Role of the Sympathetic Nervous System in Mild Chronic Inflammatory Diseases: Focus on Osteoarthritis. Neuroimmunomodulation 2023; 30:143-166. [PMID: 37429263 PMCID: PMC10428144 DOI: 10.1159/000531798] [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: 01/30/2023] [Accepted: 06/28/2023] [Indexed: 07/12/2023] Open
Abstract
The sympathetic nervous system (SNS) is a major regulatory mediator connecting the brain and the immune system that influences accordingly inflammatory processes within the entire body. In the periphery, the SNS exerts its effects mainly via its neurotransmitters norepinephrine (NE) and epinephrine (E), which are released by peripheral nerve endings in lymphatic organs and other tissues. Depending on their concentration, NE and E bind to specific α- and β-adrenergic receptor subtypes and can cause both pro- and anti-inflammatory cellular responses. The co-transmitter neuropeptide Y, adenosine triphosphate, or its metabolite adenosine are also mediators of the SNS. Local pro-inflammatory processes due to injury or pathogens lead to an activation of the SNS, which in turn induces several immunoregulatory mechanisms with either pro- or anti-inflammatory effects depending on neurotransmitter concentration or pathological context. In chronic inflammatory diseases, the activity of the SNS is persistently elevated and can trigger detrimental pathological processes. Recently, the sympathetic contribution to mild chronic inflammatory diseases like osteoarthritis (OA) has attracted growing interest. OA is a whole-joint disease and is characterized by mild chronic inflammation in the joint. In this narrative article, we summarize the underlying mechanisms behind the sympathetic influence on inflammation during OA pathogenesis. In addition, OA comorbidities also accompanied by mild chronic inflammation, such as hypertension, obesity, diabetes, and depression, will be reviewed. Finally, the potential of SNS-based therapeutic options for the treatment of OA will be discussed.
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Affiliation(s)
- Rebecca Sohn
- Department of Orthopedics (Friedrichsheim), University Hospital Frankfurt, Goethe University, Frankfurt, Germany
| | - Zsuzsa Jenei-Lanzl
- Department of Orthopedics (Friedrichsheim), University Hospital Frankfurt, Goethe University, Frankfurt, Germany
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Ma S, Li X, Cao R, Zhan G, Fu X, Xiao R, Yang Z. Developmentally regulated expression of integrin alpha-6 distinguishes neural crest derivatives in the skin. Front Cell Dev Biol 2023; 11:1140554. [PMID: 37255601 PMCID: PMC10225710 DOI: 10.3389/fcell.2023.1140554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 05/02/2023] [Indexed: 06/01/2023] Open
Abstract
Neural crest-derived cells play essential roles in skin function and homeostasis. However, how they interact with environmental cues and differentiate into functional skin cells remains unclear. Using a combination of single-cell data analysis, neural crest lineage tracing, and flow cytometry, we found that the expression of integrin α6 (ITGA6) in neural crest and its derivatives was developmentally regulated and that ITGA6 could serve as a functional surface marker for distinguishing neural crest derivatives in the skin. Based on the expression of ITGA6, Wnt1-Cre lineage neural crest derivatives in the skin could be categorized into three subpopulations, namely, ITGA6bright, ITGA6dim, and ITGA6neg, which were found to be Schwann cells, melanocytes, and fibroblasts, respectively. We further analyzed the signature genes and transcription factors that specifically enriched in each cell subpopulation, as well as the ligand or receptor molecules, mediating the potential interaction with other cells of the skin. Additionally, we found that Hmx1 and Lhx8 are specifically expressed in neural crest-derived fibroblasts, while Zic1 and homeobox family genes are expressed in mesoderm-derived fibroblasts, indicating the distinct development pathways of fibroblasts of different origins. Our study provides insights into the regulatory landscape of neural crest cell development and identifies potential markers that facilitate the isolation of different neural crest derivatives in the skin.
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Affiliation(s)
- Shize Ma
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiu Li
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Rui Cao
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Guoqin Zhan
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Xin Fu
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Ran Xiao
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhigang Yang
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Key Laboratory of External Tissue and Organ Regeneration, Chinese Academy of Medical Sciences, Beijing, China
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12
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Li S, Yuan H, Yang K, Li Q, Xiang M. Pancreatic sympathetic innervation disturbance in type 1 diabetes. Clin Immunol 2023; 250:109319. [PMID: 37024024 DOI: 10.1016/j.clim.2023.109319] [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: 01/04/2023] [Revised: 02/15/2023] [Accepted: 03/06/2023] [Indexed: 04/08/2023]
Abstract
Pancreatic sympathetic innervation can directly affect the function of islet. The disorder of sympathetic innervation in islets during the occurrence of type 1 diabetes (T1D) has been reported to be controversial with the inducing factor unclarified. Several studies have uncovered the critical role that sympathetic signals play in controlling the local immune system. The survival and operation of endocrine cells can be regulated by immune cell infiltration in islets. In the current review, we focused on the impact of sympathetic signals working on islets cell regulation, and discussed the potential factors that can induce the sympathetic innervation disorder in the islets. We also summarized the effect of interference with the islet sympathetic signals on the T1D occurrence. Overall, complete understanding of the regulatory effect of sympathetic signals on islet cells and local immune system could facilitate to design better strategies to control inflammation and protect β cells in T1D therapy.
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Affiliation(s)
- Senlin Li
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Huimin Yuan
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Keshan Yang
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Qing Li
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Ming Xiang
- Department of Pharmacology, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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13
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Černelič-Bizjak M, Kenig S, Petelin A, Jenko-Pražnikar Z, Mohorko N. Link between emotional and external eating behaviors, peripheral neuropeptide Y, and β-hydroxybutyrate in participants with obesity on 12-week ketogenic diet. Nutr Health 2023:2601060231154464. [PMID: 36734124 DOI: 10.1177/02601060231154464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Objective: Understanding the impact of stress on emotional and external eating behaviors and the psychological and the associated metabolic factors can help in designing subsequent interventions to protect health. In particular, psychological trait-like construct related to eating has been shown to be an important target for intervention. Methods and measures: This study aimed to investigate the biochemical variables associated with a decrease in emotional and external eating behaviors due to 12-week ketogenic diet (12KD) in 35 adult participants (12 males) with obesity. Results: Absolute changes in emotional and external eating were independent of changes in body mass, nutritional intake, and Δ cortisol, but were predicted with increases in serum β-hydroxybutyrate (BHB) and decreases in serum peripheral neuropeptide Y (pNPY) (all p's < 0.050). Decrease in pNPY was also associated with an increase in BHB but was independent of anthropometrical changes, Δ fasting glucose, and Δ insulin. Conclusion: The reductions in emotional and external eating behaviors in participants with obesity were uniquely predicted by an increase in BHB and a decrease in pNPY after 12KD. In ketosis, emotional and external eating dropped independently of body mass change. Change in pNPY predicted changes in emotional and external eating. The role of BHB in modulating eating behavior should be further explored.
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Affiliation(s)
| | - Saša Kenig
- Faculty of Health Sciences, 68960University of Primorska, Izola, Slovenia
| | - Ana Petelin
- Faculty of Health Sciences, 68960University of Primorska, Izola, Slovenia
| | | | - Nina Mohorko
- Faculty of Health Sciences, 68960University of Primorska, Izola, Slovenia
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14
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Chaudhary A, Patel M, Singh S. Current Debates on Etiopathogenesis and Treatment Strategies for Vitiligo. Curr Drug Targets 2022; 23:1219-1238. [PMID: 35388753 DOI: 10.2174/1389450123666220406125645] [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: 07/07/2021] [Revised: 12/12/2021] [Accepted: 12/31/2021] [Indexed: 01/25/2023]
Abstract
Vitiligo is an acquired, chronic, and progressive depigmentation or hypopigmentation characterized by the destruction of melanocytes and the occurrence of white patches or macules in the skin, mucosal surface of eyes, and ears. Melanocytes are the melanin pigment-producing cells of the skin which are destroyed in pathological conditions called vitiligo. Approximately 0.5 - 2.0% of the population is suffering from vitiligo, and a higher prevalence rate of up to 8.8% has been reported in India. It is caused by various pathogenic factors like genetic predisposition, hyperimmune activation, increased oxidative stress, and alteration in neuropeptides level. Genetic research has revealed a multi- genetic inheritance that exhibits an overlap with other autoimmune disorders. However, melanocytes specific genes are also affected (such as DDR1, XBP1, NLRP1, PTPN22, COMT, FOXP3, ACE, APE, GSTP1, TLR, SOD, and CTLA-4). A number of therapeutic options are employed for the treatment of vitiligo. The topical corticosteroids and immunomodulators are currently in practice for the management of vitiligo. Phototherapies alone and in combinations with other approaches are used in those patients who do not respond to the topical treatment. The main focus of this review is on the etiopathological factors, pharmacological management (phototherapy, topical, systemic, and surgical therapy), and herbal drugs used to treat vitiligo.
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Affiliation(s)
- Ankit Chaudhary
- Department of Pharmacology, Neuropharmacology Division, ISF College of Pharmacy, Moga, Punjab 142001, India
| | - Mayank Patel
- Department of Pharmacology, Neuropharmacology Division, ISF College of Pharmacy, Moga, Punjab 142001, India
| | - Shamsher Singh
- Department of Pharmacology, Neuropharmacology Division, ISF College of Pharmacy, Moga, Punjab 142001, India
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15
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Puri S, Kenyon BM, Hamrah P. Immunomodulatory Role of Neuropeptides in the Cornea. Biomedicines 2022; 10:1985. [PMID: 36009532 PMCID: PMC9406019 DOI: 10.3390/biomedicines10081985] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/11/2022] [Accepted: 08/12/2022] [Indexed: 12/21/2022] Open
Abstract
The transparency of the cornea along with its dense sensory innervation and resident leukocyte populations make it an ideal tissue to study interactions between the nervous and immune systems. The cornea is the most densely innervated tissue of the body and possesses both immune and vascular privilege, in part due to its unique repertoire of resident immune cells. Corneal nerves produce various neuropeptides that have a wide range of functions on immune cells. As research in this area expands, further insights are made into the role of neuropeptides and their immunomodulatory functions in the healthy and diseased cornea. Much remains to be known regarding the details of neuropeptide signaling and how it contributes to pathophysiology, which is likely due to complex interactions among neuropeptides, receptor isoform-specific signaling events, and the inflammatory microenvironment in disease. However, progress in this area has led to an increase in studies that have begun modulating neuropeptide activity for the treatment of corneal diseases with promising results, necessitating the need for a comprehensive review of the literature. This review focuses on the role of neuropeptides in maintaining the homeostasis of the ocular surface, alterations in disease settings, and the possible therapeutic potential of targeting these systems.
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Affiliation(s)
- Sudan Puri
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
| | - Brendan M. Kenyon
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
| | - Pedram Hamrah
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA 02111, USA
- Program in Neuroscience, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA
- Departments of Immunology and Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA
- Cornea Service, Tufts New England Eye Center, Boston, MA 02111, USA
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16
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Biochemistry of human tear film: A review. Exp Eye Res 2022; 220:109101. [DOI: 10.1016/j.exer.2022.109101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 04/18/2022] [Accepted: 04/26/2022] [Indexed: 12/13/2022]
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17
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Langley DB, Schofield P, Jackson J, Herzog H, Christ D. Crystal structures of human neuropeptide Y (NPY) and peptide YY (PYY). Neuropeptides 2022; 92:102231. [PMID: 35180645 DOI: 10.1016/j.npep.2022.102231] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 01/18/2022] [Accepted: 02/03/2022] [Indexed: 10/19/2022]
Abstract
Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) form the evolutionarily conserved pancreatic polypeptide family. While the fold is widely utilized in nature, crystal structures remain elusive, particularly for the human forms, with only the structure of a distant avian form of PP reported. Here we utilize a crystallization chaperone (antibody Fab fragment), specifically recognizing the amidated peptide termini, to solve the structures of human NPY and human PYY. Intriguingly, and despite limited sequence identity (~50%), the structure of human PYY closely resembles that of avian PP, highlighting the broad structural conservation of the fold throughout evolution. Specifically, the PYY structure is characterized by a C-terminal amidated α-helix, preceded by a backfolded poly-proline N-terminus, with the termini in close proximity to each other. In contrast, in the structure of human NPY the N-terminal component is disordered, while the helical component of the peptide is observed in a four-helix bundle type arrangement, consistent with a propensity for multimerization suggested by NMR studies.
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Affiliation(s)
- David B Langley
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales 2010, Australia
| | - Peter Schofield
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales 2010, Australia
| | - Jenny Jackson
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales 2010, Australia
| | - Herbert Herzog
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW, Sydney, Australia
| | - Daniel Christ
- Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, New South Wales 2010, Australia; St Vincent's Clinical School, Faculty of Medicine, UNSW, Sydney, Australia.
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18
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Anderson ZT, Dawson AD, Slominski AT, Harris ML. Current Insights Into the Role of Neuropeptide Y in Skin Physiology and Pathology. Front Endocrinol (Lausanne) 2022; 13:838434. [PMID: 35418942 PMCID: PMC8996770 DOI: 10.3389/fendo.2022.838434] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/21/2022] [Indexed: 11/13/2022] Open
Abstract
Neuropeptide Y is widely distributed within the body and has long been implicated as a contributor to skin disease based on the correlative clinical data. However, until recently, there have been few empirical investigations to determine whether NPY has a pathophysiological role in the skin. Due to appearance-altering phenotypes of atopic dermatitis, psoriasis, and vitiligo, those suffering from these diseases often face multiple forms of negative social attention. This often results in psychological stress, which has been shown to exacerbate inflammatory skin diseases - creating a vicious cycle that perpetuates disease. This has been shown to drive severe depression, which has resulted in suicidal ideation being a comorbidity of these diseases. Herein, we review what is currently known about the associations of NPY with skin diseases and stress. We also review and provide educated guessing what the effects NPY can have in the skin. Inflammatory skin diseases can affect physical appearance to have significant, negative impacts on quality of life. No cure exists for these conditions, highlighting the need for identification of novel proteins/neuropetides, like NPY, that can be targeted therapeutically. This review sets the stage for future investigations into the role of NPY in skin biology and pathology to stimulate research on therapeutic targeting NPY signaling in order to combat inflammatory skin diseases.
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Affiliation(s)
- Zoya T. Anderson
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Alex D. Dawson
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Andrzej T. Slominski
- Department of Dermatology, Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, Birmingham, AL, United States
- Veteran Administration Medical Center, Birmingham, AL, United States
| | - Melissa L. Harris
- Department of Biology, University of Alabama at Birmingham, Birmingham, AL, United States
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19
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Taniguchi A, Oda N, Morichika D, Senoo S, Itano J, Fujii U, Guo L, Sunami R, Kiura K, Maeda Y, Miyahara N. Protective effects of neuropeptide Y against elastase-induced pulmonary emphysema. Am J Physiol Lung Cell Mol Physiol 2022; 322:L539-L549. [PMID: 35107033 DOI: 10.1152/ajplung.00353.2020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Neuropeptide Y (NPY) is a neuropeptide widely expressed in not only the central nervous system but also immune cells and the respiratory epithelium. Patients with chronic obstructive pulmonary disease (COPD) reportedly exhibit decreased NPY expression in the airway epithelium, but the involvement of NPY in the pathophysiology of COPD has not been defined. We investigated the role of NPY in elastase-induced emphysema. NPY-deficient (NPY-/-) mice and wild-type (NPY+/+) mice received intratracheal instillation of porcine pancreas elastase (PPE). The numbers of inflammatory cells and the levels of cytokines and chemokines in the bronchoalveolar lavage (BAL) fluid and lung homogenates were determined along with quantitative morphometry of lung sections. Intratracheal instillation of PPE induced emphysematous changes and increased NPY levels in the lungs. Compared with NPY+/+ mice, NPY-/- mice had significantly enhanced PPE-induced emphysematous changes and alveolar enlargement. Neutrophilia seen in BAL flu12id of NPY+/+ mice on day 4 after PPE instillation was also enhanced in NPY-/- mice, and the enhancement was associated with increased levels of neutrophil-related and macrophage-related chemokines and IL-17A as well as increased numbers of type 3 innate lymphoid cells in the airways. Treatment with NPY significantly reduced PPE-induced emphysematous changes. Conversely, treatment with a NPY receptor antagonist exacerbated PPE-induced emphysematous changes. These observations indicate that NPY has protective effects against elastase-induced emphysema, and suggest that targeting NPY in emphysema has potential as a therapeutic strategy for delaying disease progression.
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Affiliation(s)
- Akihiko Taniguchi
- Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.,Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Naohiro Oda
- Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Daisuke Morichika
- Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Satoru Senoo
- Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Junko Itano
- Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Utako Fujii
- Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Lili Guo
- Department of Medical Technology, Okayama University Graduate School of Health Sciences, Okayama, Japan
| | - Ryota Sunami
- Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Katsuyuki Kiura
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Yoshinobu Maeda
- Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Nobuaki Miyahara
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan.,Department of Medical Technology, Okayama University Graduate School of Health Sciences, Okayama, Japan
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20
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Franzago M, Di Nicola M, Fraticelli F, Marchioni M, Stuppia L, Vitacolonna E. Nutrigenetic variants and response to diet/lifestyle intervention in obese subjects: a pilot study. Acta Diabetol 2022; 59:69-81. [PMID: 34480216 PMCID: PMC8758637 DOI: 10.1007/s00592-021-01787-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 08/11/2021] [Indexed: 12/19/2022]
Abstract
AIMS Nutritional and lifestyle interventions can contribute to prevent and treat obesity and its complications; however, genetic background may influence the success of a therapy. The aim of this pilot study is to evaluate the effects of the interaction between nutrigenetic variants and nutritional intervention, as well as the changes in clinical parameters and the adherence to Mediterranean diet (MedDiet) and to physical activity, of 18 overweight or obese subjects affected by T2D or dysglycemia included in a nutritional program. METHODS The subjects' clinical parameters as well as their PREDIMED score and physical activity levels were recorded and compared at baseline, at 6 months and at the end of the intervention. Rs9939609 in FTO, rs17782313 near MC4R, rs326 in LPL, rs16147 in NPY, rs2943641 near IRS-1 were genotyped. RESULTS The subjects carrying the A allele in FTO lost less weight (p = 0.022) and had a lower BMI decrease from baseline to 12 months (p-interaction = 0.047) than TT carriers. In addition, there was a significant PREDIMED score modification over time, according to genotypes for FTO rs9939609 (p = 0.025) and NPY rs16147 (p = 0.039), respectively. CONCLUSIONS These preliminary findings show a significant interaction between genetic variants and the PREDIMED score, suggesting that individuals carrying the FTO variant may lose less weight than non-carriers through diet/lifestyle intervention.
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Affiliation(s)
- Marica Franzago
- Department of Medicine and Aging, School of Medicine and Health Sciences, "G. D'Annunzio" University, Via dei Vestini, 66100, Chieti-Pescara, Chieti, Italy
- Center for Advanced Studies and Technology (CAST), "G. D'Annunzio" University, Chieti-Pescara, Chieti, Italy
| | - Marta Di Nicola
- Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, "G. D'Annunzio" University, Chieti-Pescara, Chieti, Italy
| | - Federica Fraticelli
- Department of Medicine and Aging, School of Medicine and Health Sciences, "G. D'Annunzio" University, Via dei Vestini, 66100, Chieti-Pescara, Chieti, Italy
| | - Michele Marchioni
- Laboratory of Biostatistics, Department of Medical, Oral and Biotechnological Sciences, "G. D'Annunzio" University, Chieti-Pescara, Chieti, Italy
| | - Liborio Stuppia
- Center for Advanced Studies and Technology (CAST), "G. D'Annunzio" University, Chieti-Pescara, Chieti, Italy
- Department of Psychological, Health and Territorial Sciences, School of Medicine and Health Sciences, "G. D'Annunzio" University, Chieti-Pescara, Chieti, Italy
| | - Ester Vitacolonna
- Department of Medicine and Aging, School of Medicine and Health Sciences, "G. D'Annunzio" University, Via dei Vestini, 66100, Chieti-Pescara, Chieti, Italy.
- Center for Advanced Studies and Technology (CAST), "G. D'Annunzio" University, Chieti-Pescara, Chieti, Italy.
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21
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The Role of Neuropeptide Y in Adipocyte-Macrophage Crosstalk during High Fat Diet-Induced Adipose Inflammation and Liver Steatosis. Biomedicines 2021; 9:biomedicines9111739. [PMID: 34829968 PMCID: PMC8615496 DOI: 10.3390/biomedicines9111739] [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: 10/27/2021] [Revised: 11/19/2021] [Accepted: 11/20/2021] [Indexed: 12/13/2022] Open
Abstract
Obesity is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD), which is initiated by adipocyte-macrophage crosstalk. Among the possible molecules regulating this crosstalk, we focused on neuropeptide Y (NPY), which is known to be involved in hypothalamic appetite and adipose tissue inflammation and metabolism. In this study, the NPY−/− mice showed a marked decrease in body weight and adiposity, and lower free fatty acid and adipose inflammation without food intake alteration during a high fat diet (HFD). Moreover, NPY deficiency increased the thermogenic genes expression in brown adipose tissue. Notably, NPY-mRNA expression was upregulated in macrophages from the HFD mice compared to that from the mice on a standard diet. The NPY-mRNA expression also positively correlated with the liver mass/body weight ratio. NPY deletion alleviated HFD-induced adipose inflammation and liver steatosis. Hence, our findings point toward a novel intracellular mechanism of NPY in the regulation of adipocyte-macrophage crosstalk and highlight NPY antagonism as a promising target for therapeutic approaches against obesity and NAFLD.
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22
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Yang LWY, Mehta JS, Liu YC. Corneal neuromediator profiles following laser refractive surgery. Neural Regen Res 2021; 16:2177-2183. [PMID: 33818490 PMCID: PMC8354117 DOI: 10.4103/1673-5374.308666] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/02/2020] [Accepted: 01/22/2021] [Indexed: 01/07/2023] Open
Abstract
Laser refractive surgery is one of the most commonly performed procedures worldwide. In laser refractive surgery, Femtosecond Laser in Situ Keratomileusis and Refractive Lenticule Extraction have emerged as promising alternatives to microkeratome Laser in Situ Keratomileusis and Photorefractive Keratectomy. Following laser refractive surgery, the corneal nerves, epithelial and stromal cells release neuromediators, including neurotrophins, neuropeptides and neurotransmitters. Notably, nerve growth factor, substance P, calcitonin gene-related peptide and various cytokines are important mediators of neurogenic inflammation and corneal nerve regeneration. Alterations in neuromediator profiles and ocular surface parameters following laser refractive surgery are attributed to the surgical techniques and the severity of tissue insult induced. In this review, we will discuss the (1) Functions of neuromediators and their physiological and clinical significance; (2) Changes in the neuromediators following various laser refractive surgeries; (3) Correlation between neuromediators, ocular surface health and corneal nerve status; and (4) Future directions, including the use of neuromediators as potential biomarkers for ocular surface health following laser refractive surgery, and as adjuncts to aid in corneal regeneration after laser refractive surgery.
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Affiliation(s)
- Lily Wei Yun Yang
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore
| | - Jodhbir S. Mehta
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore
- Department of Cornea and External Eye Disease, Singapore National Eye Centre, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore
| | - Yu-Chi Liu
- Tissue Engineering and Cell Therapy Group, Singapore Eye Research Institute, Singapore
- Department of Cornea and External Eye Disease, Singapore National Eye Centre, Singapore
- Ophthalmology and Visual Sciences Academic Clinical Program, Duke-NUS Medical School, Singapore
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23
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Neuro-immune-metabolism: The tripod system of homeostasis. Immunol Lett 2021; 240:77-97. [PMID: 34655659 DOI: 10.1016/j.imlet.2021.10.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Revised: 09/30/2021] [Accepted: 10/08/2021] [Indexed: 11/20/2022]
Abstract
Homeostatic regulation of cellular and molecular processes is essential for the efficient physiological functioning of body organs. It requires an intricate balance of several networks throughout the body, most notable being the nervous, immune and metabolic systems. Several studies have reported the interactions between neuro-immune, immune-metabolic and neuro-metabolic pathways. Current review aims to integrate the information and show that neuro, immune and metabolic systems form the triumvirate of homeostasis. It focuses on the cellular and molecular interactions occurring in the extremities and intestine, which are innervated by the peripheral nervous system and for the intestine in particular the enteric nervous system. While the interdependence of neuro-immune-metabolic pathways provides a fallback mechanism in case of disruption of homeostasis, in chronic pathologies of continued disequilibrium, the collapse of one system spreads to the other interacting networks as well. Current review illustrates this domino-effect using diabetes as the main example. Together, this review attempts to provide a holistic picture of the integrated network of neuro-immune-metabolism and attempts to broaden the outlook when devising a scientific study or a treatment strategy.
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24
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Chandrasekharan B, Boyer D, Owens JA, Wolfarth AA, Saeedi BJ, Dhere T, Iskandar H, Neish AS. Intracolonic Neuropeptide Y Y1 Receptor Inhibition Attenuates Intestinal Inflammation in Murine Colitis and Cytokine Release in IBD Biopsies. Inflamm Bowel Dis 2021; 28:502-513. [PMID: 34613372 PMCID: PMC8972328 DOI: 10.1093/ibd/izab243] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Indexed: 12/14/2022]
Abstract
We have demonstrated that neuropeptide Y (NPY) can regulate pro-inflammatory signaling in the gut via cross-talk with the pro-inflammatory cytokine tumor necrosis factor (TNF). Here, we investigated if selective blocking of NPY receptors, NPY1R or NPY2R, using small molecule non-peptide antagonists (BIBP-3222 for NPY1R and BIIE-0246 for NPY2R) in the colon could attenuate intestinal inflammation by lowering TNF levels (BIBP - N-[(1R)]-4-[(Aminoiminomethyl)amino-1-[[[(4-hydroxyphenyl)methyl]amino]carbonyl]butyl-α-phenylbenzeneacetamide; BIIE - N-[(1S)-4-[(Aminoiminomethyl)amino]-1-[[[2-(3,5-dioxo-1,2-diphenyl-1,2,4-triazolidin-4-yl)ethyl]amino]carbonyl]butyl]-1-[2-[4-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-yl)-1-piperazinyl]-2-oxoethyl]-cyclopentaneacetamide). Colitis was induced using dextran sodium sulfate in drinking water for 7 days, or by adoptive T-cell transfer in RAG-/- mice. Colonic biopsies from healthy subjects (n = 10) and IBD patients (n = 34, UC = 20, CD = 14) were cultured ex vivo in presence or absence of NPY antagonists (100 µM, 20 h), and cytokine release into culture supernatants was measured by ELISA. Intracolonic administration of BIBP (but not BIIE) significantly reduced clinical, endoscopic, and histological scores, and serum TNF, interleukin (IL)-6, and IL-12p70 in DSS colitis; it also significantly attenuated histological damage and serum IL-6 in T-cell colitis (P < .05). Intracolonic administration of BIBP significantly reduced TNF and interferon (IFN)-γ release from UC biopsies, whereas BIIE downregulated only IFN-γ (P < .05). BIBP significantly reduced TNF and interferon (IFN)-γ release from UC biopsies, whereas BIIE downregulated only IFN-γ (P < .05). Our data suggest a promising therapeutic value for NPY1R inhibition in alleviating intestinal inflammation in UC, possibly as enemas to IBD patients.
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Affiliation(s)
- Bindu Chandrasekharan
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA,Address correspondence to: Bindu Chandrasekharan, PhD, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA ()
| | - Darra Boyer
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA
| | - Joshua A Owens
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA
| | - Alexandra A Wolfarth
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA
| | - Bejan J Saeedi
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA
| | - Tanvi Dhere
- Department of Medicine (Digestive Diseases), Emory University, Atlanta, Georgia, USA
| | - Heba Iskandar
- Department of Medicine (Digestive Diseases), Emory University, Atlanta, Georgia, USA
| | - Andrew S Neish
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA
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25
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Pachva MC, Lai H, Jia A, Rouleau M, Sorensen PH. Extracellular Vesicles in Reprogramming of the Ewing Sarcoma Tumor Microenvironment. Front Cell Dev Biol 2021; 9:726205. [PMID: 34604225 PMCID: PMC8484747 DOI: 10.3389/fcell.2021.726205] [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: 06/16/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022] Open
Abstract
Ewing sarcoma (EwS) is a highly aggressive cancer and the second most common malignant bone tumor of children and young adults. Although patients with localized disease have a survival rate of approximately 75%, the prognosis for patients with metastatic disease remains dismal (<30%) and has not improved in decades. Standard-of-care treatments include local therapies such as surgery and radiotherapy, in addition to poly-agent adjuvant chemotherapy, and are often associated with long-term disability and reduced quality of life. Novel targeted therapeutic strategies that are more efficacious and less toxic are therefore desperately needed, particularly for metastatic disease, given that the presence of metastasis remains the most powerful predictor of poor outcome in EwS. Intercellular communication within the tumor microenvironment is emerging as a crucial mechanism for cancer cells to establish immunosuppressive and cancer-permissive environments, potentially leading to metastasis. Altering this communication within the tumor microenvironment, thereby preventing the transfer of oncogenic signals and molecules, represents a highly promising therapeutic strategy. To achieve this, extracellular vesicles (EVs) offer a candidate mechanism as they are actively released by tumor cells and enriched with proteins and RNAs. EVs are membrane-bound particles released by normal and tumor cells, that play pivotal roles in intercellular communication, including cross-talk between tumor, stromal fibroblast, and immune cells in the local tumor microenvironment and systemic circulation. EwS EVs, including the smaller exosomes and larger microvesicles, have the potential to reprogram a diversity of cells in the tumor microenvironment, by transferring various biomolecules in a cell-specific manner. Insights into the various biomolecules packed in EwS EVs as cargos and the molecular changes they trigger in recipient cells of the tumor microenvironment will shed light on various potential targets for therapeutic intervention in EwS. This review details EwS EVs composition, their potential role in metastasis and in the reprogramming of various cells of the tumor microenvironment, and the potential for clinical intervention.
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Affiliation(s)
- Manideep C Pachva
- Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Horton Lai
- Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.,Faculty of Science, University of British Columbia, Vancouver, BC, Canada
| | - Andy Jia
- Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.,Faculty of Science, University of British Columbia, Vancouver, BC, Canada
| | - Melanie Rouleau
- Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Poul H Sorensen
- Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
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26
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Zhang Y, Liu CY, Chen WC, Shi YC, Wang CM, Lin S, He HF. Regulation of neuropeptide Y in body microenvironments and its potential application in therapies: a review. Cell Biosci 2021; 11:151. [PMID: 34344469 PMCID: PMC8330085 DOI: 10.1186/s13578-021-00657-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 07/12/2021] [Indexed: 12/26/2022] Open
Abstract
Neuropeptide Y (NPY), one of the most abundant neuropeptides in the body, is widely expressed in the central and peripheral nervous systems and acts on the cardiovascular, digestive, endocrine, and nervous systems. NPY affects the nutritional and inflammatory microenvironments through its interaction with immune cells, brain-derived trophic factor (BDNF), and angiogenesis promotion to maintain body homeostasis. Additionally, NPY has great potential for therapeutic applications against various diseases, especially as an adjuvant therapy for stem cells. In this review, we discuss the research progress regarding NPY, as well as the current evidence for the regulation of NPY in each microenvironment, and provide prospects for further research on related diseases.
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Affiliation(s)
- Yan Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Chu-Yun Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Wei-Can Chen
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Yan-Chuan Shi
- Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia
| | - Cong-Mei Wang
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China
| | - Shu Lin
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China. .,Diabetes and Metabolism Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, NSW, 2010, Australia. .,Centre of Neurological and Metabolic Research, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.
| | - He-Fan He
- Department of Anesthesiology, The Second Affiliated Hospital of Fujian Medical University, No. 34 North Zhongshan Road, Quanzhou, 362000, Fujian, China.
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27
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Nucera F, Lo Bello F, Shen SS, Ruggeri P, Coppolino I, Di Stefano A, Stellato C, Casolaro V, Hansbro PM, Adcock IM, Caramori G. Role of Atypical Chemokines and Chemokine Receptors Pathways in the Pathogenesis of COPD. Curr Med Chem 2021; 28:2577-2653. [PMID: 32819230 DOI: 10.2174/0929867327999200819145327] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 06/11/2020] [Accepted: 06/18/2020] [Indexed: 11/22/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung generally resulting from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these cells, particularly those belonging to the chemokines (conventional and atypical) family. There is emerging evidence for complex roles of atypical chemokines and their receptors (such as high mobility group box 1 (HMGB1), antimicrobial peptides, receptor for advanced glycosylation end products (RAGE) or toll-like receptors (TLRs)) in the pathogenesis of COPD, both in the stable disease and during exacerbations. Modulators of these pathways represent potential novel therapies for COPD and many are now in preclinical development. Inhibition of only a single atypical chemokine or receptor may not block inflammatory processes because there is redundancy in this network. However, there are many animal studies that encourage studies for modulating the atypical chemokine network in COPD. Thus, few pharmaceutical companies maintain a significant interest in developing agents that target these molecules as potential antiinflammatory drugs. Antibody-based (biological) and small molecule drug (SMD)-based therapies targeting atypical chemokines and/or their receptors are mostly at the preclinical stage and their progression to clinical trials is eagerly awaited. These agents will most likely enhance our knowledge about the role of atypical chemokines in COPD pathophysiology and thereby improve COPD management.
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Affiliation(s)
- Francesco Nucera
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences (BIOMORF), University of Messina, Pugliatti Square 1, 98122 Messina, Italy
| | - Federica Lo Bello
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences (BIOMORF), University of Messina, Pugliatti Square 1, 98122 Messina, Italy
| | - Sj S Shen
- Faculty of Science, Centre for Inflammation, Centenary Institute, University of Technology, Ultimo, Sydney, Australia
| | - Paolo Ruggeri
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences (BIOMORF), University of Messina, Pugliatti Square 1, 98122 Messina, Italy
| | - Irene Coppolino
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences (BIOMORF), University of Messina, Pugliatti Square 1, 98122 Messina, Italy
| | - Antonino Di Stefano
- Division of Pneumology, Cyto- Immunopathology Laboratory of the Cardio-Respiratory System, Clinical Scientific Institutes Maugeri IRCCS, Veruno, Italy
| | - Cristiana Stellato
- Department of Medicine, Surgery and Dentistry, Salerno Medical School, University of Salerno, Salerno, Italy
| | - Vincenzo Casolaro
- Department of Medicine, Surgery and Dentistry, Salerno Medical School, University of Salerno, Salerno, Italy
| | - Phil M Hansbro
- Faculty of Science, Centre for Inflammation, Centenary Institute, University of Technology, Ultimo, Sydney, Australia
| | - Ian M Adcock
- Airway Disease Section, National Heart and Lung Institute, Imperial College, London, United Kingdom
| | - Gaetano Caramori
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences (BIOMORF), University of Messina, Pugliatti Square 1, 98122 Messina, Italy
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28
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Pavón-Romero GF, Serrano-Pérez NH, García-Sánchez L, Ramírez-Jiménez F, Terán LM. Neuroimmune Pathophysiology in Asthma. Front Cell Dev Biol 2021; 9:663535. [PMID: 34055794 PMCID: PMC8155297 DOI: 10.3389/fcell.2021.663535] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/15/2021] [Indexed: 12/26/2022] Open
Abstract
Asthma is a chronic inflammation of lower airway disease, characterized by bronchial hyperresponsiveness. Type I hypersensitivity underlies all atopic diseases including allergic asthma. However, the role of neurotransmitters (NT) and neuropeptides (NP) in this disease has been less explored in comparison with inflammatory mechanisms. Indeed, the airway epithelium contains pulmonary neuroendocrine cells filled with neurotransmitters (serotonin and GABA) and neuropeptides (substance P[SP], neurokinin A [NKA], vasoactive intestinal peptide [VIP], Calcitonin-gene related peptide [CGRP], and orphanins-[N/OFQ]), which are released after allergen exposure. Likewise, the autonomic airway fibers produce acetylcholine (ACh) and the neuropeptide Y(NPY). These NT/NP differ in their effects; SP, NKA, and serotonin exert pro-inflammatory effects, whereas VIP, N/OFQ, and GABA show anti-inflammatory activity. However, CGPR and ACh have dual effects. For example, the ACh-M3 axis induces goblet cell metaplasia, extracellular matrix deposition, and bronchoconstriction; the CGRP-RAMP1 axis enhances Th2 and Th9 responses; and the SP-NK1R axis promotes the synthesis of chemokines in eosinophils, mast cells, and neutrophils. In contrast, the ACh-α7nAChR axis in ILC2 diminishes the synthesis of TNF-α, IL-1, and IL-6, attenuating lung inflammation whereas, VIP-VPAC1, N/OFQ-NOP axes cause bronchodilation and anti-inflammatory effects. Some NT/NP as 5-HT and NKA could be used as biomarkers to monitor asthma patients. In fact, the asthma treatment based on inhaled corticosteroids and anticholinergics blocks M3 and TRPV1 receptors. Moreover, the administration of experimental agents such as NK1R/NK2R antagonists and exogenous VIP decrease inflammatory mediators, suggesting that regulating the effects of NT/NP represents a potential novel approach for the treatment of asthma.
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Affiliation(s)
| | | | | | | | - Luis M. Terán
- Department of Immunogenetics and Allergy, Instituto Nacional Enfermedades Respiratorias Ismael Cosío Villegas, Mexico City, Mexico
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29
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Abstract
Although Caenorhabditis elegans has been used as a model host for studying host-pathogen interactions for more than 20 years, the mechanisms by which it identifies pathogens are not well understood. This is largely due to its lack of most known pattern recognition receptors (PRRs) that recognize pathogen-derived molecules. Recent behavioral research in C. elegans indicates that its nervous system plays a major role in microbe sensing. With the increasing integration of neurobiology in immunological research, future studies may find that neuronal detection of pathogens is an integral part of C. elegans-pathogen interactions. Similar to that of mammals, the C. elegans nervous system regulates its immune system to maintain immunological homeostasis. Studies in the nematode have revealed unprecedented details regarding the molecules, cells, and signaling pathways involved in neural regulation of immunity. Notably, some of the studies indicate that some neuroimmune regulatory circuits need not be "activated" by pathogen infection because they are tonically active and that there could be a predetermined set point for internal immunity, around which the nervous system adjusts immune responses to internal or external environmental changes. Here, we review recent progress on the roles of the C. elegans nervous system in pathogen detection and immune regulation. Because of its advantageous characteristics, we expect that the C. elegans model will be critical for deciphering complex neuroimmune signaling mechanisms that integrate and process multiple sensory cues.
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Affiliation(s)
- Yiyong Liu
- Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, Washington, USA
- Genomics Core, Washington State University, Spokane, Washington, USA
| | - Jingru Sun
- Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, Washington, USA
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30
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Cuzzubbo S, Mangsbo S, Nagarajan D, Habra K, Pockley AG, McArdle SEB. Cancer Vaccines: Adjuvant Potency, Importance of Age, Lifestyle, and Treatments. Front Immunol 2021; 11:615240. [PMID: 33679703 PMCID: PMC7927599 DOI: 10.3389/fimmu.2020.615240] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/23/2020] [Indexed: 12/13/2022] Open
Abstract
Although the discovery and characterization of multiple tumor antigens have sparked the development of many antigen/derived cancer vaccines, many are poorly immunogenic and thus, lack clinical efficacy. Adjuvants are therefore incorporated into vaccine formulations to trigger strong and long-lasting immune responses. Adjuvants have generally been classified into two categories: those that ‘depot’ antigens (e.g. mineral salts such as aluminum hydroxide, emulsions, liposomes) and those that act as immunostimulants (Toll Like Receptor agonists, saponins, cytokines). In addition, several novel technologies using vector-based delivery of antigens have been used. Unfortunately, the immune system declines with age, a phenomenon known as immunosenescence, and this is characterized by functional changes in both innate and adaptive cellular immunity systems as well as in lymph node architecture. While many of the immune functions decline over time, others paradoxically increase. Indeed, aging is known to be associated with a low level of chronic inflammation—inflamm-aging. Given that the median age of cancer diagnosis is 66 years and that immunotherapeutic interventions such as cancer vaccines are currently given in combination with or after other forms of treatments which themselves have immune-modulating potential such as surgery, chemotherapy and radiotherapy, the choice of adjuvants requires careful consideration in order to achieve the maximum immune response in a compromised environment. In addition, more clinical trials need to be performed to carefully assess how less conventional form of immune adjuvants, such as exercise, diet and psychological care which have all be shown to influence immune responses can be incorporated to improve the efficacy of cancer vaccines. In this review, adjuvants will be discussed with respect to the above-mentioned important elements.
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Affiliation(s)
- Stefania Cuzzubbo
- Université de Paris, PARCC, INSERM U970, 75015, Paris, France.,Laboratoire de Recherches Biochirurgicales (Fondation Carpentier), Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Européen Georges Pompidou, Paris, France
| | - Sara Mangsbo
- Ultimovacs AB, Uppsala, Sweden.,Department of Pharmaceutical Biosciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Divya Nagarajan
- Department of Immunology, Genetics and Clinical pathology Rudbeck laboratories, Uppsala University, Uppsala, Sweden
| | - Kinana Habra
- The School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.,The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Alan Graham Pockley
- The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.,Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Stephanie E B McArdle
- The John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom.,Centre for Health, Ageing and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
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31
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Wang J, Hao D, Zeng L, Zhang Q, Huang W. Neuropeptide Y mediates cardiac hypertrophy through microRNA-216b/FoxO4 signaling pathway. Int J Med Sci 2021; 18:18-28. [PMID: 33390770 PMCID: PMC7738963 DOI: 10.7150/ijms.51133] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 10/13/2020] [Indexed: 01/13/2023] Open
Abstract
Cardiac hypertrophy (CH) is a major risk factor for heart failure accompanied by maladaptive cardiac remodeling. The role and potential mechanism of neuropeptide Y (NPY) in CH are still unclear. We will explore the role and the mechanism of NPY inactivation (NPY-I) in CH caused by pressure overload. Abdominal aortic constriction (AAC) was used to induce CH model in rats. NPY or angiotensin II (Ang II) was used to trigger CH model in vitro in neonatal rat ventricular myocytes (NRVMs). We found that NPY was increased in the heart and plasma of hypertrophic rats. However, Ang II did not increase NPY expression in cardiomyocytes. NPY-I attenuated CH as decreasing CH-related markers (ANP, BNP and β-MHC mRNA) level, reducing cell surface area, and restoring cardiac function. NPY inactivation increased miR-216b and decreased FoxO4 expression in CH heart. Moreover, NPY decreased miR-216b and increased FoxO4 expression in NRVMs which were reversed by NPY type 1 receptor (NPY1R) antagonist BIBO3304. MiR-216b mimic and FoxO4 siRNA (small interfering RNA) inhibited NPY/Ang II-induced myocardial hypertrophy in vitro. Meanwhile, BIBO3304 reversed the pro-hypertrophy effect of NPY in vitro. Collectively, NPY deficiency attenuated CH by NPY1R-miR-216b-FoxO4 axis. These findings suggested that NPY would be a potential therapeutic target for the prevention and treatment of cardiac hypertrophy.
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Affiliation(s)
- Jinghao Wang
- Department of Pharmacy, the First Affiliated Hospital, Jinan University, Guangzhou 510630, China
| | - Dan Hao
- Department of Cardiology, the First Hospital of Harbin, Harbin 150010, China
| | - Lingfeng Zeng
- Department of Pharmacy, the First Affiliated Hospital, Jinan University, Guangzhou 510630, China
| | - Qianhui Zhang
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang 163319, China
| | - Wei Huang
- Department of Pharmacology, Harbin Medical University-Daqing, Daqing, Heilongjiang 163319, China
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32
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Miyahara N. [The role of neuropeptide Y for the development of allergic airway responses]. Nihon Yakurigaku Zasshi 2020; 155:360-363. [PMID: 33132250 DOI: 10.1254/fpj.20036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Neuropeptide Y (NPY) is a neurotransmitter that is widely expressed in the brain and peripheral nervous system. Various immune cells express the receptor for NPY, Y1 receptor. NPY modulates these cells via its Y1 receptor, and involvement of NPY in the pathophysiology of bronchial asthma, has been reported. Increased plasma levels of NPY in asthmatic patients have been reported. NPY polymorphisms are associated with an increased risk for asthma in overweight subjects and young adults. We and other researchers have reported that using murine models of allergic airway responses, NPY and Y1 receptor play critical roles for the development of allergic airway inflammation and airway hyperresponsiveness. Therefore, manipulating NPY-Y1 pathway represents a novel therapeutic target to control allergic airway responses, and might be beneficial for treatment of bronchial asthma.
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Affiliation(s)
- Nobuaki Miyahara
- Department of Medical Technology, Okayama University Graduate School of Health Sciences.,Department of Allergy and Respiratory Medicine, Okayama University Hospital
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33
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Chen WC, Liu YB, Liu WF, Zhou YY, He HF, Lin S. Neuropeptide Y Is an Immunomodulatory Factor: Direct and Indirect. Front Immunol 2020; 11:580378. [PMID: 33123166 PMCID: PMC7573154 DOI: 10.3389/fimmu.2020.580378] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 09/18/2020] [Indexed: 12/12/2022] Open
Abstract
Neuropeptide Y (NPY), which is widely distributed in the nervous system, is involved in regulating a variety of biological processes, including food intake, energy metabolism, and emotional expression. However, emerging evidence points to NPY also as a critical transmitter between the nervous system and immune system, as well as a mediator produced and released by immune cells. In vivo and in vitro studies based on gene-editing techniques and specific NPY receptor agonists and antagonists have demonstrated that NPY is responsible for multifarious direct modulations on immune cells by acting on NPY receptors. Moreover, via the central or peripheral nervous system, NPY is closely connected to body temperature regulation, obesity development, glucose metabolism, and emotional expression, which are all immunomodulatory factors for the immune system. In this review, we focus on the direct role of NPY in immune cells and particularly discuss its indirect impact on the immune response.
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Affiliation(s)
- Wei-Can Chen
- Department of Anesthesiology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, China
| | - Yi-Bin Liu
- Department of Anesthesiology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, China
| | - Wei-Feng Liu
- Department of Anesthesiology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, China
| | - Ying-Ying Zhou
- Department of Anesthesiology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, China
| | - He-Fan He
- Department of Anesthesiology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, China
| | - Shu Lin
- Department of Anesthesiology, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, China.,Centre of Neurological and Metabolic Research, The Second Affiliated Hospital, Fujian Medical University, Quanzhou, China.,Diabetes and Metabolism Division, Garvan Institute of Medical Research, Sydney, NSW, Australia
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34
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Sanchez JMS, McNally JS, Cortez MM, Hemp J, Pace LA, Clardy SL. Neuroimmunogastroenterology: At the Interface of Neuroimmunology and Gastroenterology. Front Neurol 2020; 11:787. [PMID: 32849234 PMCID: PMC7412790 DOI: 10.3389/fneur.2020.00787] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 06/25/2020] [Indexed: 12/11/2022] Open
Abstract
The central nervous system (CNS) is an important regulator of the gastrointestinal tract, and CNS dysfunction can result in significant and disabling gastrointestinal symptom manifestation. For patients with neuroimmunologic and neuroinflammatory conditions, the recognition of gastrointestinal symptoms is under-appreciated, yet the gastrointestinal manifestations have a dramatic impact on quality of life. The current treatment strategies, often employed independently by the neurologist and gastroenterologist, raise the question of whether such patients are being treated optimally when siloed in one specialty. Neuroimmunogastroenterology lies at the borderlands of medical specialties, and there are few resources to guide neurologists in this area. Here, we provide an overview highlighting the potential mechanisms of crosstalk between immune-mediated neurological disorders and gastrointestinal dysfunction.
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Affiliation(s)
- John Michael S. Sanchez
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT, United States
| | - J. Scott McNally
- Department of Radiology, Utah Center for Advanced Imaging Research, University of Utah, Salt Lake City, UT, United States
| | - Melissa M. Cortez
- Department of Neurology, Imaging and Neurosciences Center, University of Utah, Salt Lake City, UT, United States
| | - James Hemp
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States
| | - Laura A. Pace
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States
| | - Stacey L. Clardy
- Department of Neurology, Imaging and Neurosciences Center, University of Utah, Salt Lake City, UT, United States
- George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, United States
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Casado-Bedmar M, Keita ÅV. Potential neuro-immune therapeutic targets in irritable bowel syndrome. Therap Adv Gastroenterol 2020; 13:1756284820910630. [PMID: 32313554 PMCID: PMC7153177 DOI: 10.1177/1756284820910630] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 02/11/2020] [Indexed: 02/04/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder characterized by recurring abdominal pain and disturbed bowel habits. The aetiology of IBS is unknown but there is evidence that genetic, environmental and immunological factors together contribute to the development of the disease. Current treatment of IBS includes lifestyle and dietary interventions, laxatives or antimotility drugs, probiotics, antispasmodics and antidepressant medication. The gut-brain axis comprises the central nervous system, the hypothalamic pituitary axis, the autonomic nervous system and the enteric nervous system. Within the intestinal mucosa there are close connections between immune cells and nerve fibres of the enteric nervous system, and signalling between, for example, mast cells and nerves has shown to be of great importance during GI disorders such as IBS. Communication between the gut and the brain is most importantly routed via the vagus nerve, where signals are transmitted by neuropeptides. It is evident that IBS is a disease of a gut-brain axis dysregulation, involving altered signalling between immune cells and neurotransmitters. In this review, we analyse the most novel and distinct neuro-immune interactions within the IBS mucosa in association with already existing and potential therapeutic targets.
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Affiliation(s)
- Maite Casado-Bedmar
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - Åsa V. Keita
- Department of Biomedical and Clinical Sciences, Medical Faculty, Linköping University, Campus US, Linköping, 581 85, Sweden
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36
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Chu C, Artis D, Chiu IM. Neuro-immune Interactions in the Tissues. Immunity 2020; 52:464-474. [PMID: 32187517 PMCID: PMC10710744 DOI: 10.1016/j.immuni.2020.02.017] [Citation(s) in RCA: 184] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 02/11/2020] [Accepted: 02/25/2020] [Indexed: 12/12/2022]
Abstract
The ability of the nervous system to sense environmental stimuli and to relay these signals to immune cells via neurotransmitters and neuropeptides is indispensable for effective immunity and tissue homeostasis. Depending on the tissue microenvironment and distinct drivers of a certain immune response, the same neuronal populations and neuro-mediators can exert opposing effects, promoting or inhibiting tissue immunity. Here, we review the current understanding of the mechanisms that underlie the complex interactions between the immune and the nervous systems in different tissues and contexts. We outline current gaps in knowledge and argue for the importance of considering infectious and inflammatory disease within a conceptual framework that integrates neuro-immune circuits both local and systemic, so as to better understand effective immunity to develop improved approaches to treat inflammation and disease.
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Affiliation(s)
- Coco Chu
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA
| | - David Artis
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Friedman Center for Nutrition and Inflammation, Joan and Sanford I. Weill Department of Medicine, Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
| | - Isaac M Chiu
- Department of Immunology, Harvard Medical School, Boston, MA, USA.
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Aerts-Kaya F, Ulum B, Mammadova A, Köse S, Aydin G, Korkusuz P, Uçkan-Çetinkaya D. Neurological Regulation of the Bone Marrow Niche. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1212:127-153. [PMID: 31342461 DOI: 10.1007/5584_2019_398] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The bone marrow (BM) hematopoietic niche is the microenvironment where in the adult hematopoietic stem and progenitor cells (HSPCs) are maintained and regulated. This regulation is tightly controlled through direct cell-cell interactions with mesenchymal stromal stem (MSCs) and reticular cells, adipocytes, osteoblasts and endothelial cells, through binding to extracellular matrix molecules and through signaling by cytokines and hematopoietic growth factors. These interactions provide a healthy environment and secure the maintenance of the HSPC pool, their proliferation, differentiation and migration. Recent studies have shown that innervation of the BM and interactions with the peripheral sympathetic neural system are important for maintenance of the hematopoietic niche, through direct interactions with HSCPs or via interactions with other cells of the HSPC microenvironment. Signaling through adrenergic receptors (ARs), opioid receptors (ORs), endocannabinoid receptors (CRs) on HSPCs and MSCs has been shown to play an important role in HSPC homeostasis and mobilization. In addition, a wide range of neuropeptides and neurotransmitters, such as Neuropeptide Y (NPY), Substance P (SP) and Tachykinins, as well as neurotrophins and neuropoietic growth factors have been shown to be involved in regulation of the hematopoietic niche. Here, a comprehensive overview is given of their role and interactions with important cells in the hematopoietic niche, including HSPCs and MSCs, and their effect on HSPC maintenance, regulation and mobilization.
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Affiliation(s)
- Fatima Aerts-Kaya
- Graduate School of Health Sciences, Department of Stem Cell Sciences, Hacettepe University, Ankara, Turkey. .,Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey.
| | - Baris Ulum
- Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey.,Faculty of Arts and Sciences, Department of Biological Sciences, Middle East Technical University, Ankara, Turkey
| | - Aynura Mammadova
- Graduate School of Health Sciences, Department of Stem Cell Sciences, Hacettepe University, Ankara, Turkey.,Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey
| | - Sevil Köse
- Faculty of Health Sciences, Department of Medical Biology, Atilim University, Ankara, Turkey
| | - Gözde Aydin
- Graduate School of Health Sciences, Department of Stem Cell Sciences, Hacettepe University, Ankara, Turkey.,Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey
| | - Petek Korkusuz
- Graduate School of Health Sciences, Department of Stem Cell Sciences, Hacettepe University, Ankara, Turkey.,Faculty of Medicine, Department of Histology and Embryology, Hacettepe University, Ankara, Turkey
| | - Duygu Uçkan-Çetinkaya
- Graduate School of Health Sciences, Department of Stem Cell Sciences, Hacettepe University, Ankara, Turkey.,Center for Stem Cell Research and Development, Hacettepe University, Ankara, Turkey
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38
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Saloman JL, Cohen JA, Kaplan DH. Intimate neuro-immune interactions: breaking barriers between systems to make meaningful progress. Curr Opin Neurobiol 2019; 62:60-67. [PMID: 31841783 DOI: 10.1016/j.conb.2019.11.021] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 11/19/2019] [Accepted: 11/25/2019] [Indexed: 12/13/2022]
Abstract
The nervous system is often viewed as an isolated system that integrates information from the environment and host. Recently, there has been a renewed focus exploring the concept that the nervous system also communicates across biological systems. Specifically, several high profile studies have recently highlighted the importance of neuro-immune communication in the context of homeostasis, central nervous system disorders, host defense and injury. Here, we discuss the history of shared mechanisms and interconnectedness of the nervous, immune and epithelial compartments. In light of these overlapping mechanisms, it is perhaps unsurprising that neuro-immune-epithelial signaling plays a key role in regulating diverse biological phenomena. In this review, we explore recent breakthroughs in understanding neuro-immune signaling to highlight the importance of interdisciplinary approaches to biomedical research and the future development of novel therapeutics.
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Affiliation(s)
- Jami L Saloman
- Department of Medicine, Division of Gastroenterology, Hepatology, & Nutrition, Department of Neurobiology, Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jonathan A Cohen
- Department of Dermatology, Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Daniel H Kaplan
- Department of Dermatology, Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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Wani KA, Goswamy D, Irazoqui JE. Nervous system control of intestinal host defense in C. elegans. Curr Opin Neurobiol 2019; 62:1-9. [PMID: 31790812 DOI: 10.1016/j.conb.2019.11.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Accepted: 11/01/2019] [Indexed: 12/16/2022]
Abstract
Interplay between the nervous and immune systems is critical for homeostasis, and its dysfunction underlies pathologies such as multiple sclerosis, autism, leukemia, and inflammation. The nematode Caenorhabditis elegans provides an opportunity to define evolutionarily conserved mechanisms of regulation of host innate immunity and inflammation in a genetically tractable whole-animal system. In the past few years, the C. elegans nervous system has emerged as an integral part of host defense against pathogens, acting through diverse mechanisms to repress or induce protective transcriptional responses to infection in distal tissues. In this review, we discuss current knowledge of the mechanisms through which the C. elegans nervous system controls the expression of host defense genes in the intestinal epithelium. Although still incomplete, the insights derived from such work have broad implications for neural regulation of epithelial function at mucosal barriers in higher organisms in health and disease.
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Affiliation(s)
- Khursheed A Wani
- Department of Microbiology and Physiological Systems and Program in Innate Immunity, University of Massachusetts Medical School, Worcester, USA
| | - Debanjan Goswamy
- Department of Microbiology and Physiological Systems and Program in Innate Immunity, University of Massachusetts Medical School, Worcester, USA
| | - Javier E Irazoqui
- Department of Microbiology and Physiological Systems and Program in Innate Immunity, University of Massachusetts Medical School, Worcester, USA.
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Sellegounder D, Liu Y, Wibisono P, Chen CH, Leap D, Sun J. Neuronal GPCR NPR-8 regulates C. elegans defense against pathogen infection. SCIENCE ADVANCES 2019; 5:eaaw4717. [PMID: 31799388 PMCID: PMC6867885 DOI: 10.1126/sciadv.aaw4717] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Accepted: 09/17/2019] [Indexed: 05/18/2023]
Abstract
Increasing evidence indicates that infection-triggered host defenses are regulated by the nervous system. However, the precise mechanisms of this regulation are not well understood. Here, we demonstrate that neuronal G protein-coupled receptor NPR-8 negatively regulates Caenorhabditis elegans defense against pathogen infection by suppressing cuticular collagen expression. NPR-8 controls the dynamics of cuticle structure in response to infection, likely through its regulation of cuticular collagen genes which, in turn, affects the nematode's defense. We further show that the defense activity of NPR-8 is confined to amphid sensory neurons AWB, ASJ, and AWC. It is generally believed that physical barrier defenses are not a response to infections but are part of the body's basic innate defense against pathogens. Our results challenge this view by showing not only that C. elegans cuticle structure dynamically changes in response to infection but also that the cuticle barrier defense is regulated by the nervous system.
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Affiliation(s)
- Durai Sellegounder
- Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA
| | - Yiyong Liu
- Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA
- Genomics Core, Washington State University, Spokane, WA, USA
| | - Phillip Wibisono
- Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA
| | - Chia-Hui Chen
- Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA
| | - David Leap
- Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA
| | - Jingru Sun
- Department of Biomedical Sciences, Elson S. Floyd College of Medicine, Washington State University, Spokane, WA, USA
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41
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Wu WQ, Peng S, Wan XQ, Lin S, Li LY, Song ZY. Physical exercise inhibits atherosclerosis development by regulating the expression of neuropeptide Y in apolipoprotein E-deficient mice. Life Sci 2019; 237:116896. [DOI: 10.1016/j.lfs.2019.116896] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 09/14/2019] [Accepted: 09/20/2019] [Indexed: 01/01/2023]
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Crosson T, Roversi K, Balood M, Othman R, Ahmadi M, Wang JC, Seadi Pereira PJ, Tabatabaei M, Couture R, Eichwald T, Latini A, Prediger RD, Rangachari M, Seehus CR, Foster SL, Talbot S. Profiling of how nociceptor neurons detect danger - new and old foes. J Intern Med 2019; 286:268-289. [PMID: 31282104 DOI: 10.1111/joim.12957] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The host evolves redundant mechanisms to preserve physiological processing and homeostasis. These functions range from sensing internal and external threats, creating a memory of the insult and generating reflexes, which aim to resolve inflammation. Impairment in such functioning leads to chronic inflammatory diseases. By interacting through a common language of ligands and receptors, the immune and sensory nervous systems work in concert to accomplish such protective functions. Whilst this bidirectional communication helps to protect from danger, it can contribute to disease pathophysiology. Thus, the somatosensory nervous system is anatomically positioned within primary and secondary lymphoid tissues and mucosa to modulate immunity directly. Upstream of this interplay, neurons detect danger, which prompts the release of neuropeptides initiating (i) defensive reflexes (ranging from withdrawal response to coughing) and (ii) chemotaxis, adhesion and local infiltration of immune cells. The resulting outcome of such neuro-immune interplay is still ill-defined, but consensual findings start to emerge and support neuropeptides not only as blockers of TH 1-mediated immunity but also as drivers of TH 2 immune responses. However, the modalities detected by nociceptors revealed broader than mechanical pressure and temperature sensing and include signals as various as cytokines and pathogens to immunoglobulins and even microRNAs. Along these lines, we aggregated various dorsal root ganglion sensory neuron expression profiling datasets supporting such wide-ranging sensing capabilities to help identifying new danger detection modalities of these cells. Thus, revealing unexpected aspects of nociceptor neuron biology might prompt the identification of novel drivers of immunity, means to resolve inflammation and strategies to safeguard homeostasis.
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Affiliation(s)
- T Crosson
- From the, Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - K Roversi
- From the, Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.,Departamento de Farmacologia Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - M Balood
- From the, Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.,Axe Neurosciences, Centre de recherche du CHU, Université Laval, Québec, QC, Canada.,Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, QC, Canada
| | - R Othman
- From the, Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - M Ahmadi
- From the, Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - J-C Wang
- From the, Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada.,Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | | | - M Tabatabaei
- From the, Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - R Couture
- From the, Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
| | - T Eichwald
- Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - A Latini
- Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - R D Prediger
- Departamento de Farmacologia Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Brazil
| | - M Rangachari
- Axe Neurosciences, Centre de recherche du CHU, Université Laval, Québec, QC, Canada.,Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Québec, QC, Canada
| | - C R Seehus
- FM Kirby Neurobiology Center, Children's Hospital, Boston, MA, USA
| | - S L Foster
- Depression Clinical Research Program, Massachusetts General Hospital, Boston, MA, USA
| | - S Talbot
- From the, Département de Pharmacologie et Physiologie, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada
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43
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Murugesan V, Dwivedi R, Saini M, Gupta V, Dada T, Vivekanandhan S. Tear neuromediators in eyes on chronic topical antiglaucoma therapy with and without BAK preservatives. Br J Ophthalmol 2019; 105:141-148. [PMID: 31383648 DOI: 10.1136/bjophthalmol-2019-314234] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Revised: 06/18/2019] [Accepted: 07/19/2019] [Indexed: 11/03/2022]
Abstract
PURPOSE To evaluate tear neuropeptides (NPs) (vasoactive intestinal peptide (VIP), neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), substance P (SP), nerve growth factor (NGF)) in chronic ocular topical hypotensive therapy with and without benzalkonium chloride (BAK) preservative. METHODS A comparative, open label, cross-sectional study of patients using antiglaucoma medications for >6 months with BAK (group I), without BAK (group II) and controls was done. Tear NPs (ELISA), ocular surface evaluation tests (tear breakup time (TBUT), Schirmer's test, corneal and conjunctival staining score) and confocal central corneal subbasal nerve fibre layer (SBNFL) imaging was done. RESULTS Of 153 eyes evaluated, group 1 (82 eyes (41 patients; mean age 48±14.5 years)) and group 2 (71 eyes (36 patients; mean age 43.11±15 years)) were on therapy for a mean duration of 10.05±2.0 and 9.67±2.3 months, respectively. Tear analysis showed elevated SP and NGF (p<0.01); decreased CGRP (p=0.03), VIP and NPY (p<0.01) compared with controls (n=30, mean age 29.33±5.7 years). Tear NP levels (SP (p=0.1), NGF (p=0.33), CGRP (p=1), VIP (p=0.87), NPY (p=0.83)) and SBNFL (p=0.09) were comparable in both groups. There was no correlation seen between tear NP levels and clinical tests and SBNFL. CONCLUSION Our study analysis points towards altered tear NP levels in eyes on chronic topical hypotensive therapy in comparison with controls with no significant difference in tear NP levels and central corneal SBNFL density between the BAK preservative and BAK-free antiglaucoma therapy.
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Affiliation(s)
- Vanathi Murugesan
- Dr R P Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Delhi, India
| | - Roopa Dwivedi
- Dr R P Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Delhi, India
| | - Manu Saini
- Dr R P Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Delhi, India
| | - Viney Gupta
- Dr R P Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Delhi, India
| | - Tanuj Dada
- Dr R P Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Delhi, India
| | - S Vivekanandhan
- Neurobiochemistry Lab, C N Centre, All India Institute of Medical Sciences, New Delhi, India
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Ruiz HH, Becker S, Bai Y, Cortes-Burgos LA, Eckersdorff MM, Macdonald LE, Croll SD. Pharmacological inhibition of NPY receptors illustrates dissociable features of experimental colitis in the mouse DSS model: Implications for preclinical evaluation of efficacy in an inflammatory bowel disease model. PLoS One 2019; 14:e0220156. [PMID: 31369588 PMCID: PMC6675069 DOI: 10.1371/journal.pone.0220156] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Accepted: 07/08/2019] [Indexed: 12/24/2022] Open
Abstract
Administration of dextran sodium sulfate (DSS) to rodents at varying concentrations and exposure times is commonly used to model human inflammatory bowel disease (IBD). Currently, the criteria used to assess IBD-like pathology seldom include surrogate measures of visceral pain. Thus, we sought to standardize the model and then identify surrogate measures to assess effects on visceral pain. We used various 4% DSS protocols and evaluated effects on weight loss, colon pathology, biochemistry, RNA signature, and open field behavior. We then tested the therapeutic potential of NPY Y1 and/or Y2 receptor inhibition for the treatment of IBD pathology using this expanded panel of outcome measures. DSS caused weight loss and colon shrinkage, increased colon NPY and inflammatory cytokine expression, altered behaviors in the open field and induced a distinct gene metasignature that significantly overlapped with that of human IBD patients. Inhibition of Y1 and/or Y2 receptors failed to improve gross colon pathology. Y1 antagonism significantly attenuated colon inflammatory cytokine expression without altering pain-associated behaviors while Y2 antagonism significantly inhibited pain-associated behaviors in spite of a limited effect on inflammatory markers. A protocol using 7 days of 4% DSS most closely modeled human IBD pathology. In this model, rearing behavior potentially represents a tool for evaluating visceral pain/discomfort that may be pharmacologically dissociable from other features of pathology. The finding that two different NPY receptor antagonists exhibited different efficacy profiles highlights the benefit of including a variety of outcome measures in IBD efficacy studies to most fully evaluate the therapeutic potential of experimental treatments.
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Affiliation(s)
- Henry H. Ruiz
- Regeneron Pharmaceuticals, Neuroscience, Tarrytown, New York, United States of America
- The Graduate Center of the City University of New York, Graduate Program in Neuropsychology, New York, New York, United States of America
| | - Stephanie Becker
- Regeneron Pharmaceuticals, Neuroscience, Tarrytown, New York, United States of America
| | - Yu Bai
- Regeneron Pharmaceuticals, Neuroscience, Tarrytown, New York, United States of America
| | - Luz A. Cortes-Burgos
- Regeneron Pharmaceuticals, Neuroscience, Tarrytown, New York, United States of America
| | | | - Lynn E. Macdonald
- Regeneron Pharmaceuticals, Neuroscience, Tarrytown, New York, United States of America
| | - Susan D. Croll
- Regeneron Pharmaceuticals, Neuroscience, Tarrytown, New York, United States of America
- The Graduate Center of the City University of New York, Graduate Program in Neuropsychology, New York, New York, United States of America
- Queens College of the City University of New York, Psychology, Flushing, New York, United States of America
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45
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Choi B, Shin MK, Kim EY, Park JE, Lee H, Kim SW, Song JK, Chang EJ. Elevated Neuropeptide Y in Endothelial Dysfunction Promotes Macrophage Infiltration and Smooth Muscle Foam Cell Formation. Front Immunol 2019; 10:1701. [PMID: 31379881 PMCID: PMC6657015 DOI: 10.3389/fimmu.2019.01701] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 07/08/2019] [Indexed: 12/19/2022] Open
Abstract
Endothelial dysfunction has been linked to vascular inflammation and foam cell formation but the underlying mechanisms still remain unclear. We sought to define the factors inducing inflammation and smooth muscle foam cell formation under endothelial dysfunction using endothelial nitric oxide synthase (eNOS)-deficient mice. Vascular smooth muscle cells (VSMCs) from eNOS-deficient mice displayed increased expression of macrophage-related genes and elevated lipid uptake. Neuropeptide Y (NPY) was upregulated in the aorta from the eNOS-deficient mice and promoted macrophage chemotaxis toward VSMCs while enhancing the activity of matrix metalloproteinase-3. Notably, NPY induced lipid uptake in VSMCs, facilitating smooth muscle foam cell formation, in association with enhanced expression of genes related to modified low-density lipoprotein uptake and macrophages. NPY was augmented by inflammatory pentraxin 3 (PTX3) in VSMCs. PTX3 enhanced macrophage migratory capacity through the NPY/neuropeptide Y receptor axis and this effect was attenuated by pharmacological inhibition with a receptor-specific antagonist. These observations suggest that endothelial dysfunction leads to the elevation of NPY that amplifies vascular inflammation by increasing inflammatory cell chemotaxis and triggers smooth muscle foam cell formation.
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Affiliation(s)
- Bongkun Choi
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Min-Kyung Shin
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Eun-Young Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ji-Eun Park
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Halim Lee
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Seong Who Kim
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Jae-Kwan Song
- Division of Cardiology, Asan Medical Center, Research Institute for Valvular Heart Disease University of Ulsan College of Medicine, Seoul, South Korea
| | - Eun-Ju Chang
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.,Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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Schneider S, Wright CM, Heuckeroth RO. Unexpected Roles for the Second Brain: Enteric Nervous System as Master Regulator of Bowel Function. Annu Rev Physiol 2019; 81:235-259. [DOI: 10.1146/annurev-physiol-021317-121515] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
At the most fundamental level, the bowel facilitates absorption of small molecules, regulates fluid and electrolyte flux, and eliminates waste. To successfully coordinate this complex array of functions, the bowel relies on the enteric nervous system (ENS), an intricate network of more than 500 million neurons and supporting glia that are organized into distinct layers or plexi within the bowel wall. Neuron and glial diversity, as well as neurotransmitter and receptor expression in the ENS, resembles that of the central nervous system. The most carefully studied ENS functions include control of bowel motility, epithelial secretion, and blood flow, but the ENS also interacts with enteroendocrine cells, influences epithelial proliferation and repair, modulates the intestinal immune system, and mediates extrinsic nerve input. Here, we review the many different cell types that communicate with the ENS, integrating data about ENS function into a broader view of human health and disease. In particular, we focus on exciting new literature highlighting relationships between the ENS and its lesser-known interacting partners.
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Affiliation(s)
- Sabine Schneider
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Christina M. Wright
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Robert O. Heuckeroth
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Abramson Research Center, The Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania 19104, USA
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Khalil M, Zhang Z, Engel MA. Neuro-Immune Networks in Gastrointestinal Disorders. Visc Med 2019; 35:52-60. [PMID: 31312651 DOI: 10.1159/000496838] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Accepted: 01/11/2019] [Indexed: 12/13/2022] Open
Abstract
Tissue homeostasis is controlled by multilateral cell interactions. Established in autoimmune diseases of the central nervous system, growing evidence shows a fundamental role of bidirectional communication between the nervous and immune systems in various gastrointestinal disorders. Primarily the primary sensory nervous system seems to play an important role in this cross talk because of its ability for transducing inflammatory signals and to convey them to the central nervous system, which in turn responds in an efferent manner (gut-brain axis vs. brain-gut axis). Moreover, sensory neurons that play a central role in pain processing immediately respond to inflammatory stimuli through releasing a myriad of immunomodulatory neuropeptides and neurotransmitters whose receptors are expressed in different immune cell populations. Thus, a better understanding of neuro-immune networks will pave the way to novel therapeutic strategies in inflammatory as well as functional gastrointestinal disorders.
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Affiliation(s)
- Mohammad Khalil
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Zehua Zhang
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
| | - Matthias A Engel
- Department of Medicine 1, Universitätsklinikum Erlangen, Erlangen, Germany
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Oda N, Miyahara N, Taniguchi A, Morichika D, Senoo S, Fujii U, Itano J, Gion Y, Kiura K, Kanehiro A, Maeda Y. Requirement for neuropeptide Y in the development of type 2 responses and allergen-induced airway hyperresponsiveness and inflammation. Am J Physiol Lung Cell Mol Physiol 2019; 316:L407-L417. [PMID: 30604629 DOI: 10.1152/ajplung.00386.2018] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Neuropeptide Y (NPY) is a neurotransmitter that is widely expressed in the brain and peripheral nervous system. Various immune cells express the NPY Y1 receptor. NPY modulates these cells via its Y1 receptor; however, involvement of NPY in the pathophysiology of bronchial asthma, particularly airway hyperresponsiveness (AHR), has not been defined. NPY-deficient and wild-type mice were intranasally sensitized and challenged to house dust mite (HDM) extract, and airway responses were monitored. After sensitization and challenge, NPY-deficient mice showed significantly lower AHR than wild-type mice, and numbers of eosinophils and levels of type 2 cytokines [interleukin (IL)-4, IL-5, and IL-13] in bronchoalveolar lavage fluid were significantly lower. Type 2 cytokine production from splenic mononuclear cells of HDM-sensitized mice was also significantly lower in NPY-deficient mice. Flow cytometry analysis showed that the number of CD4 T cells and CD11c+ antigen-presenting cells (APCs) was significantly lower in the lungs of NPY-deficient mice than in wild-type mice following sensitization and challenge. Significantly fewer CD11c+ APCs phagocytosed HDM in the mediastinal lymph nodes of NPY-deficient mice than in those of wild-type mice. Treatment with BIBO-3304, a NPY receptor antagonist, significantly suppressed development of HDM-induced AHR and inflammation in wild-type mice. These data identify an important contribution of NPY to allergen-induced AHR and inflammation through accumulation of dendritic cells in the airway and promotion of the type 2 immune response. Thus, manipulating NPY represents a novel therapeutic target to control allergic airway responses.
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Affiliation(s)
- Naohiro Oda
- Department of Hematology, Oncology, Allergy, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama , Japan
| | - Nobuaki Miyahara
- Department of Medical Technology, Okayama University Graduate School of Health Sciences , Okayama , Japan.,Department of Allergy and Respiratory Medicine, Okayama University Hospital , Okayama , Japan
| | - Akihiko Taniguchi
- Department of Hematology, Oncology, Allergy, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama , Japan
| | - Daisuke Morichika
- Department of Hematology, Oncology, Allergy, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama , Japan
| | - Satoru Senoo
- Department of Hematology, Oncology, Allergy, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama , Japan
| | - Utako Fujii
- Department of Hematology, Oncology, Allergy, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama , Japan
| | - Junko Itano
- Department of Hematology, Oncology, Allergy, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama , Japan
| | - Yuka Gion
- Department of Medical Technology, Okayama University Graduate School of Health Sciences , Okayama , Japan.,Division of Pathophysiology, Okayama University Graduate School of Health Sciences , Okayama , Japan
| | - Katsuyuki Kiura
- Department of Allergy and Respiratory Medicine, Okayama University Hospital , Okayama , Japan
| | - Arihiko Kanehiro
- Department of Hematology, Oncology, Allergy, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama , Japan.,Department of Allergy and Respiratory Medicine, Okayama Rosai Hospital , Okayama , Japan
| | - Yoshinobu Maeda
- Department of Hematology, Oncology, Allergy, and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama , Japan
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Bottasso E. Toward the Existence of a Sympathetic Neuroplasticity Adaptive Mechanism Influencing the Immune Response. A Hypothetical View-Part I. Front Endocrinol (Lausanne) 2019; 10:632. [PMID: 31616373 PMCID: PMC6763740 DOI: 10.3389/fendo.2019.00632] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 08/30/2019] [Indexed: 12/21/2022] Open
Abstract
The nervous system exerts a profound influence on the function of the immune system (IS), mainly through the sympathetic arm of the autonomic nervous system. In fact, the sympathetic nervous system richly innervates secondary lymphoid organs (SLOs) such as the spleen and lymph nodes. For decades, different research groups working in the field have consistently reported changes in the sympathetic innervation of the SLOs during the activation of the IS, which are characterized by a decreased noradrenergic activity and retraction of these fibers. Most of these groups interpreted these changes as a pathological phenomenon, referred to as "damage" or "injury" of the noradrenergic fibers. Some of them postulated that this "injury" was probably due to toxic effects of released endogenous mediators. Others, working on animal models of chronic stimulation of the IS, linked it to the very chronic nature of processes. Unlike these views, this first part of the present work reviews evidence which supports the hypothesis of a specific adaptive mechanism of neural plasticity from sympathetic fibers innervating SLOs, encompassing structural and functional changes of noradrenergic nerves. This plasticity mechanism would involve segmental retraction and degeneration of these fibers during the activation of the IS with subsequent regeneration once the steady state is recovered. The candidate molecules likely to mediate this phenomenon are also here introduced. The second part will extend this view as to the potential changes in sympathetic innervation likely to occur in inflamed non-lymphoid peripheral tissues and its possible immunological implications.
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Christiansen AT, Sørensen NB, Haanes KA, Blixt FW, la Cour M, Warfvinge K, Klemp K, Woldbye DPD, Kiilgaard JF. Neuropeptide Y treatment induces retinal vasoconstriction and causes functional and histological retinal damage in a porcine ischaemia model. Acta Ophthalmol 2018; 96:812-820. [PMID: 30218483 DOI: 10.1111/aos.13806] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 04/04/2018] [Indexed: 01/10/2023]
Abstract
PURPOSE To investigate the effects of intravitreal neuropeptide Y (NPY) treatment following acute retinal ischaemia in an in vivo porcine model. In addition, we evaluated the vasoconstrictive potential of NPY on porcine retinal arteries ex vivo. METHODS Twelve pigs underwent induced retinal ischaemia by elevated intraocular pressure clamping the ocular perfusion pressure at 5 mmHg for 2 hr followed by intravitreal injection of NPY or vehicle. After 4 weeks, retinas were evaluated functionally by standard and global-flash multifocal electroretinogram (mfERG) and histologically by thickness of retinal layers and number of ganglion cells. Additionally, the vasoconstrictive effects of NPY and its involved receptors were tested using wire myographs and NPY receptor antagonists on porcine retinal arteries. RESULTS Intravitreal injection of NPY after induced ischaemia caused a significant reduction in the mean induced component (IC) amplitude ratio (treated/normal eye) compared to vehicle-treated eyes. This reduction was accompanied by histological damage, where NPY treatment reduced the mean thickness of inner retinal layers and number of ganglion cells. In retinal arteries, NPY-induced vasoconstriction to a plateau of approximately 65% of potassium-induced constriction. This effect appeared to be mediated via Y1 and Y2, but not Y5. CONCLUSION In seeming contrast to previous in vitro studies, intravitreal NPY treatment caused functional and histological damage compared to vehicle after a retinal ischaemic insult. Furthermore, we showed for the first time that NPY induces Y1- and Y2- but not Y5-mediated vasoconstriction in retinal arteries. This constriction could explain the worsening in vivo effect induced by NPY treatment following an ischaemic insult and suggests that future studies on exploring the neuroprotective effects of NPY might focus on other receptors than Y1 and Y2.
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Affiliation(s)
- Anders T. Christiansen
- Laboratory of Neural Plasticity; Department of Neuroscience; University of Copenhagen; Copenhagen Denmark
- Department of Ophthalmology; Copenhagen University Hospital; Rigshospitalet; Copenhagen Denmark
| | - Nina B. Sørensen
- Department of Ophthalmology; Copenhagen University Hospital; Rigshospitalet; Copenhagen Denmark
| | - Kristian A. Haanes
- Department of Clinical Experimental Research; Glostrup Research Institute; Copenhagen University Hospital; Rigshospitalet; Copenhagen Denmark
| | - Frank W. Blixt
- Department of Clinical Sciences; Division of Experimental Vascular Research; Lund University; Lund Sweden
| | - Morten la Cour
- Department of Ophthalmology; Copenhagen University Hospital; Rigshospitalet; Copenhagen Denmark
| | - Karin Warfvinge
- Department of Clinical Experimental Research; Glostrup Research Institute; Copenhagen University Hospital; Rigshospitalet; Copenhagen Denmark
| | - Kristian Klemp
- Department of Ophthalmology; Copenhagen University Hospital; Rigshospitalet; Copenhagen Denmark
| | - David P. D. Woldbye
- Laboratory of Neural Plasticity; Department of Neuroscience; University of Copenhagen; Copenhagen Denmark
| | - Jens F. Kiilgaard
- Department of Ophthalmology; Copenhagen University Hospital; Rigshospitalet; Copenhagen Denmark
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