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Brunner SM, Gaisbauer S, Pallier PN, Yip PK, Ramspacher A, Leitner J, Sternberg F, Erhardt-Kreutzer C, Haslauer T, Huber S, Bieler L, Couillard-Despres S, Kofler B. Impact of galanin receptors 2 and 3 double-knockout on neuroinflammation and functional recovery following traumatic brain injury. Peptides 2025:171415. [PMID: 40412555 DOI: 10.1016/j.peptides.2025.171415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 05/16/2025] [Accepted: 05/22/2025] [Indexed: 05/27/2025]
Abstract
Traumatic brain injury (TBI) is one of the world's leading causes of death and disability in young individuals and the mechanism underlying TBI-associated neuroinflammation is poorly understood. The regulatory neuropeptide galanin (GAL) and its three receptors (GAL1-3R) are assumed to modulate the neuroinflammatory response following TBI, especially by signalling via GAL2R and GAL3R. Therefore, the role of GALRs in acute neuroinflammation and functional recovery following moderate Controlled Cortical Impact TBI was studied using GAL2/3R-double-KO (GAL2/3R-KO) mice. Brains and cerebrospinal fluid (CSF) were collected at day 1 and 30 days post TBI. Functional recovery post TBI was assessed by the modified Neurological Severity Score (mNSS), Elevated Plus Maze (EPM) and Morris Water Maze (MWM) test. Post TBI (day 1 to 28 post injury), neurological dysfunction was more severe in GAL2/3R-KO mice than in WT mice. At 1 day post TBI, inflammatory markers and several nerve growth factors significantly increased in the ipsilateral hemisphere, compared to the contralateral hemisphere in both GAL2/3R-KO and WT mice. At 4 days post surgery, TBI mice entered significantly more frequent the open-arms in the EPM compared to Sham-operated mice, suggestive of increased exploratory behaviour in TBI mice. At 30 days post TBI, immunostaining of brain sections revealed significant differences in vascularisation and glial scarring in the cortex when comparing TBI and Sham-operated mice, but genotypes were similar. In summary, the results indicate that GAL2R and/or GAL3R have a neuroprotective role following moderate TBI, as the severity was significantly lower in their presence than in their absence.
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Affiliation(s)
- Susanne M Brunner
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria.
| | - Stefanie Gaisbauer
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria.
| | - Patrick N Pallier
- Centre for Neuroscience, Surgery and Trauma, The Blizard Institute, Queen Mary University of London, United Kingdom.
| | - Ping K Yip
- Centre for Neuroscience, Surgery and Trauma, The Blizard Institute, Queen Mary University of London, United Kingdom.
| | - Andrea Ramspacher
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria.
| | - Julia Leitner
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria.
| | - Felix Sternberg
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria.
| | - Christina Erhardt-Kreutzer
- Institute of Experimental Neurogeneration, Paracelsus Medical University, Salzburg, Austria; Department of General, Visceral and Thoracic Surgery, University Hospital of the Paracelsus Medical University, Salzburg, Austria.
| | - Theresa Haslauer
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria.
| | - Sara Huber
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria.
| | - Lara Bieler
- Institute of Experimental Neurogeneration, Paracelsus Medical University, Salzburg, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria.
| | - Sebastien Couillard-Despres
- Institute of Experimental Neurogeneration, Paracelsus Medical University, Salzburg, Austria; Austrian Cluster for Tissue Regeneration, Vienna, Austria.
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria.
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Michalickova D, Kramarikova I, Ozturk HK, Kucera T, Vacik T, Hrncir T, Kutinova Canova N, Sima M, Slanar O. Detection of galanin receptors in the spinal cord in experimental autoimmune encephalomyelitis. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2023; 167:36-42. [PMID: 35147137 DOI: 10.5507/bp.2022.005] [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: 07/01/2021] [Accepted: 01/28/2022] [Indexed: 11/23/2022] Open
Abstract
AIMS The neuropeptide galanin is a widely distributed neurotransmitter/neuromodulator that regulates a variety of physiological processes and also participates in the regulation of stress responses. The aims of the present study were to investigate the expression of galanin receptors (GalR1, GalR2, GalR3) in the spinal cords in a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) using qPCR analysis and to determine GalR1 cellular localization (oligodendrocytes, microglia, astrocytes, ependymal cells, and endothelial cells in the capillaries) by immunohistochemistry. METHODS Twelve samples from the EAE group and 14 samples from the control group were analyzed. Spinal cords samples were obtained at the peak of the EAE disease. RESULTS The GalR1 mRNA level was significantly decreased in the EAE mice compared with the controls (P=0.016), whereas the mRNA levels of GalR2 and GalR3 were not significantly different for the EAE and the control mice. No significant correlations were found between the severity of the EAE disease and the mRNA levels of GalR1, GalR2 and GalR3. Immunochemical detection of the GalR1 revealed its expression in the ependymal and endothelial cells. Additionally, a weak GalR1 immunoreactivity was occasionally detected in the oligodendrocytes. CONCLUSION This study provides additional evidence of galanin involvement in EAE pathophysiology, but this has to be further investigated.
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Affiliation(s)
- Danica Michalickova
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Ivana Kramarikova
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Hatice Kubra Ozturk
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Tomas Kucera
- Institute of Histology and Embryology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Tomas Vacik
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Tomas Hrncir
- Institute of Microbiology, Czech Academy of Sciences, Novy Hradek, Czech Republic
| | - Nikolina Kutinova Canova
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Martin Sima
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
| | - Ondrej Slanar
- Institute of Pharmacology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic
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Ortega JT, Parmar T, Jastrzebska B. Galanin receptor 3 - A new pharmacological target in retina degeneration. Pharmacol Res 2023; 188:106675. [PMID: 36693600 PMCID: PMC9918719 DOI: 10.1016/j.phrs.2023.106675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/16/2023] [Accepted: 01/20/2023] [Indexed: 01/22/2023]
Abstract
The neuropeptide galanin receptor 3 (GALR3) is a class A G protein-coupled receptor (GPCR) broadly expressed in the nervous system, including the retina. GALR3 is involved in the modulation of immune and inflammatory responses. Tight control of these processes is critical for maintaining homeostasis in the retina and is required to sustain vision. Here, we investigated the role of GALR3 in retina pathologies triggered by bright light and P23H mutation in the rhodopsin (RHO) gene, associated with the activation of oxidative stress and inflammatory responses. We used a multiphase approach involving pharmacological inhibition of GALR3 with its antagonist SNAP-37889 and genetic depletion of GALR3 to modulate the GALR3 signaling. Our in vitro experiments in the retinal pigment epithelium-derived cells (ARPE19) susceptible to all-trans-retinal toxicity indicated that GALR3 could be involved in the cellular stress response to this phototoxic product. Indeed, blocking the GALR3 signaling in Abca4-/-/Rdh8-/- and wild-type Balb/cJ mice, sensitive to bright light-induced retina damage, protected retina health in these mice exposed to light. The retina morphology and function were substantially improved, and stress response processes were reduced in these mouse models compared to the controls. Furthermore, in P23H Rho knock-in mice, a model of retinitis pigmentosa (RP), both pharmacological inhibition and genetic ablation of GALR3 prolonged the survival of photoreceptors. These results indicate that GALR3 signaling contributes to acute light-induced and chronic RP-linked retinopathies. Together, this work provides the pharmacological knowledge base to evaluate GALR3 as a potential target for developing novel therapies to combat retinal degeneration.
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Affiliation(s)
- Joseph T Ortega
- Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA
| | - Tanu Parmar
- Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA
| | - Beata Jastrzebska
- Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA.
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Distribution and possible function of galanin about headache and immune system in the rat dura mater. Sci Rep 2022; 12:5206. [PMID: 35338230 PMCID: PMC8956595 DOI: 10.1038/s41598-022-09325-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/22/2022] [Indexed: 12/20/2022] Open
Abstract
Galanin (GAL) is a nociceptive transmitter or modulator in the trigeminal sensory system. In this study, GAL expression was investigated in the rat dura mater to demonstrate its possible function in headache using immunohistochemical techniques. The cerebral falx and cerebellar dura mater received abundant blood and nerve supply, and were significantly thicker compared to other portions in the cerebral dura mater. GAL-immunoreactivity was expressed by cell and nerve fiber profiles. Presumed macrophages and dendritic cells contained GAL-immunoreactivity, and co-expressed with CD11b-immunoreactivity. Many isolated and perivascular nerve fibers also showed GAL-immunoreactivity. In addition, GAL-immunoreactive nerve fibers were present in the vicinity of macrophages and dendritic cells with either GAL- or ED1-immunoreactivity. GAL-immunoreactive cells and nerve fibers were common in the cerebral falx and cerebellar dura mater and infrequent in other portions. And, GAL-immunoreactive nerve fibers usually co-expressed calcitonin gene-related peptide (CGRP)-immunoreactivity. In the trigeminal ganglion, a substantial proportion of sensory neurons innervating the dura mater contained GAL-immunoreactivity (mean ± SD, 3.4 ± 2.2%), and co-expressed CGRP-immunoreactivity (2.7 ± 2.1%). The present study may suggest that GAL is associated with nociceptive transduction or modulation in the dura mater. GAL also possibly plays a role in the immune mechanism of the dura mater.
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A New Gal in Town: A Systematic Review of the Role of Galanin and Its Receptors in Experimental Pain. Cells 2022; 11:cells11050839. [PMID: 35269462 PMCID: PMC8909084 DOI: 10.3390/cells11050839] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/23/2022] [Accepted: 02/28/2022] [Indexed: 11/17/2022] Open
Abstract
Galanin is a neuropeptide expressed in a small percentage of sensory neurons of the dorsal root ganglia and the superficial lamina of the dorsal horn of the spinal cord. In this work, we systematically reviewed the literature regarding the role of galanin and its receptors in nociception at the spinal and supraspinal levels, as well as in chronic pain conditions. The literature search was performed in PubMed, Web of Science, Scopus, ScienceDirect, OVID, TRIP, and EMBASE using "Galanin" AND "pain" as keywords. Of the 1379 papers that were retrieved in the initial search, we included a total of 141 papers in this review. Using the ARRIVE guidelines, we verified that 89.1% of the works were of good or moderate quality. Galanin shows a differential role in pain, depending on the pain state, site of action, and concentration. Under normal settings, galanin can modulate nociceptive processing through both a pro- and anti-nociceptive action, in a dose-dependent manner. This peptide also plays a key role in chronic pain conditions and its antinociceptive action at both a spinal and supraspinal level is enhanced, reducing animals' hypersensitivity to both mechanical and thermal stimulation. Our results highlight galanin and its receptors as potential therapeutic targets in pain conditions.
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Aggarwal S, Ranjha R, Paul J. Neuroimmunomodulation by gut bacteria: Focus on inflammatory bowel diseases. World J Gastrointest Pathophysiol 2021; 12:25-39. [PMID: 34084590 PMCID: PMC8160600 DOI: 10.4291/wjgp.v12.i3.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/01/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Microbes colonize the gastrointestinal tract are considered as highest complex ecosystem because of having diverse bacterial species and 150 times more genes as compared to the human genome. Imbalance or dysbiosis in gut bacteria can cause dysregulation in gut homeostasis that subsequently activates the immune system, which leads to the development of inflammatory bowel disease (IBD). Neuromediators, including both neurotransmitters and neuropeptides, may contribute to the development of aberrant immune response. They are emerging as a regulator of inflammatory processes and play a key role in various autoimmune and inflammatory diseases. Neuromediators may influence immune cell’s function via the receptors present on these cells. The cytokines secreted by the immune cells, in turn, regulate the neuronal functions by binding with their receptors present on sensory neurons. This bidirectional communication of the enteric nervous system and the enteric immune system is involved in regulating the magnitude of inflammatory pathways. Alterations in gut bacteria influence the level of neuromediators in the colon, which may affect the gastrointestinal inflammation in a disease condition. Changed neuromediators concentration via dysbiosis in gut microbiota is one of the novel approaches to understand the pathogenesis of IBD. In this article, we reviewed the existing knowledge on the role of neuromediators governing the pathogenesis of IBD, focusing on the reciprocal relationship among the gut microbiota, neuromediators, and host immunity. Understanding the neuromediators and host-microbiota interactions would give a better insight in to the disease pathophysiology and help in developing the new therapeutic approaches for the disease.
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Affiliation(s)
- Surbhi Aggarwal
- Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology, Delhi 110016, India
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
| | - Raju Ranjha
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
- Field Unit Raipur, ICMR-National Institute of Malaria Research, Raipur 492015, Chhattisgarh, India
| | - Jaishree Paul
- School of Life Sciences, Jawaharlal Nehru University, Delhi 110067, India
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Oliveira Volpe CM, Vaz T, Rocha-Silva F, Villar-Delfino PH, Nogueira-Machado JA. Is Galanin a Promising Therapeutic Resource for Neural and Nonneural Diseases? Curr Drug Targets 2021; 21:922-929. [PMID: 32096740 DOI: 10.2174/1389450121666200225112055] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Galanin (GAL) constitutes a family of neuropeptides composed of four peptides: (i) galanin (GAL), (ii) galanin-message associated peptide (GAMP), (iii) galanin-like peptide (GALP), and (iv) alarin. GAL contains 29/30 amino acids, and its biological action occurs through the interactions with its various receptors (GALR1, GALR2, and GALR3). The neuropeptide GAL regulates several physiological and pathophysiological functions in the central nervous system, the peripheral nervous system, and the peripheral organs. GAL is secreted mainly by oligodendrocytes, astrocytes, and the gastrointestinal tract, and its effect depends on the interaction with its different receptors. These receptors are expressed mainly in the central, peripheral nervous systems and the intestines. OBJECTIVE The present review evaluates the role of GAL family in inflammatory diseases. An overview is given of the signaling and pharmacological effects due to the interaction between GAL and GALR in different cell types. The potential use of GAL as a therapeutic resource is critically discussed. CONCLUSION GAL is suggested to have an anti-inflammatory function in some situations and a proinflammatory function in others. The literature on GAL is controversial and currently not conclusive. This could be due to the complexity of the metabolic network signaling induced by the interactions between GAL and GALR. In the next future, GAL might be a promising therapeutic resource for several diseases, but its practical use for disease control is presently not advisable.
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Affiliation(s)
- Caroline Maria Oliveira Volpe
- Nucleo de Pos-Graduacao e Pesquisa, Hospital Santa Casa de Belo Horizonte, Rua Domingos Vieira 590, Santa Efigenia, 30150-240, Belo Horizonte, MG, Brazil
| | - Tatiana Vaz
- Nucleo de Pos-Graduacao e Pesquisa, Hospital Santa Casa de Belo Horizonte, Rua Domingos Vieira 590, Santa Efigenia, 30150-240, Belo Horizonte, MG, Brazil
| | - Fabiana Rocha-Silva
- Nucleo de Pos-Graduacao e Pesquisa, Hospital Santa Casa de Belo Horizonte, Rua Domingos Vieira 590, Santa Efigenia, 30150-240, Belo Horizonte, MG, Brazil
| | - Pedro Henrique Villar-Delfino
- Nucleo de Pos-Graduacao e Pesquisa, Hospital Santa Casa de Belo Horizonte, Rua Domingos Vieira 590, Santa Efigenia, 30150-240, Belo Horizonte, MG, Brazil
| | - José Augusto Nogueira-Machado
- Nucleo de Pos-Graduacao e Pesquisa, Hospital Santa Casa de Belo Horizonte, Rua Domingos Vieira 590, Santa Efigenia, 30150-240, Belo Horizonte, MG, Brazil
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Matyas JR, Klein C, Ponjevic D, Duncan NA, Kawchuk GN. Repetitive in vivo manual loading of the spine elicits cellular responses in porcine annuli fibrosi. PLoS One 2021; 16:e0248104. [PMID: 33755684 PMCID: PMC7987143 DOI: 10.1371/journal.pone.0248104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 02/21/2021] [Indexed: 11/19/2022] Open
Abstract
Back pain and intervertebral disc degeneration are prevalent, costly, and widely treated by manual therapies, yet the underlying causes of these diseases are indeterminate as are the scientific bases for such treatments. The present studies characterize the effects of repetitive in vivo manual loads on porcine intervertebral disc cell metabolism using RNA deep sequencing. A single session of repetitive manual loading applied to the lumbar spine induced both up- and down-regulation of a variety of genes transcribed by cells in the ventral annuli fibrosi. The effect of manual therapy at the level of loading was greater than at a level distant to the applied load. Gene ontology and molecular pathway analyses categorized biological, molecular, and cellular functions influenced by repetitive manual loading, with over-representation of membrane, transmembrane, and pericellular activities. Weighted Gene Co-expression Network Analysis discerned enrichment in genes in pathways of inflammation and skeletogenesis. The present studies support previous findings of intervertebral disc cell mechanotransduction, and are the first to report comprehensively on the repertoire of gene targets influenced by mechanical loads associated with manual therapy interventions. The present study defines the cellular response of repeated, low-amplitude loads on normal healthy annuli fibrosi and lays the foundation for future work defining how healthy and diseased intervertebral discs respond to single or low-frequency manual loads typical of those applied clinically.
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Affiliation(s)
- John Robert Matyas
- Department of Comparative Biology & Experimental Medicine, McCaig Institute of Bone and Joint Health, University of Calgary Faculty of Veterinary Medicine, Calgary, Alberta, Canada
- * E-mail:
| | - Claudia Klein
- Department of Clinical and Veterinary Clinical Sciences, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Dragana Ponjevic
- Department of Comparative Biology & Experimental Medicine, McCaig Institute of Bone and Joint Health, University of Calgary Faculty of Veterinary Medicine, Calgary, Alberta, Canada
| | - Neil A. Duncan
- Department of Civil Engineering, Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada
| | - Gregory N. Kawchuk
- Department of Physical Therapy, Faculty of Rehabilitation Medicine, University of Alberta, Edmonton, Alberta, Canada
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Capsaicin-Sensitive Peptidergic Sensory Nerves Are Anti-Inflammatory Gatekeepers in the Hyperacute Phase of a Mouse Rheumatoid Arthritis Model. Int J Mol Sci 2021; 22:ijms22041682. [PMID: 33567493 PMCID: PMC7915323 DOI: 10.3390/ijms22041682] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 01/26/2021] [Accepted: 02/03/2021] [Indexed: 02/08/2023] Open
Abstract
Capsaicin-sensitive peptidergic sensory nerves play complex, mainly protective regulatory roles in the inflammatory cascade of the joints via neuropeptide mediators, but the mechanisms of the hyperacute arthritis phase has not been investigated. Therefore, we studied the involvement of these afferents in the early, "black box" period of a rheumatoid arthritis (RA) mouse model. Capsaicin-sensitive fibres were defunctionalized by pretreatment with the ultrapotent capsaicin analog resiniferatoxin and arthritis was induced by K/BxN arthritogenic serum. Disease severity was assessed by clinical scoring, reactive oxygen species (ROS) burst by chemiluminescent, vascular permeability by fluorescent in vivo imaging. Contrast-enhanced magnetic resonance imaging was used to correlate the functional and morphological changes. After sensory desensitization, both early phase ROS-burst and vascular leakage were significantly enhanced, which was later followed by the increased clinical severity scores. Furthermore, the early vascular leakage and ROS-burst were found to be good predictors of later arthritis severity. We conclude that the anti-inflammatory role of peptidergic afferents depends on their activity in the hyperacute phase, characterized by decreased cellular and vascular inflammatory components presumably via anti-inflammatory neuropeptide release. Therefore, these fibres might serve as important gatekeepers in RA.
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Protective Role of Galanin during Chemically Induced Inflammation in Zebrafish Larvae. BIOLOGY 2021; 10:biology10020099. [PMID: 33573348 PMCID: PMC7911020 DOI: 10.3390/biology10020099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/23/2021] [Accepted: 01/25/2021] [Indexed: 11/16/2022]
Abstract
During a pathological condition, many different systems are involved in the response of an affected organism. Galanin is considered to be a neuropeptide that plays an important role in the central nervous system; however, it is involved in many other biological processes, including the immune response. During our studies, we showed that galanin became upregulated in zebrafish larvae when exposed to copper sulfate. Moreover, the presence of normal levels of galanin, administration of a galanin analog NAX 5055 or galanin overexpression led to lowered lateral line damage and enhanced expression of inflammatory markers compared to the knockout larvae. The results showed that the neuroendocrine system acts multifunctionally and should be considered as a part of the complex neuro-immune-endocrine axis.
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11
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Brunner SM, Reichmann F, Leitner J, Wölfl S, Bereswill S, Farzi A, Schneider AM, Klieser E, Neureiter D, Emberger M, Heimesaat MM, Weghuber D, Lang R, Holzer P, Kofler B. Galanin receptor 3 attenuates inflammation and influences the gut microbiota in an experimental murine colitis model. Sci Rep 2021; 11:564. [PMID: 33436730 PMCID: PMC7803768 DOI: 10.1038/s41598-020-79456-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 10/29/2020] [Indexed: 12/11/2022] Open
Abstract
The regulatory (neuro)peptide galanin and its three receptors (GAL1-3R) are involved in immunity and inflammation. Galanin alleviated inflammatory bowel disease (IBD) in rats. However, studies on the galanin receptors involved are lacking. We aimed to determine galanin receptor expression in IBD patients and to evaluate if GAL2R and GAL3R contribute to murine colitis. Immunohistochemical analysis revealed that granulocytes in colon specimens of IBD patients (Crohn's disease and ulcerative colitis) expressed GAL2R and GAL3R but not GAL1R. After colitis induction with 2% dextran sulfate sodium (DSS) for 7 days, mice lacking GAL3R (GAL3R-KO) lost more body weight, exhibited more severe colonic inflammation and aggravated histologic damage, with increased infiltration of neutrophils compared to wild-type animals. Loss of GAL3R resulted in higher local and systemic inflammatory cytokine/chemokine levels. Remarkably, colitis-associated changes to the intestinal microbiota, as assessed by quantitative culture-independent techniques, were most pronounced in GAL3R-KO mice, characterized by elevated numbers of enterobacteria and bifidobacteria. In contrast, GAL2R deletion did not influence the course of colitis. In conclusion, granulocyte GAL2R and GAL3R expression is related to IBD activity in humans, and DSS-induced colitis in mice is strongly affected by GAL3R loss. Consequently, GAL3R poses a novel therapeutic target for IBD.
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MESH Headings
- Animals
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/microbiology
- Colitis, Ulcerative/therapy
- Crohn Disease/genetics
- Crohn Disease/microbiology
- Crohn Disease/therapy
- Gastrointestinal Microbiome
- Gene Expression
- Humans
- Inflammation
- Mice, Inbred C57BL
- Mice, Knockout
- Molecular Targeted Therapy
- Rats
- Receptor, Galanin, Type 3/genetics
- Receptor, Galanin, Type 3/metabolism
- Receptor, Galanin, Type 3/physiology
- Mice
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Affiliation(s)
- Susanne M Brunner
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Muellner Hauptstr. 48, 5020, Salzburg, Austria.
| | - Florian Reichmann
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria
| | - Julia Leitner
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Muellner Hauptstr. 48, 5020, Salzburg, Austria
| | - Soraya Wölfl
- Laboratory for Pathology Weger, Emberger, Strubergasse 20, 5020, Salzburg, Austria
| | - Stefan Bereswill
- Institute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine Berlin, Garystr. 5, 14195, Berlin, Germany
| | - Aitak Farzi
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria
| | - Anna-Maria Schneider
- Department of Pediatrics, University Hospital of the Paracelsus Medical University, Muellner Hauptstr. 48, 5020, Salzburg, Austria
| | - Eckhard Klieser
- Institute of Pathology, University Hospital of the Paracelsus Medical University, Muellner Hauptstr. 48, 5020, Salzburg, Austria
| | - Daniel Neureiter
- Institute of Pathology, University Hospital of the Paracelsus Medical University, Muellner Hauptstr. 48, 5020, Salzburg, Austria
| | - Michael Emberger
- Laboratory for Pathology Weger, Emberger, Strubergasse 20, 5020, Salzburg, Austria
| | - Markus M Heimesaat
- Institute of Microbiology, Infectious Diseases and Immunology, Charité - University Medicine Berlin, Garystr. 5, 14195, Berlin, Germany
| | - Daniel Weghuber
- Department of Pediatrics, University Hospital of the Paracelsus Medical University, Muellner Hauptstr. 48, 5020, Salzburg, Austria
| | - Roland Lang
- Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, Muellner Hauptstr. 48, 5020, Salzburg, Austria
| | - Peter Holzer
- Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Universitätsplatz 4, 8010, Graz, Austria
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Muellner Hauptstr. 48, 5020, Salzburg, Austria
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12
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Falkenstetter S, Leitner J, Brunner SM, Rieder TN, Kofler B, Weis S. Galanin System in Human Glioma and Pituitary Adenoma. Front Endocrinol (Lausanne) 2020; 11:155. [PMID: 32265844 PMCID: PMC7105811 DOI: 10.3389/fendo.2020.00155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 03/06/2020] [Indexed: 11/20/2022] Open
Abstract
Expression of neuropeptides and their corresponding receptors has been demonstrated in different cancer types, where they can play a role in tumor cell growth, invasion, and migration. Human galanin (GAL) is a 30-amino-acid regulatory neuropeptide which acts through three G protein-coupled receptors, GAL1-R, GAL2-R, and GAL3-R that differ in their signal transduction pathways. GAL and galanin receptors (GALRs) are expressed by different tumors, and direct involvement of GAL in tumorigenesis has been shown. Despite its strong expression in the central nervous system (CNS), the role of GAL in CNS tumors has not been extensively studied. To date, GAL peptide expression, GAL receptor binding and mRNA expression have been reported in glioma, meningioma, and pituitary adenoma. However, data on the cellular distribution of GALRs are sparse. The aim of the present study was to examine the expression of GAL and GALRs in different brain tumors by immunohistochemistry. Anterior pituitary gland (n = 7), pituitary adenoma (n = 9) and glioma of different WHO grades I-IV (n = 55) were analyzed for the expression of GAL and the three GALRs with antibodies recently extensively validated for specificity. While high focal GAL immunoreactivity was detected in up to 40% of cells in the anterior pituitary gland samples, only one pituitary adenoma showed focal GAL expression, at a low level. In the anterior pituitary, GAL1-R and GAL3-R protein expression was observed in up to 15% of cells, whereas receptor expression was not detected in pituitary adenoma. In glioma, diffuse and focal GAL staining was noticed in the majority of cases. GAL1-R was observed in eight out of nine glioma subtypes. GAL2-R immunoreactivity was not detected in glioma and pituitary adenoma, while GAL3-R expression was significantly associated to high-grade glioma (WHO grade IV). Most interestingly, expression of GAL and GALRs was observed in tumor-infiltrating immune cells, including neutrophils and glioma-associated macrophages/microglia. The presence of GALRs on tumor-associated immune cells, especially macrophages, indicates that GAL signaling contributes to homeostasis of the tumor microenvironment. Thus, our data indicate that GAL signaling in tumor-supportive myeloid cells could be a novel therapeutic target.
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MESH Headings
- Adenoma/genetics
- Adenoma/metabolism
- Adenoma/pathology
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Brain Neoplasms/genetics
- Brain Neoplasms/metabolism
- Brain Neoplasms/pathology
- Child
- Child, Preschool
- Galanin/genetics
- Galanin/metabolism
- Gene Expression Regulation, Neoplastic
- Glioma/genetics
- Glioma/metabolism
- Glioma/pathology
- Humans
- Middle Aged
- Pituitary Neoplasms/genetics
- Pituitary Neoplasms/metabolism
- Pituitary Neoplasms/pathology
- Receptor, Galanin, Type 1/genetics
- Receptor, Galanin, Type 1/metabolism
- Receptor, Galanin, Type 2/genetics
- Receptor, Galanin, Type 2/metabolism
- Receptor, Galanin, Type 3/genetics
- Receptor, Galanin, Type 3/metabolism
- Receptors, Galanin/genetics
- Receptors, Galanin/metabolism
- Young Adult
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Affiliation(s)
- Sarah Falkenstetter
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Julia Leitner
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Susanne M. Brunner
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Tim N. Rieder
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
- *Correspondence: Barbara Kofler
| | - Serge Weis
- Division of Neuropathology, Department of Pathology and Neuropathology, Neuromed, School of Medicine Campus, Kepler University Hospital, Johannes Kepler University, Linz, Austria
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13
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Ramspacher A, Neudert M, Koller A, Schlager S, Kofler B, Brunner SM. Influence of the regulatory peptide galanin on cytokine expression in human monocytes. Ann N Y Acad Sci 2019; 1455:185-195. [PMID: 31074091 PMCID: PMC6899851 DOI: 10.1111/nyas.14111] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 03/27/2019] [Accepted: 04/05/2019] [Indexed: 01/08/2023]
Abstract
Current research into neuropeptides is bringing to light many remarkable functions of these endocrine/neurocrine/paracrine factors, such as their roles in modulating immune responses. Galanin is a neuropeptide expressed in both neural and non‐neural tissues and exerts its effects through three G protein–coupled receptors, GAL1,2,3‐R. It has been demonstrated that galanin has modulatory effects on immune cells, including neutrophils and natural killer cells. Because monocytes express GAL2‐R, and therefore are expected to be a target of galanin, we analyzed the effect of galanin on the expression of cytokines and chemokines by monocytes. Galanin increased the expression of IL‐1β up to 1.5‐fold, TNF‐α, IL‐10, IL‐18, and CCL3 up to twofold, and CXCL8 up to fourfold in nonactivated monocytes, but had no major effect on activated monocytes. A cross‐correlation analysis of cytokine expression profiles, irrespective of the activation status of the monocytes, revealed that galanin changed the cross‐correlation of the expression of certain cytokines. Galanin abolished several significant correlations in IFN‐γ–stimulated monocytes. For example, treatment with 10 nM galanin changed the Spearman's rank coefficient of IL‐18 and CXCL8 from 0.622 (P ≤ 0.01) to 0.126. These results further emphasize the importance of neuroregulatory peptides, such as galanin and their therapeutic potential to treat inflammatory diseases.
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Affiliation(s)
- Andrea Ramspacher
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Magdalena Neudert
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Andreas Koller
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria.,University Clinic of Ophthalmology and Optometry, Research Program for Ophthalmology and Glaucoma Research, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Sandra Schlager
- Department of Blood Group Serology and Transfusion Medicine, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Barbara Kofler
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
| | - Susanne Maria Brunner
- Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, University Hospital of the Paracelsus Medical University, Salzburg, Austria
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14
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Galanin is a potent modulator of cytokine and chemokine expression in human macrophages. Sci Rep 2019; 9:7237. [PMID: 31076613 PMCID: PMC6510899 DOI: 10.1038/s41598-019-43704-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 04/26/2019] [Indexed: 12/14/2022] Open
Abstract
The regulatory peptide galanin is broadly distributed in the central- and peripheral nervous systems as well as in non-neuronal tissues, where it exerts its diverse physiological functions via three G-protein-coupled receptors (GAL1-3-R). Regulatory peptides are important mediators of the cross-communication between the nervous- and immune systems and have emerged as a focus of new therapeutics for a variety of inflammatory diseases. Studies on inflammatory animal models and immune cells revealed both pro- and anti-inflammatory functions of galanin. Here, we probed specific immune-related functions of the galanin system and found galanin and GAL1-R and GAL2-R mRNA to be expressed in a range of human immune cells. In particular, macrophages displayed differentiation- and polarization-dependent expression of galanin and its receptors. Exposure to exogenous galanin affected the cytokine/chemokine expression profile of macrophages differently, depending on their differentiation and polarization, and mainly modulated the expression of chemokines (CCL2, CCL3, CCL5 and CXCL8) and anti-inflammatory cytokines (TGF-β, IL-10 and IL-1Ra), especially in type-1 macrophages. Cytokine/chemokine expression levels in interferon-gamma- and lipopolysaccharide-polarized macrophages were upregulated whereas in unpolarized macrophages they were downregulated upon galanin treatment for 20 hours. This study illuminates the regulation of important cytokines/chemokines in macrophages by galanin, depending on specific cell activation.
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Horváth Á, Borbély É, Bölcskei K, Szentes N, Kiss T, Belák M, Rauch T, Glant T, Zákány R, Juhász T, Karanyicz E, Boldizsár F, Helyes Z, Botz B. Regulatory role of capsaicin-sensitive peptidergic sensory nerves in the proteoglycan-induced autoimmune arthritis model of the mouse. J Neuroinflammation 2018; 15:335. [PMID: 30509328 PMCID: PMC6276168 DOI: 10.1186/s12974-018-1364-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 11/08/2018] [Indexed: 12/11/2022] Open
Abstract
Objective The regulatory role of capsaicin-sensitive peptidergic sensory nerves has been shown in acute inflammation, but little is known about their involvement in T/B-cell driven autoimmune arthritis. This study integratively characterized the function of these nerve endings in the proteoglycan-induced chronic arthritis (PGIA), a translational model of rheumatoid arthritis. Methods Peptidergic afferents were defunctionalized by resiniferatoxin (RTX) pretreatment in BALB/c mice, PGIA was induced by repeated antigen challenges. Hind paw volume, arthritis severity, grasping ability and the mechanonociceptive threshold were monitored during the 17-week experiment. Myeloperoxidase activity, vascular leakage and bone turnover were evaluated by in vivo optical imaging. Bone morphology was assessed using micro-CT, the intertarsal small joints were processed for histopathological analysis. Results Following desensitization of the capsaicin-sensitive afferents, ankle edema, arthritis severity and mechanical hyperalgesia were markedly diminished. Myeloperoxidase activity was lower in the early, but increased in the late phase, whilst plasma leakage and bone turnover were not altered. Desensitized mice displayed similar bone spurs and erosions, but increased trabecular thickness of the tibia and bony ankylosis of the spine. Intertarsal cartilage thickness was not altered in the model, but desensitization increased this parameter in both the non-arthritic and arthritic groups. Conclusion This is the first integrative in vivo functional and morphological characterization of the PGIA mouse model, wherein peptidergic afferents have an important regulatory function. Their overall effect is proinflammatory by increasing acute inflammation, immune cell activity and pain. Meanwhile, their activation decreases spinal ankylosis, arthritis-induced altered trabecularity, and cartilage thickness in small joints. Electronic supplementary material The online version of this article (10.1186/s12974-018-1364-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ádám Horváth
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti u. 12, Pécs, 7624, Hungary.,János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary.,Department of Pharmacology and Pharmacotherapy, National Brain Research Program 20017-1.2.1-NKP-2017-00002, Chronic Pain Research Group, University of Pécs Medical School, Pécs, Hungary
| | - Éva Borbély
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti u. 12, Pécs, 7624, Hungary.,János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary.,Department of Pharmacology and Pharmacotherapy, National Brain Research Program 20017-1.2.1-NKP-2017-00002, Chronic Pain Research Group, University of Pécs Medical School, Pécs, Hungary
| | - Kata Bölcskei
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti u. 12, Pécs, 7624, Hungary.,János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary.,Department of Pharmacology and Pharmacotherapy, National Brain Research Program 20017-1.2.1-NKP-2017-00002, Chronic Pain Research Group, University of Pécs Medical School, Pécs, Hungary
| | - Nikolett Szentes
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti u. 12, Pécs, 7624, Hungary.,János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary.,Department of Pharmacology and Pharmacotherapy, National Brain Research Program 20017-1.2.1-NKP-2017-00002, Chronic Pain Research Group, University of Pécs Medical School, Pécs, Hungary
| | - Tamás Kiss
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti u. 12, Pécs, 7624, Hungary.,János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary.,Department of Pharmacology and Pharmacotherapy, National Brain Research Program 20017-1.2.1-NKP-2017-00002, Chronic Pain Research Group, University of Pécs Medical School, Pécs, Hungary
| | - Mátyás Belák
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti u. 12, Pécs, 7624, Hungary
| | - Tibor Rauch
- Department of Orthopedic Surgery, Section of Molecular Medicine, Rush University Medical Center, Chicago, USA
| | - Tibor Glant
- Department of Orthopedic Surgery, Section of Molecular Medicine, Rush University Medical Center, Chicago, USA
| | - Róza Zákány
- Department of Anatomy, Histology, and Embryology, University of Debrecen, Debrecen, Hungary
| | - Tamás Juhász
- Department of Anatomy, Histology, and Embryology, University of Debrecen, Debrecen, Hungary
| | - Edina Karanyicz
- Department of Anatomy, Histology, and Embryology, University of Debrecen, Debrecen, Hungary
| | - Ferenc Boldizsár
- Medical School, Department of Immunology, University of Pécs, Pécs, Hungary
| | - Zsuzsanna Helyes
- Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Szigeti u. 12, Pécs, 7624, Hungary. .,János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary. .,Department of Pharmacology and Pharmacotherapy, National Brain Research Program 20017-1.2.1-NKP-2017-00002, Chronic Pain Research Group, University of Pécs Medical School, Pécs, Hungary.
| | - Bálint Botz
- János Szentágothai Research Centre, Molecular Pharmacology Research Team and Centre for Neuroscience, University of Pécs, Pécs, Hungary.,Medical School, Department of Radiology, University of Pécs, Pécs, Hungary
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16
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Sternberg F, Vidali S, Holub BS, Stockinger J, Brunner SM, Ebner S, Koller A, Trost A, Reitsamer HA, Schwarzenbacher D, Lang R, Kofler B. Lack of Galanin Receptor 3 Alleviates Psoriasis by Altering Vascularization, Immune Cell Infiltration, and Cytokine Expression. J Invest Dermatol 2018; 138:199-207. [PMID: 28844939 DOI: 10.1016/j.jid.2017.08.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 07/26/2017] [Accepted: 08/01/2017] [Indexed: 01/30/2023]
Abstract
The neuropeptide galanin is distributed in the central and peripheral nervous systems and in non-neuronal peripheral organs, including the skin. Galanin acts via three G protein-coupled receptors which, except galanin receptor 1, are expressed in various skin structures. The galanin system has been associated with inflammatory processes of the skin and of several other organs. Psoriasis is an inflammatory skin disease with increased neovascularization, keratinocyte hyperproliferation, a proinflammatory cytokine milieu, and immune cell infiltration. In this study, we showed that galanin receptor 3 is present in endothelial cells in human and murine dermal vessels and is co-expressed with nestin in neo-vessels of psoriatic patients. Moreover, in a murine psoriasis model, we showed that C57/BL6 mice lacking galanin receptor 3 display a milder course of psoriasis upon imiquimod treatment, leading to decreased disease severity, delayed neo-vascularization, reduced infiltration of neutrophils, and significantly lower levels of proinflammatory cytokines compared with wild-type mice. In contrast, galanin receptor 2-knockout animals did not differ significantly from wild type mice at both the macroscopic and molecular levels in their inflammatory response to imiquimod treatment. Our data indicate that galanin receptor 3, but not galanin receptor 2, plays an important role in psoriasis-like skin inflammation.
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Affiliation(s)
- Felix Sternberg
- Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Silvia Vidali
- Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Barbara S Holub
- Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria; Department of Dermatology, Paracelsus Medical University, Salzburg, Austria
| | - Julia Stockinger
- Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Susanne M Brunner
- Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Sabine Ebner
- Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Andreas Koller
- Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Andrea Trost
- Department of Ophthalmology/Optometry, Research Program Experimental Ophthalmology, Paracelsus Medical University Salzburg, Austria
| | - Herbert A Reitsamer
- Department of Ophthalmology/Optometry, Research Program Experimental Ophthalmology, Paracelsus Medical University Salzburg, Austria
| | - David Schwarzenbacher
- Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria
| | - Roland Lang
- Department of Dermatology, Paracelsus Medical University, Salzburg, Austria
| | - Barbara Kofler
- Laura Bassi Centre of Expertise-THERAPEP, Research Program for Receptor Biochemistry and Tumor Metabolism, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria.
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