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Abed OA, Attlassy Y, Xu J, Han K, Moon JJ. Emerging Nanotechnologies and Microbiome Engineering for the Treatment of Inflammatory Bowel Disease. Mol Pharm 2022; 19:4393-4410. [PMID: 35878420 PMCID: PMC9763926 DOI: 10.1021/acs.molpharmaceut.2c00222] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by the chronic inflammation of the gastrointestinal tract and impacts almost 7 million people across the globe. Current therapeutics are effective in treating the symptoms, but they often do not address the root cause or selectively target areas of inflammation. Notably, self-assembled nanoparticles show great promise as drug delivery systems for the treatment of IBD. Nanoparticles can be designed to survive the harsh gastric conditions and reach inflamed areas of the gastrointestinal tract. Oral drug delivery with nanoparticles can localize drugs to the impacted inflamed region using active and/or passive targeting and promote a high rate of drug dispersion in local tissues, thus reducing potential off-target toxicities. Since a dysregulated gut microbiome is implicated in the development and progression of IBD, it is also important to develop nanoparticles and biomaterials that can restore symbiotic microbes while reducing the proliferation of harmful microbes. In this review, we highlight recent advances in self-assembled nanosystems designed for addressing inflammation and dysregulated gut microbiomes as potential treatments for IBD. Nanoparticles have a promising future in improving the delivery of current therapeutics, increasing patient compliance by providing an oral method of medication, and reducing side effects. However, remaining challenges include scale-up synthesis of nanoparticles, potential side effects, and financial obstacles of clinical trials. It would be in the patients' best interest to continue research on nanoparticles in the pursuit of more effective therapeutics for the treatment of IBD.
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Affiliation(s)
- Omar A Abed
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States
- Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Younes Attlassy
- Department of Medicine, New York University School of Medicine, New York, New York 10012, United States
| | - Jin Xu
- Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - Kai Han
- Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States
| | - James J Moon
- Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States
- Biointerfaces Institute, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States
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2
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ILCs-Crucial Players in Enteric Infectious Diseases. Int J Mol Sci 2022; 23:ijms232214200. [PMID: 36430676 PMCID: PMC9695539 DOI: 10.3390/ijms232214200] [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: 10/31/2022] [Accepted: 11/12/2022] [Indexed: 11/18/2022] Open
Abstract
Research of the last decade has remarkably increased our understanding of innate lymphoid cells (ILCs). ILCs, in analogy to T helper (Th) cells and their cytokine and transcription factor profile, are categorized into three distinct populations: ILC1s express the transcription factor T-bet and secrete IFNγ, ILC2s depend on the expression of GATA-3 and release IL-5 and IL-13, and ILC3s express RORγt and secrete IL-17 and IL-22. Noteworthy, ILCs maintain a level of plasticity, depending on exposed cytokines and environmental stimuli. Furthermore, ILCs are tissue resident cells primarily localized at common entry points for pathogens such as the gut-associated lymphoid tissue (GALT). They have the unique capacity to initiate rapid responses against pathogens, provoked by changes of the cytokine profile of the respective tissue. Moreover, they regulate tissue inflammation and homeostasis. In case of intracellular pathogens entering the mucosal tissue, ILC1s respond by secreting cytokines (e.g., IFNγ) to limit the pathogen spread. Upon infection with helminths, intestinal epithelial cells produce alarmins (e.g., IL-25) and activate ILC2s to secrete IL-13, which induces differentiation of intestinal stem cells into tuft and goblet cells, important for parasite expulsion. Additionally, during bacterial infection ILC3-derived IL-22 is required for bacterial clearance by regulating antimicrobial gene expression in epithelial cells. Thus, ILCs can limit infectious diseases via secretion of inflammatory mediators and interaction with other cell types. In this review, we will address the role of ILCs during enteric infectious diseases.
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Schneider KM, Kim J, Bahnsen K, Heuckeroth RO, Thaiss CA. Environmental perception and control of gastrointestinal immunity by the enteric nervous system. Trends Mol Med 2022; 28:989-1005. [PMID: 36208986 DOI: 10.1016/j.molmed.2022.09.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 05/25/2022] [Accepted: 09/07/2022] [Indexed: 12/12/2022]
Abstract
The enteric nervous system (ENS) forms a versatile sensory system along the gastrointestinal tract that interacts with most cell types in the bowel. Herein, we portray host-environment interactions at the intestinal mucosal surface through the lens of the enteric nervous system. We describe local cellular interactions as well as long-range circuits between the enteric, central, and peripheral nervous systems. Additionally, we discuss recently discovered mechanisms by which enteric neurons and glia respond to biotic and abiotic environmental changes and how they regulate intestinal immunity and inflammation. The enteric nervous system emerges as an integrative sensory system with manifold immunoregulatory functions under both homeostatic and pathophysiological conditions.
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Affiliation(s)
- Kai Markus Schneider
- Microbiology Department, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, PA, USA
| | - Jihee Kim
- Microbiology Department, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, PA, USA
| | - Klaas Bahnsen
- Microbiology Department, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, PA, USA
| | - Robert O Heuckeroth
- Department of Pediatrics, Children's Hospital of Philadelphia Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Christoph A Thaiss
- Microbiology Department, Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, PA, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, PA, USA.
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4
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Yu HB, Yang H, Allaire JM, Ma C, Graef FA, Mortha A, Liang Q, Bosman ES, Reid GS, Waschek JA, Osborne LC, Sokol H, Vallance BA, Jacobson K. Vasoactive intestinal peptide promotes host defense against enteric pathogens by modulating the recruitment of group 3 innate lymphoid cells. Proc Natl Acad Sci U S A 2021; 118:e2106634118. [PMID: 34625492 PMCID: PMC8521691 DOI: 10.1073/pnas.2106634118] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2021] [Indexed: 01/10/2023] Open
Abstract
Group 3 innate lymphoid cells (ILC3s) control the formation of intestinal lymphoid tissues and play key roles in intestinal defense. They express neuropeptide vasoactive intestinal peptide (VIP) receptor 2 (VPAC2), through which VIP modulates their function, but whether VIP exerts other effects on ILC3 remains unclear. We show that VIP promotes ILC3 recruitment to the intestine through VPAC1 independent of the microbiota or adaptive immunity. VIP is also required for postnatal formation of lymphoid tissues as well as the maintenance of local populations of retinoic acid (RA)-producing dendritic cells, with RA up-regulating gut-homing receptor CCR9 expression by ILC3s. Correspondingly, mice deficient in VIP or VPAC1 suffer a paucity of intestinal ILC3s along with impaired production of the cytokine IL-22, rendering them highly susceptible to the enteric pathogen Citrobacter rodentium This heightened susceptibility to C. rodentium infection was ameliorated by RA supplementation, adoptive transfer of ILC3s, or by recombinant IL-22. Thus, VIP regulates the recruitment of intestinal ILC3s and formation of postnatal intestinal lymphoid tissues, offering protection against enteric pathogens.
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Affiliation(s)
- Hong Bing Yu
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The University of British Columbia, Vancouver, BC, V5Z 4H4, Canada;
| | - Hyungjun Yang
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Joannie M Allaire
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Caixia Ma
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Franziska A Graef
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Arthur Mortha
- Department of Immunology, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Qiaochu Liang
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Else S Bosman
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - Gregor S Reid
- Division of Oncology, Department of Pediatrics, The University of British Columbia, Vancouver, BC, V5Z 4H4, Canada
| | - James A Waschek
- The Semel Institute and Department of Psychiatry, The David Geffen School of Medicine, University of California, Los Angeles, CA 90095
| | - Lisa C Osborne
- Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada
| | - Harry Sokol
- Gastroenterology Department, INSERM, Centre de Recherche Saint Antoine, Sorbonne Université, Paris, F-75012, France
- Institut national de la recherche agronomique, Micalis Institute and AgroParisTech, Jouy en Josas, F-78350, France
- Paris Center for Microbiome Medicine, Fédérations Hospitalo-universitaires, Paris, F-75012, France
| | - Bruce A Vallance
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The University of British Columbia, Vancouver, BC, V5Z 4H4, Canada;
| | - Kevan Jacobson
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The University of British Columbia, Vancouver, BC, V5Z 4H4, Canada;
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Zhang W, Michalowski CB, Beloqui A. Oral Delivery of Biologics in Inflammatory Bowel Disease Treatment. Front Bioeng Biotechnol 2021; 9:675194. [PMID: 34150733 PMCID: PMC8209478 DOI: 10.3389/fbioe.2021.675194] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/19/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD) has been posed as a great worldwide health threat. Having an onset during early adulthood, IBD is a chronic inflammatory disease characterized by remission and relapse. Due to its enigmatic etiology, no cure has been developed at the moment. Conventionally, steroids, 5-aminosalicylic acid, and immunosuppressants have been applied clinically to relieve patients’ syndrome which, unfavorably, causes severe adverse drug reactions including diarrhea, anemia, and glaucoma. Insufficient therapeutic effects also loom, and surgical resection is mandatory in half of the patients within 10 years after diagnosis. Biologics demonstrated unique and differentiative therapeutic mechanism which can alleviate the inflammation more effectively. However, their application in IBD has been hindered considering their stability and toxicity. Scientists have brought up with the concept of nanomedicine to achieve the targeted drug delivery of biologics for IBD. Here, we provide an overview of biologics for IBD treatment and we review existing formulation strategies for different biological categories including antibodies, gene therapy, and peptides. This review highlights the current trends in oral delivery of biologics with an emphasis on the important role of nanomedicine in the development of reliable methods for biologic delivery in IBD treatment.
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Affiliation(s)
- Wunan Zhang
- Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Cecilia Bohns Michalowski
- Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Ana Beloqui
- Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
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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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7
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Sun X, Huang Y, Zhang YL, Qiao D, Dai YC. Research advances of vasoactive intestinal peptide in the pathogenesis of ulcerative colitis by regulating interleukin-10 expression in regulatory B cells. World J Gastroenterol 2020; 26:7593-7602. [PMID: 33505138 PMCID: PMC7789055 DOI: 10.3748/wjg.v26.i48.7593] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 11/14/2020] [Accepted: 11/29/2020] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic relapsed intestinal disease with an increasing incidence around the world. The pathophysiology of UC remains unclear. However, the role of the interaction between the enteric nervous system and the immune system in the pathogenesis of UC has been the focus of attention and has become a research hotspot. Vasoactive intestinal peptide (VIP) is a kind of endogenous neuropeptide with regulatory activity on intestinal immunity. It has been shown to regulate immune disorders in animal and human experiments and has become an effective anti-inflammatory and immune modulator that affects the innate immune system and adaptive immune system. Regulatory B cells (Bregs) are a new group of B cells that negatively regulate the immunity and have received extensive attention in immune circles. Bregs can regulate immune tolerance by producing interleukin (IL)-10, IL-35, and transforming growth factor-β, suppressing autoimmune diseases or excessive inflammatory responses. The secretion of IL-10 by Bregs induces the development of T helper (Th) 0 and Th2 cells. It also induces Th2 cytokines and inhibits Th1 cytokines, thereby inhibiting Th1 cells and the Th1/Th2 balance. With further clarity on the mechanism of the regulation of IL-10 expression by VIP in Bregs in colitis patients, we believe that Bregs can provide a novel strategy for the clinical treatment of UC. Thus, we aim to review the current literature on this evolving topic.
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Affiliation(s)
- Xiong Sun
- Department of Gastroenterology, Shanghai PuTuo District People's Hospital Affiliated to Tongji University, Tongji University School of Medicine, Shanghai 200060, China
| | - Yao Huang
- Department of Digestive Diseases, Jing'an District Central Hospital, Fudan University, Shanghai 200040, China
| | - Ya-Li Zhang
- Institute of Digestive Diseases, LongHua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Dan Qiao
- Department of Gastroenterology, Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China
| | - Yan-Cheng Dai
- Department of Gastroenterology, Shanghai Traditional Chinese Medicine Integrated Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200082, China.
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Xu H, Shi X, Li X, Zou J, Zhou C, Liu W, Shao H, Chen H, Shi L. Neurotransmitter and neuropeptide regulation of mast cell function: a systematic review. J Neuroinflammation 2020; 17:356. [PMID: 33239034 PMCID: PMC7691095 DOI: 10.1186/s12974-020-02029-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 11/09/2020] [Indexed: 02/06/2023] Open
Abstract
The existence of the neural control of mast cell functions has long been proposed. Mast cells (MCs) are localized in association with the peripheral nervous system (PNS) and the brain, where they are closely aligned, anatomically and functionally, with neurons and neuronal processes throughout the body. They express receptors for and are regulated by various neurotransmitters, neuropeptides, and other neuromodulators. Consequently, modulation provided by these neurotransmitters and neuromodulators allows neural control of MC functions and involvement in the pathogenesis of mast cell–related disease states. Recently, the roles of individual neurotransmitters and neuropeptides in regulating mast cell actions have been investigated extensively. This review offers a systematic review of recent advances in our understanding of the contributions of neurotransmitters and neuropeptides to mast cell activation and the pathological implications of this regulation on mast cell–related disease states, though the full extent to which such control influences health and disease is still unclear, and a complete understanding of the mechanisms underlying the control is lacking. Future validation of animal and in vitro models also is needed, which incorporates the integration of microenvironment-specific influences and the complex, multifaceted cross-talk between mast cells and various neural signals. Moreover, new biological agents directed against neurotransmitter receptors on mast cells that can be used for therapeutic intervention need to be more specific, which will reduce their ability to support inflammatory responses and enhance their potential roles in protecting against mast cell–related pathogenesis.
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Affiliation(s)
- Huaping Xu
- Department of Rehabilitation, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi Province, China
| | - Xiaoyun Shi
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - Xin Li
- School of Food Science, Nanchang University, Nanchang, 330047, Jiangxi Province, China
| | - Jiexin Zou
- Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Nanchang University, 461 Bayi Avenue, Nanchang, 330006, Jiangxi Province, People's Republic of China
| | - Chunyan Zhou
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, Jiangxi Province, China
| | - Wenfeng Liu
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, Jiangxi Province, China
| | - Huming Shao
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, Jiangxi Province, China
| | - Hongbing Chen
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, 330047, Jiangxi Province, China
| | - Linbo Shi
- Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Nanchang University, 461 Bayi Avenue, Nanchang, 330006, Jiangxi Province, People's Republic of China.
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9
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Zeng HT, Liu JQ, Zhao M, Yu D, Yang G, Mo LH, Liu ZQ, Wang S, Liu ZG, Yang PC. Exosomes carry IL-10 and antigen/MHC II complexes to induce antigen-specific oral tolerance. Cytokine 2020; 133:155176. [PMID: 32563958 DOI: 10.1016/j.cyto.2020.155176] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 01/10/2023]
Abstract
BACKGROUND It is known that the immune tolerance can be naturally established in the intestine, while the mechanism by which the immune tolerance development in the intestine is not fully understood yet. Vasoactive intestinal peptides (VIP) has the immune regulatory functions. This study aims to investigate the role of VIP in the immune tolerance development in the intestine. METHODS Intestinal epithelial cell (IEC)-derived exosomes were prepared. The exosomes carried IL-10 and antigen/MHC II complexes. VIP-deficient (VIPd) mice and wild type mice were employed to test the role of VIP in the development of immune tolerance in the intestine. RESULTS VIPd mice failed to induce type 1 regulatory T cells (Tr1 cells) in the intestine and retarded the establishment of antigen (Ag)-specific immune tolerance. Exposure to VIP in the culture induced IL-10 expression in intestinal epithelial cells (IECs). Exosomes derived from ovalbumin (OVA, used as a specific Ag)/VIP-primed IECs carried IL-10 and OVA/MHC II complexes; these exosomes were designated IL10CARs (IL-10/chimeric antigen receptor-carrying exosomes). IL10CARs could recognize OVA-specific CD4+ T cells and converted OVA-specific CD4± T cells to OVA-specific Tr1 cells. Administration of IL10CARs suppressed experimental food allergy. CONCLUSIONS The data show that IL10CARs are capable of suppressing experimental FA by inducing antigen-specific Tr1 cells, which has the translation potential for FA treatment.
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Affiliation(s)
- Hao-Tao Zeng
- Department of Allergy, Longgang ENT Hospital & Shenzhen Key Laboratory of ENT, Institute of ENT, Shenzhen, China
| | - Jiang-Qi Liu
- Department of Allergy, Longgang ENT Hospital & Shenzhen Key Laboratory of ENT, Institute of ENT, Shenzhen, China
| | - Miao Zhao
- Department of Allergy, Longgang ENT Hospital & Shenzhen Key Laboratory of ENT, Institute of ENT, Shenzhen, China
| | - Dian Yu
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Gui Yang
- Department of Otolaryngology, Longgang Central Hospital, Shenzhen, China
| | - Li-Hua Mo
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
| | - Zhi-Qiang Liu
- Department of Allergy, Longgang ENT Hospital & Shenzhen Key Laboratory of ENT, Institute of ENT, Shenzhen, China
| | - Shuai Wang
- Department of Allergy, Longgang ENT Hospital & Shenzhen Key Laboratory of ENT, Institute of ENT, Shenzhen, China.
| | - Zhi-Gang Liu
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China.
| | - Ping-Chang Yang
- Research Center of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China; Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Shenzhen, China.
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Khare T, Palakurthi SS, Shah BM, Palakurthi S, Khare S. Natural Product-Based Nanomedicine in Treatment of Inflammatory Bowel Disease. Int J Mol Sci 2020; 21:E3956. [PMID: 32486445 PMCID: PMC7312938 DOI: 10.3390/ijms21113956] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 05/26/2020] [Accepted: 05/29/2020] [Indexed: 02/06/2023] Open
Abstract
: Many synthetic drugs and monoclonal antibodies are currently in use to treat Inflammatory Bowel Disease (IBD). However, they all are implicated in causing severe side effects and long-term use results in many complications. Numerous in vitro and in vivo experiments demonstrate that phytochemicals and natural macromolecules from plants and animals reduce IBD-related complications with encouraging results. Additionally, many of them modify enzymatic activity, alleviate oxidative stress, and downregulate pro-inflammatory transcriptional factors and cytokine secretion. Translational significance of natural nanomedicine and strategies to investigate future natural product-based nanomedicine is discussed. Our focus in this review is to summarize the use of phytochemicals and macromolecules encapsulated in nanoparticles for the treatment of IBD and IBD-associated colorectal cancer.
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Affiliation(s)
- Tripti Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
| | - Sushesh Srivatsa Palakurthi
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Brijesh M. Shah
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Srinath Palakurthi
- Department of Pharmaceutical Sciences, Rangel College of Pharmacy, Texas A&M University, Kingsville, TX 78363, USA; (S.S.P.); (B.M.S.); (S.P.)
| | - Sharad Khare
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO 65212, USA;
- Harry S. Truman Veterans Hospital, Columbia, MO 65201, USA
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11
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Zhang Y, Zhang H, Zhang K, Li Z, Guo T, Wu T, Hou X, Feng N. Co-hybridized composite nanovesicles for enhanced transdermal eugenol and cinnamaldehyde delivery and their potential efficacy in ulcerative colitis. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2020; 28:102212. [PMID: 32334099 DOI: 10.1016/j.nano.2020.102212] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 02/16/2020] [Accepted: 04/10/2020] [Indexed: 02/06/2023]
Abstract
Percutaneous absorption of drugs can be enhanced by ethosomes, which are nanocarriers with excellent deformability and drug-loading properties. However, the ethanol within ethosomes increases phospholipid membrane fluidity and permeability, leading to drug leakage during storage. Here, we developed and characterized a new phospholipid nanovesicles that is co-hybridized with hyaluronic acid (HA), ethanol and the encapsulated volatile oil medicines (eugenol and cinnamaldehyde [EUG/CAH]) for transdermal administration. In comparison with EUG/CAH-loaded ethosomes (ES), the formulation stability and percutaneous drug absorption of EUG/CAH-loaded HA-immobilized ethosomes (HA-ES) were significantly improved. After transdermal administration of HA-ES, the interstitial cells of Cajal in the colon of rats with trinitrobenzene sulfonate-induced ulcerative colitis (UC) were significantly increased, and the stem cell factor/c-kit signaling pathway was partly repaired. Overall, HA-ES possesses excellent deformability and showed improved efficacy against UC compared with ES, which is demonstrated as a promising transdermal delivery vehicle for volatile oil medicines.
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Affiliation(s)
- Yongtai Zhang
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hongyu Zhang
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kai Zhang
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhe Li
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Teng Guo
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Tong Wu
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xuefeng Hou
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Nianping Feng
- Department of Pharmaceutical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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12
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Martínez C, Juarranz Y, Gutiérrez-Cañas I, Carrión M, Pérez-García S, Villanueva-Romero R, Castro D, Lamana A, Mellado M, González-Álvaro I, Gomariz RP. A Clinical Approach for the Use of VIP Axis in Inflammatory and Autoimmune Diseases. Int J Mol Sci 2019; 21:E65. [PMID: 31861827 PMCID: PMC6982157 DOI: 10.3390/ijms21010065] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 12/16/2019] [Accepted: 12/18/2019] [Indexed: 12/11/2022] Open
Abstract
The neuroendocrine and immune systems are coordinated to maintain the homeostasis of the organism, generating bidirectional communication through shared mediators and receptors. Vasoactive intestinal peptide (VIP) is the paradigm of an endogenous neuropeptide produced by neurons and endocrine and immune cells, involved in the control of both innate and adaptive immune responses. Exogenous administration of VIP exerts therapeutic effects in models of autoimmune/inflammatory diseases mediated by G-protein-coupled receptors (VPAC1 and VPAC2). Currently, there are no curative therapies for inflammatory and autoimmune diseases, and patients present complex diagnostic, therapeutic, and prognostic problems in daily clinical practice due to their heterogeneous nature. This review focuses on the biology of VIP and VIP receptor signaling, as well as its protective effects as an immunomodulatory factor. Recent progress in improving the stability, selectivity, and effectiveness of VIP/receptors analogues and new routes of administration are highlighted, as well as important advances in their use as biomarkers, contributing to their potential application in precision medicine. On the 50th anniversary of VIP's discovery, this review presents a spectrum of potential clinical benefits applied to inflammatory and autoimmune diseases.
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Affiliation(s)
- Carmen Martínez
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Yasmina Juarranz
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Irene Gutiérrez-Cañas
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Mar Carrión
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Selene Pérez-García
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Raúl Villanueva-Romero
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - David Castro
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Amalia Lamana
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
| | - Mario Mellado
- Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología (CNB)/CSIC, 28049 Madrid, Spain;
| | - Isidoro González-Álvaro
- Servicio de Reumatología, Instituto de Investigación Médica, Hospital Universitario La Princesa, 28006 Madrid, Spain;
| | - Rosa P. Gomariz
- Departamento de Biología Celular, Facultad de Biología y Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain; (Y.J.); (I.G.-C.); (M.C.); (S.P.-G.); (R.V.-R.); (D.C.); (A.L.); (R.P.G.)
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13
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Casado-Bedmar M, Heil SDS, Myrelid P, Söderholm JD, Keita ÅV. Upregulation of intestinal mucosal mast cells expressing VPAC1 in close proximity to vasoactive intestinal polypeptide in inflammatory bowel disease and murine colitis. Neurogastroenterol Motil 2019; 31:e13503. [PMID: 30407703 DOI: 10.1111/nmo.13503] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 09/24/2018] [Accepted: 10/07/2018] [Indexed: 01/01/2023]
Abstract
BACKGROUND Mast cells (MCs) and vasoactive intestinal polypeptide (VIP) have been proposed as regulators of the intestinal barrier and inflammation. Our aim was to map the distribution in inflammatory bowel disease (IBD) and murine colitis. METHODS MCs, VIP, and VIP-receptors (VPACs) were quantified by immunofluorescence and enzyme-immunoassay (EIA) in ileal tissues (villus epithelium (VE) and adjacent VE, ie, VE next to the follicle-associated epithelium, (FAE)) from Crohn's disease (CD; n = 16) and non-IBD patients, and in colonic specimens of ulcerative colitis (UC; n = 12) and healthy controls (HCs). In addition, VIP levels were measured in plasma from HCs, non-IBD, and IBD in remission (CD n = 30; UC n = 30). Colon, ileum, and plasma from mice with dextran sulfate sodium (DSS)-induced colitis and control mice were analyzed likewise. KEY RESULTS FAE-adjacent VE in ileum of CD possessed more MCs (P < 0.05) and MCs expressing VPAC1 (P < 0.05), but not VPAC2, compared to controls. Both adjacent and regular VE of CD had more MCs co-localizing/in close proximity to VIP (P < 0.05). In UC colon, more MCs (P < 0.0005), MCs close to VIP (P < 0.0005), and MCs expressing VPAC1 (P < 0.05) were found compared to controls. VIP levels were elevated in plasma from CD and UC compared to controls (P < 0.0005). Colon of DSS mice showed more MCs and MCs close to VIP (P < 0.05) compared to control mice. In vitro experiments revealed MCs expressing VPACs and internalized VIP after 120 minutes of VIP-stimulation. CONCLUSIONS AND INFERENCES Communication between MCs and VIP is upregulated during IBD and mice colitis. In CD patients, the epithelium next to FAE seems to be more involved than the surrounding VE, suggesting increased MC-VIP-interactions in this intestinal region.
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Affiliation(s)
- Maite Casado-Bedmar
- Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics & Oncology, Linköping University, Linköping, Sweden
| | - Stéphanie D S Heil
- Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics & Oncology, Linköping University, Linköping, Sweden
| | - Pär Myrelid
- Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics & Oncology, Linköping University, Linköping, Sweden
- Department of Surgery, County Council of Östergötland, Linköping, Sweden
| | - Johan D Söderholm
- Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics & Oncology, Linköping University, Linköping, Sweden
- Department of Surgery, County Council of Östergötland, Linköping, Sweden
| | - Åsa V Keita
- Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics & Oncology, Linköping University, Linköping, Sweden
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14
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Cheng X, Svensson M, Yang Y, Deierborg T, Ekblad E, Voss U. Focal, but not global, cerebral ischaemia causes loss of myenteric neurons and upregulation of vasoactive intestinal peptide in mouse ileum. Int J Exp Pathol 2018; 99:38-45. [PMID: 29577471 DOI: 10.1111/iep.12263] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 01/14/2018] [Indexed: 02/06/2023] Open
Abstract
Reduced blood flow to the brain induces cerebral ischaemia, potentially causing central injury and peripheral complications including gastrointestinal (GI) dysfunction. The pathophysiology behind GI symptoms is suspected to be neuropathy in the enteric nervous system (ENS), which is essential in regulating GI function. This study investigates if enteric neuropathy occurs after cerebral ischaemia, by analysing neuronal survival and relative numbers of vasoactive intestinal peptide (VIP) and neuronal nitric oxide synthase (nNOS) expressing neurons in mouse ileum after three types of cerebral ischaemia. Focal cerebral ischaemia, modelled by permanent middle cerebral artery occlusion (pMCAO) and global cerebral ischaemia, modelled with either transient occlusion of both common carotid arteries followed by reperfusion (GCIR) or chronic cerebral hypoperfusion (CCH) was performed on C56BL/6 mice. Sham-operated mice for each ischaemia model served as control. Ileum was collected after 1-17 weeks, depending on model, and analysed using morphometry and immunocytochemistry. For each group, intestinal mucosa and muscle layer thicknesses, neuronal numbers and relative proportions of neurons immunoreactive (IR) for nNOS or VIP were estimated. No alterations in mucosa or muscle layer thicknesses were noted in any of the groups. Loss of myenteric neurons and an increased number of VIP-IR submucous neurons were found in mouse ileum 7 days after pMCAO. None of the global ischaemia models showed any alterations in neuronal survival or relative numbers of VIP- and nNOS-IR neurons. We conclude that focal cerebral ischaemia and global cerebral ischaemia influence enteric neuronal survival differently. This is suggested to reflect differences in peripheral neuro-immune responses.
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Affiliation(s)
- Xiaowen Cheng
- Neurogastroenterology, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Martina Svensson
- Neuroinflammation Units, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Yiyi Yang
- Neuroinflammation Units, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Tomas Deierborg
- Neuroinflammation Units, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Eva Ekblad
- Neurogastroenterology, Department of Experimental Medical Science, Lund University, Lund, Sweden
| | - Ulrikke Voss
- Neurogastroenterology, Department of Experimental Medical Science, Lund University, Lund, Sweden
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15
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Xu CL, Guo Y, Qiao L, Ma L, Cheng YY. Recombinant expressed vasoactive intestinal peptide analogue ameliorates TNBS-induced colitis in rats. World J Gastroenterol 2018; 24:706-715. [PMID: 29456409 PMCID: PMC5807673 DOI: 10.3748/wjg.v24.i6.706] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 12/19/2017] [Accepted: 12/26/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the modulatory effect of recombinant-expressed vasoactive intestinal peptide (VIP) analogue (rVIPa) on trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats.
METHODS Forty-eight rats were randomized into six groups: normal control group (Control), model control group (TNBS), ethanol treatment group (ETOH), and VIP treatment groups with different dosage (rVIPa1nmol, rVIPa2nmol, rVIPa4nmol). Diarrhea and bloody stool were observed. Colonic damage was evaluated histologically. The levels of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), myeloperoxidase (MPO) and endotoxin in colonic tissue and serum were determined by enzyme-linked immunosorbent assay (ELISA). The expression of occludin, ZO-1, Toll-like receptor 4 (TLR4), and nuclear factor-kappa B p65 (NF-κB p65), IκBα, and p-IκBα were detected by Western blot.
RESULTS Administration with 2 nmol rVIPa prevented TNBS-induced necrosis, hyperemia, swelling, inflammation, etc., pathologic changes observed in the inner surface of colon in experimental rats. Moreover, rVIPa significantly decreased colonic TNF-α level (P < 0.001), MPO activity (P < 0.001) and serum endotoxin level (P < 0.01), and remarkably increased colonic IL-10 content (P < 0.001) in rats with TNBS-induced colitis. Furthermore, compared to the TNBS-induced colitis group, 2 nmol rVIPa treatment up-regulated the levels of occludin (P < 0.05) and ZO-1 (P < 0.05), NF-κB p65 (P < 0.01) and IκBα (P < 0.001), and down-regulated the levels of TLR4.
CONCLUSION rVIPa ameliorates TNBS-induced colonic injury and inflammation and effectively protected the intestinal mucosal barrier function in rats. The mechanism may be related to TLR4/NF-κB-mediated signaling pathway. rVIPa could be used as a new alternative therapy for intestinal inflammatory disorders.
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Affiliation(s)
- Chun-Lan Xu
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Yu Guo
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Lei Qiao
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Li Ma
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Yi-Yi Cheng
- The Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
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16
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Jayawardena D, Anbazhagan AN, Guzman G, Dudeja PK, Onyuksel H. Vasoactive Intestinal Peptide Nanomedicine for the Management of Inflammatory Bowel Disease. Mol Pharm 2017; 14:3698-3708. [PMID: 28991483 DOI: 10.1021/acs.molpharmaceut.7b00452] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the intestine, with increasing incidence worldwide. At present, the management of IBD is an unmet medical need due to the ineffectiveness of currently available drugs in treating all patients, and there is strong demand for novel therapeutics. In this regard, vasoactive intestinal peptide, a potent anti-inflammatory endogenous hormone, has shown promise in managing multiple immune disorders in animal models. However, when administered in the free form, VIP undergoes rapid degradation in vivo, and with continuous infusion, it causes severe dose limiting side effects. To overcome these barriers, we have developed a superior mode to deliver VIP in its native form, using sterically stabilized micelles (VIP-SSM). Our previous studies demonstrated that, VIP, when administered in SSM, prevented joint damage and inflammation in a mouse model of rheumatoid arthritis at a significantly lower dose than the free peptide, completely abrogating the serious side effect of hypotension associated with VIP. In the current study, we demonstrate the therapeutic benefit of VIP-SSM over free peptide in reversing severe colitis associated with IBD. First, we conducted preliminary studies with dextran sulfate sodium (DSS) induced colitis in mice, to determine the effectiveness of VIP administered on alternate days in reducing disease severity. Thereafter, a single intra peritoneal injection of VIP-SSM or the free peptide was used to determine its therapeutic effect on the reversal of colitis and associated diarrhea. The results demonstrated that when administered on alternate days, both VIP-SSM and VIP were capable of alleviating DSS colitis in mice. However, when administered as a single dose, in a therapeutic setting, VIP-SSM showed superior benefits compared to the free peptide in ameliorating colitis phenotype. Namely, the loss of solid fecal pellets and increased fluid accumulation in colon resulting from DSS insult was abrogated in VIP-SSM treated mice and not with free VIP. Furthermore, reduced protein and mRNA levels of the major chloride bicarbonate exchanger, down regulated in adenoma (DRA), seen with DSS was reversed with VIP-SSM, but not with the free peptide. Similarly, VIP-SSM treatment significantly reduced the elevated mRNA levels of pro-inflammatory cytokines and showed significant histologic recovery when compared to mice treated with free VIP. Therefore, these results demonstrated that as a single dose, the anti-inflammatory and antidiarrheal effects of VIP can be achieved effectively when administered as a nanomedicine. Therefore, we propose VIP-SSM to be developed as a potential therapeutic tool for treating ulcerative colitis, a type of IBD.
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Affiliation(s)
| | | | | | - Pradeep K Dudeja
- Jesse Brown VA Medical Center , Chicago Illinois 60612, United States
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17
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Chedid P, Boussetta T, Dang PMC, Belambri SA, Marzaioli V, Fasseau M, Walker F, Couvineau A, El-Benna J, Marie JC. Vasoactive intestinal peptide dampens formyl-peptide-induced ROS production and inflammation by targeting a MAPK-p47 phox phosphorylation pathway in monocytes. Mucosal Immunol 2017; 10:332-340. [PMID: 27271317 DOI: 10.1038/mi.2016.51] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 05/03/2016] [Indexed: 02/08/2023]
Abstract
Reactive oxygen species (ROS) produced by the phagocyte NADPH oxidase (NOX2) are required for microbial clearance; however, when produced in excess they exacerbate inflammatory response and injure surrounding tissues. NOX2 is a multicomponent enzyme composed of membrane-associated cytochrome b588 and cytosolic components p47phox, p67phox, p40phox, and rac1/2. We investigated whether vasoactive intestinal peptide (VIP), an endogenous immune-modulatory peptide, could affect ROS production by NOX2 in primary human phagocytes. VIP did not modulate basal ROS production by phagocytes, but it inhibited monocyte and not neutrophil ROS production in response to the bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLF). The action of VIP was essentially mediated by high-affinity G-protein coupled receptors VPAC1 as its specific agonist, [ALA11,22,28]VIP, mimicked VIP-inhibitory effect, whereas the specific VPAC1 antagonist, PG97-269, blunted VIP action. Further, we showed that VIP inhibited fMLF-induced phosphorylation of ERK1/2 (extracellular signal-regulated kinase 1/2), p38MAPK (p38 mitogen-activated protein kinase) pathways, and phosphorylation of p47phox on Ser345 residue. Also, VIP exerted an anti-inflammatory effect in a model of carrageenan-induced inflammation in rats. We thus found that VIP exerts anti-inflammatory effects by inhibiting the "MAPK-p47phox phosphorylation-NOX2 activation" axis. These data suggest that VIP acts as a natural anti-inflammatory agent of the mucosal system and its analogs could be novel anti-inflammatory molecules.
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Affiliation(s)
- P Chedid
- Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - T Boussetta
- Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - P M-C Dang
- Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - S A Belambri
- Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - V Marzaioli
- Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - M Fasseau
- Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France
| | - F Walker
- Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France
- Service d'Anatomie et Cytologie Pathologique, Hopital Xavier Bichat, Paris, France
| | - A Couvineau
- Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - J El-Benna
- Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France
| | - J-C Marie
- Inserm, U1149, CNRS-ERL8252, Centre de Recherche sur l'Inflammation (CRI), Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Laboratoire d'Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Paris, France
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18
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Jimeno R, Leceta J, Garín M, Ortiz AM, Mellado M, Rodríguez-Frade JM, Martínez C, Pérez-García S, Gomariz RP, Juarranz Y. Th17 polarization of memory Th cells in early arthritis: the vasoactive intestinal peptide effect. J Leukoc Biol 2015; 98:257-69. [PMID: 25957307 DOI: 10.1189/jlb.3a0714-327r] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 04/12/2015] [Indexed: 01/15/2023] Open
Abstract
Several studies in humans indicate the implication of Th17 cells in RA. Therapies targeting their pathogenicity, as well as their plasticity to the Th17/1 phenotype, could ameliorate the progression of the pathology. The neuroendocrine environment has a major impact on the differentiation of lymphoid cells. VIP is present in the microenvironment of the joint, and its known therapeutic effects are supported by several studies on RA. We examine the ability of VIP to modulate the differentiation of Th17 cells. Peripheral blood CD4(+)CD45RO(+) T cells from HD and eRA patients were expanded under Th17-polarizing conditions in the presence of TGF-β. After 7 days, the higher IL-17A, IL-21, and IL-9 levels and lower IL-22 levels indicate the nonpathogenic profile for Th17 cells in HD. In contrast, Th17 cells from eRA patients produced significantly more IL-22 and IFN-γ, and these cells show a more Th17/1 profile, indicating a pathogenic phenotype. Interestingly, when VIP was present in the Th17 conditioned medium, increased levels of IL-10 and IL-9 were detected in HD and eRA patients. VIP also reduced the levels of IL-22 in eRA patients. These data suggest that VIP reduces the pathogenic profile of the Th17-polarized cells. This effect was accompanied by an increased in the Treg/Th17 profile, as shown by the increase levels of Foxp3. In conclusion, this report addresses a novel and interesting question on the effect of VIP on human Th17 cells and adds clinical relevance by analyzing, in parallel, HD and eRA patients.
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Affiliation(s)
- Rebeca Jimeno
- Departamento de Biología Celular, Facultad de *Biología y Medicina, Universidad Complutense de Madrid, Madrid, Spain; División de Terapias Innovadoras en el S. Hematopoyético, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad Mixta de Terapias Avanzadas, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/IIS Fundación Jiménez Díaz, Madrid, Spain; Servicio de Reumatología, Instituto de Investigación Sanitaria Hospital La Princesa, Madrid, Spain; and Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Javier Leceta
- Departamento de Biología Celular, Facultad de *Biología y Medicina, Universidad Complutense de Madrid, Madrid, Spain; División de Terapias Innovadoras en el S. Hematopoyético, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad Mixta de Terapias Avanzadas, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/IIS Fundación Jiménez Díaz, Madrid, Spain; Servicio de Reumatología, Instituto de Investigación Sanitaria Hospital La Princesa, Madrid, Spain; and Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Marina Garín
- Departamento de Biología Celular, Facultad de *Biología y Medicina, Universidad Complutense de Madrid, Madrid, Spain; División de Terapias Innovadoras en el S. Hematopoyético, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad Mixta de Terapias Avanzadas, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/IIS Fundación Jiménez Díaz, Madrid, Spain; Servicio de Reumatología, Instituto de Investigación Sanitaria Hospital La Princesa, Madrid, Spain; and Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Ana M Ortiz
- Departamento de Biología Celular, Facultad de *Biología y Medicina, Universidad Complutense de Madrid, Madrid, Spain; División de Terapias Innovadoras en el S. Hematopoyético, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad Mixta de Terapias Avanzadas, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/IIS Fundación Jiménez Díaz, Madrid, Spain; Servicio de Reumatología, Instituto de Investigación Sanitaria Hospital La Princesa, Madrid, Spain; and Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Mario Mellado
- Departamento de Biología Celular, Facultad de *Biología y Medicina, Universidad Complutense de Madrid, Madrid, Spain; División de Terapias Innovadoras en el S. Hematopoyético, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad Mixta de Terapias Avanzadas, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/IIS Fundación Jiménez Díaz, Madrid, Spain; Servicio de Reumatología, Instituto de Investigación Sanitaria Hospital La Princesa, Madrid, Spain; and Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Jose Miguel Rodríguez-Frade
- Departamento de Biología Celular, Facultad de *Biología y Medicina, Universidad Complutense de Madrid, Madrid, Spain; División de Terapias Innovadoras en el S. Hematopoyético, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad Mixta de Terapias Avanzadas, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/IIS Fundación Jiménez Díaz, Madrid, Spain; Servicio de Reumatología, Instituto de Investigación Sanitaria Hospital La Princesa, Madrid, Spain; and Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Carmen Martínez
- Departamento de Biología Celular, Facultad de *Biología y Medicina, Universidad Complutense de Madrid, Madrid, Spain; División de Terapias Innovadoras en el S. Hematopoyético, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad Mixta de Terapias Avanzadas, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/IIS Fundación Jiménez Díaz, Madrid, Spain; Servicio de Reumatología, Instituto de Investigación Sanitaria Hospital La Princesa, Madrid, Spain; and Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Selene Pérez-García
- Departamento de Biología Celular, Facultad de *Biología y Medicina, Universidad Complutense de Madrid, Madrid, Spain; División de Terapias Innovadoras en el S. Hematopoyético, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad Mixta de Terapias Avanzadas, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/IIS Fundación Jiménez Díaz, Madrid, Spain; Servicio de Reumatología, Instituto de Investigación Sanitaria Hospital La Princesa, Madrid, Spain; and Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Rosa P Gomariz
- Departamento de Biología Celular, Facultad de *Biología y Medicina, Universidad Complutense de Madrid, Madrid, Spain; División de Terapias Innovadoras en el S. Hematopoyético, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad Mixta de Terapias Avanzadas, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/IIS Fundación Jiménez Díaz, Madrid, Spain; Servicio de Reumatología, Instituto de Investigación Sanitaria Hospital La Princesa, Madrid, Spain; and Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - Yasmina Juarranz
- Departamento de Biología Celular, Facultad de *Biología y Medicina, Universidad Complutense de Madrid, Madrid, Spain; División de Terapias Innovadoras en el S. Hematopoyético, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/Centro de Investigación Biomédica en Red de Enfermedades Raras, Unidad Mixta de Terapias Avanzadas, Centro de Investigaciones Energéticas Medioambientales y Tecnológicas/IIS Fundación Jiménez Díaz, Madrid, Spain; Servicio de Reumatología, Instituto de Investigación Sanitaria Hospital La Princesa, Madrid, Spain; and Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, Madrid, Spain
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Chaudhuri A. Regulation of Macrophage Polarization by RON Receptor Tyrosine Kinase Signaling. Front Immunol 2014; 5:546. [PMID: 25400637 PMCID: PMC4215628 DOI: 10.3389/fimmu.2014.00546] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 10/13/2014] [Indexed: 12/13/2022] Open
Abstract
The M1 and M2 states of macrophage polarization are the two extremes of a physiologic/phenotypic continuum that is dynamically influenced by environmental signals. The M1/M2 paradigm is an excellent framework to understand and appreciate some of the diverse functions that macrophages perform. Molecular analysis of mouse and human macrophages indicated that they gain M1 and M2-related functions after encountering specific ligands in the tissue environment. In this perspective, I discuss the function of recepteur d’origine nantais (RON) receptor tyrosine kinase in regulating the M2-like state of macrophage activation Besides decreasing pro-inflammatory cytokine production in response to toll-like receptor-4 activation, macrophage-stimulating protein strongly suppresses nitric oxide synthase and at the same time upregulates arginase, which is the rate limiting enzyme in the ornithine biosynthesis pathway. Interestingly, RON signaling preserved some of the characteristics of the M1 state, while still promoting the hallmarks of M2 polarization. Therefore, therapeutic modulation of RON activity can shift the activation state of macrophages between acute and chronic inflammatory states.
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Qiu X, Zhang M, Yang X, Hong N, Yu C. Faecalibacterium prausnitzii upregulates regulatory T cells and anti-inflammatory cytokines in treating TNBS-induced colitis. J Crohns Colitis 2013; 7:e558-e568. [PMID: 23643066 DOI: 10.1016/j.crohns.2013.04.002] [Citation(s) in RCA: 194] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2013] [Revised: 03/11/2013] [Accepted: 04/02/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Faecalibacterium prausnitzii (F. prausnitzii) is a common anaerobic bacteria colonized in the human gut and inflammatory bowel disease (IBD) patients are usually lack of F. prausnitzii. The aims of this study were to evaluate the anti-inflammatory and immunomodulatory capacity of F. prausnitzii by comparing it with Bifidobacterium longum (B. longum) in both cellular and animal experiments. METHODS Human peripheral blood mononuclear cells (PBMCs) and 2, 4, 6-trinitrobenzenesulphonic acid (TNBS)-induced colitis rat models were treated with F. prausnitzii, B. longum, F. prausnitzii supernatant or F. prausnitzii medium, respectively. Interleukin (IL)-10, TGF-β1 and IL-12p70 in human PBMCs culture supernatant and rat blood serum were detected. The frequency of CD25(+)Foxp3(+)Treg in human PBMCs, rat PBMCs and rat splenocytes were investigated. Besides, the T-bet, GATA-3, ROR-γt and Foxp3 mRNA in human PBMCs, histopathologic characteristics of the intestinal mucosal and weight loss in the rat models were examined. RESULTS F. prausnitzii, B. longum and F. prausnitzii supernatant clearly facilitated the induction of IL-10 and TGF-β1, while induced relatively mild production of IL-12p70 in both cellular and animal models. The F. prausnitzii, B. longum and supernatant differed in their capacity to induce T-bet, GATA-3 and ROR-γt mRNA expression in human PBMCs (both bacterial strains inhibited the expression of ROR-γt while supernatant inhibited the T-bet and GATA-3). However, all of them induced the Foxp3 and Treg production and ameliorated the TNBS-induced colitis. In addition, F. prausnitzii supernatant exhibited the supreme anti-inflammatory capacity. CONCLUSIONS F. prausnitzii and its unidentified metabolites in the supernatant are promising candidates in treating IBD, and further research remains necessary to elucidate the safety, efficacy, optimum and mechanism of this bacterium in the clinical practice.
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Affiliation(s)
- Xinyun Qiu
- Department of Gastroenterology, Peking University People Hospital, Beijing 100044, China; Department of Gastroenterology, Gulou School of Clinical Medicine, Nanjing Medical University, Nanjing 210008, China
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