|
1
|
Sais D, Chowdhury S, Dalton JP, Tran N, Donnelly S. Both host and parasite non-coding RNAs co-ordinate the regulation of macrophage gene expression to reduce pro-inflammatory immune responses and promote tissue repair pathways during infection with fasciola hepatica. RNA Biol 2024; 21:62-77. [PMID: 39344634 PMCID: PMC11445894 DOI: 10.1080/15476286.2024.2408706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 09/06/2024] [Accepted: 09/17/2024] [Indexed: 10/01/2024] Open
Abstract
Parasitic worms (helminths) establish chronic infection within mammalian hosts by strategically regulating their host's immune responses. Deciphering the mechanisms by which host non-coding RNAs (ncRNA) co-ordinate the activation and regulation of immune cells is essential to understanding host immunity and immune-related pathology. It is also important to comprehend how pathogens secrete specific ncRNAs to manipulate gene expression of host immune cells and influence their response to infection. To investigate the contribution of both host and helminth derived ncRNAs to the activation and/or regulation of innate immune responses during a parasite infection, we examined ncRNA expression in the peritoneal macrophages from mice infected with Fasciola hepatica. We discovered the presence of several parasitic-derived miRNAs within host macrophages at 6 hrs and 18 hrs post infection. Target prediction analysis showed that these Fasciola miRNAs regulate host genes associated with the activation of host pro-inflammatory macrophages. Concomitantly, there was a distinct shift in host ncRNA expression, which was significant at 5 days post-infection. Prediction analysis suggested that these host ncRNAs target a different cohort of host genes compared to the parasite miRNAs, although the functional outcome was predicted to be similar i.e. reduced pro-inflammatory response and the promotion of a reparative/tolerant phenotype. Taken together, these observations uncover the interplay between host and parasitic ncRNAs and reveal a complementary regulation of the immune response that allows the parasite to evade immune detection and promote tissue repair for the host. These findings will provide a new understanding of the molecular interaction between parasites and host.
Collapse
Affiliation(s)
- Dayna Sais
- School of Biomedical Engineering, Faculty of Engineering and Information Technology, The University of Technology Sydney, Ultimo, NSW, Australia
| | - Sumaiya Chowdhury
- School of Biomedical Engineering, Faculty of Engineering and Information Technology, The University of Technology Sydney, Ultimo, NSW, Australia
- School of Life Sciences, Faculty of Science, The University of Technology Sydney, Ultimo, NSW, Australia
| | - John. P. Dalton
- Molecular Parasitology Laboratory, School of Natural Sciences, University of Galway, Galway, Ireland
| | - Nham Tran
- School of Biomedical Engineering, Faculty of Engineering and Information Technology, The University of Technology Sydney, Ultimo, NSW, Australia
| | - Sheila Donnelly
- School of Life Sciences, Faculty of Science, The University of Technology Sydney, Ultimo, NSW, Australia
- Molecular Parasitology Laboratory, School of Natural Sciences, University of Galway, Galway, Ireland
| |
Collapse
|
|
2
|
Loghry HJ, Kwon H, Smith RC, Sondjaja NA, Minkler SJ, Young S, Wheeler NJ, Zamanian M, Bartholomay LC, Kimber MJ. Extracellular vesicles secreted by Brugia malayi microfilariae modulate the melanization pathway in the mosquito host. Sci Rep 2023; 13:8778. [PMID: 37258694 PMCID: PMC10232515 DOI: 10.1038/s41598-023-35940-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 05/26/2023] [Indexed: 06/02/2023] Open
Abstract
Vector-borne, filarial nematode diseases cause significant disease burdens in humans and domestic animals worldwide. Although there is strong direct evidence of parasite-driven immunomodulation of mammalian host responses, there is less evidence of parasite immunomodulation of the vector host. We have previously reported that all life stages of Brugia malayi, a filarial nematode and causative agent of Lymphatic filariasis, secrete extracellular vesicles (EVs). Here we investigate the immunomodulatory effects of microfilariae-derived EVs on the vector host Aedes aegypti. RNA-seq analysis of an Ae. aegypti cell line treated with B. malayi microfilariae EVs showed differential expression of both mRNAs and miRNAs. AAEL002590, an Ae. aegypti gene encoding a serine protease, was shown to be downregulated when cells were treated with biologically relevant EV concentrations in vitro. Injection of adult female mosquitoes with biologically relevant concentrations of EVs validated these results in vivo, recapitulating the downregulation of AAEL002590 transcript. This gene was predicted to be involved in the mosquito phenoloxidase (PO) cascade leading to the canonical melanization response and correspondingly, both suppression of this gene using RNAi and parasite EV treatment reduced PO activity in vivo. Our data indicate that parasite-derived EVs interfere with critical immune responses in the vector host, including melanization.
Collapse
Affiliation(s)
- Hannah J Loghry
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA.
| | - Hyeogsun Kwon
- Department of Entomology, College of Agriculture and Life Sciences, Iowa State University, Ames, IA, USA
| | - Ryan C Smith
- Department of Entomology, College of Agriculture and Life Sciences, Iowa State University, Ames, IA, USA
| | - Noelle A Sondjaja
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Sarah J Minkler
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Sophie Young
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| | - Nicolas J Wheeler
- Department of Biology, College of Arts and Sciences, University of Wisconsin-Eau Claire, Eau Claire, WI, USA
| | - Mostafa Zamanian
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Lyric C Bartholomay
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA
| | - Michael J Kimber
- Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, IA, USA
| |
Collapse
|
|
3
|
Li Q, Shen L, Liang P, Dong Y, Fang T, Wang L, Song Y. Dl-3-n-Butylphthalide Protects against Memory Deficits in Vascular Dementia Rats by Attenuating Pyroptosis via TLR-4/NF-κB Signaling Pathway. Neuropsychobiology 2023:1-8. [PMID: 36990058 DOI: 10.1159/000522001] [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: 05/21/2021] [Accepted: 01/15/2022] [Indexed: 03/31/2023]
Abstract
INTRODUCTION Inflammation is closely associated with the pathogenesis of vascular dementia (VD). Dl-3-n-butylphthalide (NBP) is a small molecule compound extracted from the seeds of Chinese celery, which have anti-inflammatory properties in animal models of acute ischemia and patients with stroke. In this experiment, we studied the protective effects of NBP in a rat model of VD induced by permanent bilateral occlusion of the common carotid arteries and investigated the role of the TLR-4/NF-κB inflammatory signaling pathway in the pathology of VD. METHODS The Morris water maze test was used to evaluate cognitive deficits in the VD rats. Western blot, immunohistochemistry, and PCR analyses were used to analyze the molecular basis of the inflammatory response. RESULTS NBP significantly improved the learning and memory ability of VD rats. With regard to the protective mechanism, the results showed that NBP significantly downregulated the relative expression of Cleaved Cas-1/Cas-1 and Cleaved GSDMD/GSDMD. Moreover, NBP decreased the levels of the TLR-4 and NF-κB (P65) protein and phosphorylation of P65 in the hippocampus of VD rats via the TLR-4/NF-κB signaling pathway. CONCLUSION These findings demonstrate that NBP protects against memory deficits in permanent bilateral common carotid artery occlusion-induced VD rats by attenuating pyroptosis via the TLR-4/NF-κB signaling pathway.
Collapse
Affiliation(s)
- Qiang Li
- Department of Neurology, The Fourth Central Clinical College, Tianjin Medical University, Tianjin, China
| | - LinNa Shen
- Department of Gastroenterology, The Fourth Central Clinical College, Tianjin Medical University, Tianjin, China
| | - Peifen Liang
- Department of Neurology, The Fourth Central Clinical College, Tianjin Medical University, Tianjin, China
| | - Yinhua Dong
- Department of Neurology, The Fourth Central Clinical College, Tianjin Medical University, Tianjin, China
| | - Tao Fang
- Metabolic Center, The Fourth Central Clinical College, Tianjin Medical University, Tianjin, China
| | - LiJun Wang
- Department of Neurology, The Fourth Central Clinical College, Tianjin Medical University, Tianjin, China
| | - YiJun Song
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| |
Collapse
|
|
4
|
Ariyaratne A, Kim SY, Pollo SMJ, Perera S, Liu H, Nguyen WNT, Coria AL, Luzzi MDC, Bowron J, Szabo EK, Patel KD, Wasmuth JD, Nair MG, Finney CAM. Trickle infection with Heligmosomoides polygyrus results in decreased worm burdens but increased intestinal inflammation and scarring. Front Immunol 2022; 13:1020056. [PMID: 36569914 PMCID: PMC9773095 DOI: 10.3389/fimmu.2022.1020056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 11/03/2022] [Indexed: 12/13/2022] Open
Abstract
Introduction Intestinal roundworms cause chronic debilitating disease in animals, including humans. Traditional experimental models of these types of infection use a large single-dose infection. However, in natural settings, hosts are exposed to parasites on a regular basis and when mice are exposed to frequent, smaller doses of Heligmosomoides polygyrus, the parasites are cleared more quickly. Whether this more effective host response has any negative consequences for the host is not known. Results Using a trickle model of infection, we found that worm clearance was associated with known resistance-related host responses: increased granuloma and tuft cell numbers, increased levels of granuloma IgG and decreased intestinal transit time, as well as higher serum IgE levels. However, we found that the improved worm clearance was also associated with an inflammatory phenotype in and around the granuloma, increased smooth muscle hypertrophy/hyperplasia, and elevated levels of Adamts gene expression. Discussion To our knowledge, we are the first to identify the involvement of this protein family of matrix metalloproteinases (MMPs) in host responses to helminth infections. Our results highlight the delicate balance between parasite clearance and host tissue damage, which both contribute to host pathology. When continually exposed to parasitic worms, improved clearance comes at a cost.
Collapse
Affiliation(s)
- Anupama Ariyaratne
- Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB, Canada
- Host Parasite Interactions Training Network, University of Calgary, Calgary, AB, Canada
| | - Sang Yong Kim
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA, United States
| | - Stephen M. J. Pollo
- Host Parasite Interactions Training Network, University of Calgary, Calgary, AB, Canada
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Shashini Perera
- Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB, Canada
- Host Parasite Interactions Training Network, University of Calgary, Calgary, AB, Canada
| | - Hongrui Liu
- Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB, Canada
- Host Parasite Interactions Training Network, University of Calgary, Calgary, AB, Canada
| | - William N. T. Nguyen
- Departments of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, AB, Canada
| | - Aralia Leon Coria
- Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB, Canada
- Host Parasite Interactions Training Network, University of Calgary, Calgary, AB, Canada
| | - Mayara de Cassia Luzzi
- Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB, Canada
- Host Parasite Interactions Training Network, University of Calgary, Calgary, AB, Canada
| | - Joel Bowron
- Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB, Canada
- Host Parasite Interactions Training Network, University of Calgary, Calgary, AB, Canada
| | - Edina K. Szabo
- Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB, Canada
- Host Parasite Interactions Training Network, University of Calgary, Calgary, AB, Canada
| | - Kamala D. Patel
- Departments of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, AB, Canada
| | - James D. Wasmuth
- Host Parasite Interactions Training Network, University of Calgary, Calgary, AB, Canada
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Meera G. Nair
- Division of Biomedical Sciences, School of Medicine, University of California Riverside, Riverside, CA, United States
| | - Constance A. M. Finney
- Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB, Canada
- Host Parasite Interactions Training Network, University of Calgary, Calgary, AB, Canada
| |
Collapse
|
|
5
|
Shears RK, Grencis RK. Whipworm secretions and their roles in host-parasite interactions. Parasit Vectors 2022; 15:348. [PMID: 36175934 PMCID: PMC9524059 DOI: 10.1186/s13071-022-05483-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 09/01/2022] [Indexed: 11/10/2022] Open
Abstract
Whipworm (Trichuris) is a genus of roundworms that causes gastrointestinal infections in humans and animals. Of particular interest are T. trichiura, the causative agent of human trichuriasis, a neglected tropical disease that affects 477 million people worldwide, and T. suis, the pig whipworm species, responsible for growth stunting and economic losses within the agricultural industry. The naturally occurring mouse whipworm, T. muris, has been used for decades as a model for trichuriasis, yielding knowledge on the biology of these parasites and the host response to infection. Ex vivo culture of T. muris (and to some extent, T. suis) has provided insight into the composition of the excretory/secretory (E/S) products released by worms, which include a myriad of proteins, RNAs, lipids, glycans, metabolites and extracellular vesicles. T. muris E/S has formed the basis of the search for whipworm vaccine candidates, while the immunomodulatory potential of T. suis and T. muris secretions has been investigated with the aim of improving our understanding of how these parasites modulate host immunity, as well as identifying immunomodulatory candidates with therapeutic potential in the context of inflammatory diseases. This article will review the various components found within Trichuris E/S, their potential as vaccine candidates and their immunomodulatory properties.
Collapse
Affiliation(s)
- Rebecca K Shears
- Centre for Bioscience, Manchester Metropolitan University, Manchester, M1 5DG, UK.
- Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, M1 5DG, UK.
| | - Richard K Grencis
- Lydia Becker Institute for Immunology and Inflammation, Manchester, M13 9PT, UK
- Wellcome Trust Centre for Cell Matrix Research, Manchester, M13 9PT, UK
- Division of Infection, Immunity and Respiratory Medicine, Manchester, M13 9PT, UK
- School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, M13 9PL, UK
| |
Collapse
|
|
6
|
Zakeri A, Everts B, Williams AR, Nejsum P. Antigens from the parasitic nematode Trichuris suis induce metabolic reprogramming and trained immunity to constrain inflammatory responses in macrophages. Cytokine 2022; 156:155919. [DOI: 10.1016/j.cyto.2022.155919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 05/13/2022] [Accepted: 05/17/2022] [Indexed: 11/27/2022]
|
|
7
|
A Helminth-Derived Chitinase Structurally Similar to Mammalian Chitinase Displays Immunomodulatory Properties in Inflammatory Lung Disease. J Immunol Res 2021; 2021:6234836. [PMID: 34869783 PMCID: PMC8639245 DOI: 10.1155/2021/6234836] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 10/25/2021] [Indexed: 12/18/2022] Open
Abstract
Immunomodulation of airway hyperreactivity by excretory-secretory (ES) products of the first larval stage (L1) of the gastrointestinal nematode Trichuris suis is reported by us and others. Here, we aimed to identify the proteins accounting for the modulatory effects of the T. suis L1 ES proteins and studied six selected T. suis L1 proteins for their immunomodulatory efficacy in a murine OVA-induced allergic airway disease model. In particular, an enzymatically active T. suis chitinase mediated amelioration of clinical signs of airway hyperreactivity, primarily associated with suppression of eosinophil recruitment into the lung, the associated chemokines, and increased numbers of RELMα+ interstitial lung macrophages. While there is no indication of T. suis chitinase directly interfering with dendritic cell activation or antigen presentation to CD4 T cells, treatment of allergic mice with the worm chitinase influenced the hosts' own chitinase activity in the inflamed lung. The three-dimensional structure of the T. suis chitinase as determined by high-resolution X-ray crystallography revealed high similarities to mouse acidic mammalian chitinase (AMCase) but a unique ability of T. suis chitinase to form dimers. Our data indicate that the structural similarities between the parasite and host chitinase contribute to the disease-ameliorating effect of the helminth-derived chitinase on allergic lung inflammation.
Collapse
|
|
8
|
The yin and yang of human soil-transmitted helminth infections. Int J Parasitol 2021; 51:1243-1253. [PMID: 34774540 PMCID: PMC9145206 DOI: 10.1016/j.ijpara.2021.11.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/01/2021] [Accepted: 11/02/2021] [Indexed: 12/22/2022]
Abstract
The major soil-transmitted helminths that infect humans are the roundworms, whipworms and hookworms. Soil-transmitted helminth infections rank among the most important neglected tropical diseases in terms of morbidity, and almost one billion people are still infected with at least one species. While anthelmintic drugs are available, they do not offer long term protection against reinfection, precipitating the need for vaccines that provide long-term immunologic defense. Vaccine discovery and development is in advanced clinical development for hookworm infection, with a bivalent human hookworm vaccine in clinical trials in Brazil and Africa, but is in its infancy for both roundworm (ascariasis) and whipworm (trichuriasis) infections. One of the greatest hurdles to developing soil-transmitted helminth vaccines is the potent immunoregulatory properties of these helminths, creating a barrier to the induction of meaningful long-term protective immunity. While challenging for vaccinologists, this phenomenon presents unique opportunities to develop an entirely new class of anti-inflammatory drugs that capitalise on these immunomodulatory strategies. Epidemiologic studies and clinical trials employing experimental soil-transmitted helminth challenge models, when coupled with findings from animal models, show that at least some soil-transmitted helminth-derived molecules can protect against the onset of autoimmune, allergic and metabolic disorders, and several natural products with the desired bioactivity have been isolated and tested in pre-clinical settings. The yin and yang of soil-transmitted helminth infections reflect both the urgency for effective vaccines and the potential for new immunoregulatory molecules from parasite products.
Collapse
|
|
9
|
Cai X, Yao Y, Teng F, Li Y, Wu L, Yan W, Lin N. The role of P2X7 receptor in infection and metabolism: Based on inflammation and immunity. Int Immunopharmacol 2021; 101:108297. [PMID: 34717202 DOI: 10.1016/j.intimp.2021.108297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 12/20/2022]
Abstract
The P2X7 receptor (P2X7R) is a ligand-gated receptor belonging to the P2 receptor family. It is distributed in various tissues of the human body and is involved in regulating the physiological functions of tissues and cells to affect the occurrence and development of diseases. Unlike all other P2 receptors, the P2X7 receptor is mainly expressed in immune cells and can be activated not only by extracellular nucleotides but also by non-nucleotide substances which act as positive allosteric modulators. In this review, we comprehensively describe the role of the P2X7 receptor in infection and metabolism based on its role as an important regulator of inflammation and immunity, and briefly introduce the structure and general function of the P2X7 receptor. These provide a clear knowledge framework for the study of the P2X7 receptor in human health. Targeting the P2X7 receptor may be an effective method for the treatment of inflammatory and immune diseases. And its role in microbial infection and metabolism may be the main direction for in-depth research on the P2X7 receptor in the future.
Collapse
Affiliation(s)
- Xiaoyu Cai
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yao Yao
- Department of Pharmacy, Women's Hospital School of Medicine Zhejiang University, Hangzhou 310006, China
| | - Fei Teng
- College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China
| | - Yangling Li
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Linwen Wu
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Wei Yan
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China.
| | - Nengming Lin
- Department of Clinical Pharmacology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou 310006, China; College of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
| |
Collapse
|
|
10
|
Zakeri A, Whitehead BJ, Stensballe A, de Korne C, Williams AR, Everts B, Nejsum P. Parasite worm antigens instruct macrophages to release immunoregulatory extracellular vesicles. J Extracell Vesicles 2021; 10:e12131. [PMID: 34429858 PMCID: PMC8365858 DOI: 10.1002/jev2.12131] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/14/2021] [Accepted: 07/16/2021] [Indexed: 12/12/2022] Open
Abstract
Emerging evidence suggests that immune cells not only communicate with each other through cytokines, chemokines, and cell surface receptors, but also by releasing small membranous structures known as extracellular vesicles (EVs). EVs carry a variety of different molecules that can be taken up by recipient cells. Parasitic worms are well known for their immunomodulatory properties, but whether they can affect immune responses by altering EV-driven communication between host immune cells remains unclear. Here we provide evidence that stimulation of bone marrow-derived macrophages (BMDMs) with soluble products of Trichuris suis (TSPs), leads to the release of EVs with anti-inflammatory properties. Specifically, we found that EVs from TSP-pulsed BMDMs, but not those from unstimulated BMDMs can suppress TNFα and IL-6 release in LPS-stimulated BMDMs and BMDCs. However, no polarization toward M1 or M2 was observed in macrophages exposed to EVs. Moreover, EVs enhanced reactive oxygen species (ROS) production in the exposed BMDMs, which was associated with a deregulated redox homeostasis as revealed by pathway analysis of transcriptomic data. Proteomic analysis identified cytochrome p450 (CYP450) as a potential source of ROS in EVs from TSP-pulsed BMDMs. Finally, pharmacological inhibition of CYP450 activity could suppress ROS production in those BMDMs. In summary, we find that TSPs can modulate immune responses not only via direct interactions but also indirectly by eliciting the release of EVs from BMDMs that exert anti-inflammatory effects on recipient cells.
Collapse
Affiliation(s)
- Amin Zakeri
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
| | | | - Allan Stensballe
- Department of Medicine and Health TechnologyAalborg UniversityAalborgDenmark
| | - Clarize de Korne
- Department of ParasitologyLeiden University Medical CentreLeidenNetherlands
- Interventional Molecular Imaging laboratoryDepartment of RadiologyLeiden University Medical CentreLeidenNetherlands
| | - Andrew R. Williams
- Department of Veterinary and Animal SciencesFaculty of Health and Medical SciencesUniversity of CopenhagenFrederiksbergDenmark
| | - Bart Everts
- Department of ParasitologyLeiden University Medical CentreLeidenNetherlands
| | - Peter Nejsum
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
| |
Collapse
|
|
11
|
Darlan DM, Rozi MF, Yulfi H. Overview of Immunological Responses and Immunomodulation Properties of Trichuris sp.: Prospects for Better Understanding Human Trichuriasis. Life (Basel) 2021; 11:188. [PMID: 33673676 PMCID: PMC7997218 DOI: 10.3390/life11030188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/17/2021] [Accepted: 02/24/2021] [Indexed: 12/23/2022] Open
Abstract
Trichuris sp. infection has appeared as a pathological burden in the population, but the immunomodulation features could result in an opportunity to discover novel treatments for diseases with prominent inflammatory responses. Regarding the immunological aspects, the innate immune responses against Trichuris sp. are also responsible for determining subsequent immune responses, including the activation of innate lymphoid cell type 2 (ILC2s), and encouraging the immune cell polarization of the resistant host phenotype. Nevertheless, this parasite can establish a supportive niche for worm survival and finally avoid host immune interference. Trichuris sp. could skew antigen recognition and immune cell activation and proliferation through the generation of specific substances, called excretory/secretory (ESPs) and soluble products (SPs), which mainly mediate its immunomodulation properties. Through this review, we elaborate and discuss innate-adaptive immune responses and immunomodulation aspects, as well as the clinical implications for managing inflammatory-based diseases, such as inflammatory bowel diseases, allergic, sepsis, and other autoimmune diseases.
Collapse
Affiliation(s)
- Dewi Masyithah Darlan
- Department of Parasitology, Faculty of Medicine, Universitas Sumatera Utara, Medan 20155, Indonesia; (D.M.D.); (H.Y.)
| | | | - Hemma Yulfi
- Department of Parasitology, Faculty of Medicine, Universitas Sumatera Utara, Medan 20155, Indonesia; (D.M.D.); (H.Y.)
| |
Collapse
|
|
12
|
Soare AY, Freeman TL, Min AK, Malik HS, Osota EO, Swartz TH. P2RX7 at the Host-Pathogen Interface of Infectious Diseases. Microbiol Mol Biol Rev 2021; 85:e00055-20. [PMID: 33441488 PMCID: PMC7849353 DOI: 10.1128/mmbr.00055-20] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
The P2X7 receptor (P2RX7) is an important molecule that functions as a danger sensor, detecting extracellular nucleotides from injured cells and thus signaling an inflammatory program to nearby cells. It is expressed in immune cells and plays important roles in pathogen surveillance and cell-mediated responses to infectious organisms. There is an abundance of literature on the role of P2RX7 in inflammatory diseases and the role of these receptors in host-pathogen interactions. Here, we describe the current knowledge of the role of P2RX7 in the host response to a variety of pathogens, including viruses, bacteria, fungi, protozoa, and helminths. We describe in vitro and in vivo evidence for the critical role these receptors play in mediating and modulating immune responses. Our observations indicate a role for P2X7 signaling in sensing damage-associated molecular patterns released by nearby infected cells to facilitate immunopathology or protection. In this review, we describe how P2RX7 signaling can play critical roles in numerous cells types in response to a diverse array of pathogens in mediating pathogenesis and immunity to infectious agents.
Collapse
Affiliation(s)
- Alexandra Y Soare
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
- Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Tracey L Freeman
- Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Alice K Min
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Hagerah S Malik
- University of Chicago Pritzker School of Medicine, Chicago, Illinois, USA
| | - Elizabeth O Osota
- University of California San Diego, Graduate School of Biomedical Sciences, San Diego, California, USA
| | - Talia H Swartz
- Division of Infectious Diseases, Department of Medicine, Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| |
Collapse
|
|
13
|
Cleenewerk L, Garssen J, Hogenkamp A. Clinical Use of Schistosoma mansoni Antigens as Novel Immunotherapies for Autoimmune Disorders. Front Immunol 2020; 11:1821. [PMID: 32903582 PMCID: PMC7438586 DOI: 10.3389/fimmu.2020.01821] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 07/07/2020] [Indexed: 12/11/2022] Open
Abstract
The hygiene hypothesis states that improved hygiene and the resulting disappearance of once endemic diseases is at the origin of the enormous increase in immune related disorders such as autoimmune diseases seen in the industrialized world. Helminths, such as Schistosoma mansoni, are thought to provide protection against the development of autoimmune diseases by regulating the host's immune response. This modulation primarily involves induction of regulatory immune responses, such as generation of tolerogenic dendritic cells and alternatively activated macrophages. This points toward the potential of employing helminths or their products/metabolites as therapeutics for autoimmune diseases that are characterized by an excessive inflammatory state, such as multiple sclerosis (MS), type I diabetes (T1D) and inflammatory bowel disease (IBD). In this review, we examine the known mechanisms of immune modulation by S. mansoni, explore preclinical and clinical studies that investigated the use of an array helminthic products in these diseases, and propose that helminthic therapy opens opportunities in the treatment of chronic inflammatory disorders.
Collapse
Affiliation(s)
- L Cleenewerk
- Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Beta Sciences, Utrecht University, Utrecht, Netherlands
| | - Johan Garssen
- Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Beta Sciences, Utrecht University, Utrecht, Netherlands.,Division of Immunology, Danone Nutricia Research B.V., Utrecht, Netherlands
| | - Astrid Hogenkamp
- Division of Pharmacology, Department of Pharmaceutical Sciences, Faculty of Beta Sciences, Utrecht University, Utrecht, Netherlands
| |
Collapse
|
|
14
|
Effects of the dietary fibre inulin and Trichuris suis products on inflammatory responses in lipopolysaccharide-stimulated macrophages. Mol Immunol 2020; 121:127-135. [PMID: 32200170 DOI: 10.1016/j.molimm.2020.03.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/04/2020] [Accepted: 03/11/2020] [Indexed: 01/15/2023]
Abstract
Consumption of fermentable dietary fibres, such as inulin, or administration of helminth products (e.g. Trichuris suis ova) have independently been shown to alleviate inflammation in vivo. We recently found that dietary inulin and T. suis infection in pigs co-operatively suppressed type-1 inflammatory responses in the gut, suggesting the potential of dietary components to augment anti-inflammatory responses induced by certain helminths. Here, we explored whether T. suis antigens and inulin could directly suppress inflammatory responses in vitro in a cooperative manner. T. suis soluble products (TsSP) strongly suppressed lipopolysaccharide (LPS)-induced IL-6 and TNF-α secretion from murine macrophages and induced an anti-inflammatory phenotype as evidenced by transcriptomic and gene pathway analyses. Inulin regulated the expression of a small number of genes and transcriptional pathways in macrophages after exposure to LPS, but did not enhance the suppressive activity of TsSP, either directly or in co-culture experiments with intestinal epithelial cells. Culture of macrophages with short-chain fatty acids, the products of microbial fermentation of inulin, did however appear to enhance TsSP-mediated inhibition of TNF-α production. Our results confirm a direct role for helminth products in suppressing inflammatory responses in macrophages. In contrast, inulin had little capacity to directly modulate LPS-induced responses. Our results suggest distinct mode-of-actions of T. suis and inulin in regulating inflammatory responses, and that the role of inulin in modulating the response to helminth infection may be dependent on other factors such as production of metabolites by the gut microbiota.
Collapse
|
|
15
|
Jakobsen SR, Myhill LJ, Williams AR. Effects of Ascaris and Trichuris antigens on cytokine production in porcine blood mononuclear and epithelial cells. Vet Immunol Immunopathol 2019; 211:6-9. [PMID: 31084896 DOI: 10.1016/j.vetimm.2019.03.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 03/26/2019] [Accepted: 03/30/2019] [Indexed: 12/11/2022]
Abstract
Helminth parasites are highly prevalent in swine production, causing chronic infections and considerable morbidity due to growth retardation. Moreover, helminths actively modulate host immune responses to other pathogens and/or vaccines. Here, we investigated the modulatory effects of Ascaris suum adult body fluid (ABF) and Trichuris suis Soluble Products (TsSP) on the cytokine response in porcine peripheral blood mononuclear cells (PBMCs) and the intestinal epithelial cell line IPEC-J2. In PBMCs, TsSP induced the secretion of IL-6, IL-10 and IL-1β, but not TNF-α. Moreover, TsSP significantly enhanced the production of bacterial lipopolysaccharide (LPS)-induced IL-6 and IL-10 but suppressed the production of LPS-induced TNF-α. ABF did not induce cytokine secretion from PBMC, but suppressed LPS-induced secretion of TNF-α and IL-6. ABF did not have any effect on cytokine production in IPEC-J2 cells. In contrast, TsSP selectively induced the secretion of IL-6, and enhanced the IL-6 response induced by LPS. The IL-6 response appeared to be a conserved response to T. suis products, as significant secretion was also observed in alveolar macrophages. Thus, T. suis products have diverse modulatory effects on cytokine secretion in vitro, with IL-6 production a consistent feature of the innate host response.
Collapse
Affiliation(s)
- Simon R Jakobsen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Laura J Myhill
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Andrew R Williams
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.
| |
Collapse
|
|
16
|
Sharifi L, Moshiri M, Dallal MM, Asgardoon MH, Nourizadeh M, Bokaie S, Mirshafiey A. The Inhibitory Role of M2000 (β-D-Mannuronic Acid) on Expression of Toll-like Receptor 2 and 4 in HT29 Cell Line. RECENT PATENTS ON INFLAMMATION & ALLERGY DRUG DISCOVERY 2019; 13:57-65. [PMID: 30539708 PMCID: PMC6778985 DOI: 10.2174/1872213x13666181211160238] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 12/01/2018] [Accepted: 12/04/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND/OBJECTIVES Anti-inflammatory agents play a crucial role in controlling inflammatory diseases such as Inflammatory Bowel Disease (IBD) but their use is restricted due to their vast side effects. M2000 (β-D-mannuronic acid) is a new immunomodulatory drug. According to the capacity of M2000 in suppressing some molecules involved in Toll Like Receptors (TLRs) signaling and reducing oxidative stress we hypothesize that, this molecule may have a potential role in decreasing inflammatory responses in IBD. The aim of this study was to evaluate the cytotoxicity of M2000 and its effect on the gene expression of TLR2 and TLR4. METHODS HEK293 cell line was grown and divided into 96-well cell plate and MTT assay was performed. HT29 cells were cultured and treated with low and high doses of M2000. Total RNA was extracted and cDNA synthesized and quantitative real-time PCR was done to quantify the TLR2 and TLR4 mRNA expression. RESULTS We found that M2000 at the concentration of ≤ 1000µg/ml had no obvious cytotoxicity effect on the HEK293 cells. Also, low and high doses of M2000 could significantly down-regulate both TLR2 and TLR4 mRNA expression. Moreover, a significant reduction in gene expression of TLR2 and TLR4 in an inflammatory condition resulted in high doses of M2000 in the presence of LPS. CONCLUSION Our study which was conducted in colonic epithelial cell model, shows that M2000 can be considered as a new anti-inflammatory agent in IBD. However, more comprehensive experimental and clinical studies are required to recognize the molecular mechanism of M2000 and also its safety and efficacy.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Abbas Mirshafiey
- Address correspondence to this author at the Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Tel/Fax: +98 (21) 88954913; E-mail:
| |
Collapse
|
|
17
|
Leroux LP, Nasr M, Valanparambil R, Tam M, Rosa BA, Siciliani E, Hill DE, Zarlenga DS, Jaramillo M, Weinstock JV, Geary TG, Stevenson MM, Urban JF, Mitreva M, Jardim A. Analysis of the Trichuris suis excretory/secretory proteins as a function of life cycle stage and their immunomodulatory properties. Sci Rep 2018; 8:15921. [PMID: 30374177 PMCID: PMC6206011 DOI: 10.1038/s41598-018-34174-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 10/12/2018] [Indexed: 12/21/2022] Open
Abstract
Parasitic worms have a remarkable ability to modulate host immune responses through several mechanisms including excreted/secreted proteins (ESP), yet the exact nature of these proteins and their targets often remains elusive. Here, we performed mass spectrometry analyses of ESP (TsESP) from larval and adult stages of the pig whipworm Trichuris suis (Ts) and identified ~350 proteins. Transcriptomic analyses revealed large subsets of differentially expressed genes in the various life cycle stages of the parasite. Exposure of bone marrow-derived macrophages and dendritic cells to TsESP markedly diminished secretion of the pro-inflammatory cytokines TNFα and IL-12p70. Conversely, TsESP exposure strongly induced release of the anti-inflammatory cytokine IL-10, and also induced high levels of nitric oxide (NO) and upregulated arginase activity in macrophages. Interestingly, TsESP failed to directly induce CD4+ CD25+ FoxP3+ regulatory T cells (Treg cells), while OVA-pulsed TsESP-treated dendritic cells suppressed antigen-specific OT-II CD4+ T cell proliferation. Fractionation of TsESP identified a subset of proteins that promoted anti-inflammatory functions, an activity that was recapitulated using recombinant T. suis triosephosphate isomerase (TPI) and nucleoside diphosphate kinase (NDK). Our study helps illuminate the intricate balance that is characteristic of parasite-host interactions at the immunological interface, and further establishes the principle that specific parasite-derived proteins can modulate immune cell functions.
Collapse
Affiliation(s)
- Louis-Philippe Leroux
- Institute of Parasitology McGill University, Sainte-Anne-de-Bellevue, QC, Canada
- Centre for Host-Parasite Interaction (CHPI), Montreal, Canada
- Institut National de la Recherche Scientifique (INRS)-Institut Armand-Frappier (IAF), Laval, QC, Canada
| | - Mohamad Nasr
- Institute of Parasitology McGill University, Sainte-Anne-de-Bellevue, QC, Canada
- Centre for Host-Parasite Interaction (CHPI), Montreal, Canada
| | - Rajesh Valanparambil
- Centre for Host-Parasite Interaction (CHPI), Montreal, Canada
- Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, Canada
| | - Mifong Tam
- Centre for Host-Parasite Interaction (CHPI), Montreal, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Bruce A Rosa
- McDonnell Genome Institute, Washington University in, St. Louis, MO, USA
| | - Elizabeth Siciliani
- Institute of Parasitology McGill University, Sainte-Anne-de-Bellevue, QC, Canada
| | - Dolores E Hill
- United States Department of Agriculture, Beltsville, MD, USA
| | | | - Maritza Jaramillo
- Centre for Host-Parasite Interaction (CHPI), Montreal, Canada
- Institut National de la Recherche Scientifique (INRS)-Institut Armand-Frappier (IAF), Laval, QC, Canada
| | - Joel V Weinstock
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Tufts Medical Center, Boston, MA, USA
| | - Timothy G Geary
- Institute of Parasitology McGill University, Sainte-Anne-de-Bellevue, QC, Canada
- Centre for Host-Parasite Interaction (CHPI), Montreal, Canada
| | - Mary M Stevenson
- Centre for Host-Parasite Interaction (CHPI), Montreal, Canada
- Division of Experimental Medicine, Department of Medicine, McGill University, Montreal, QC, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Joseph F Urban
- United States Department of Agriculture, Beltsville, MD, USA
| | - Makedonka Mitreva
- McDonnell Genome Institute, Washington University in, St. Louis, MO, USA
- Division of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Armando Jardim
- Institute of Parasitology McGill University, Sainte-Anne-de-Bellevue, QC, Canada.
- Centre for Host-Parasite Interaction (CHPI), Montreal, Canada.
| |
Collapse
|
|
18
|
Almeida S, Nejsum P, Williams AR. Modulation of human macrophage activity by Ascaris antigens is dependent on macrophage polarization state. Immunobiology 2018; 223:405-412. [DOI: 10.1016/j.imbio.2017.11.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 11/14/2017] [Accepted: 11/14/2017] [Indexed: 11/26/2022]
|
|
19
|
Savio LEB, de Andrade Mello P, da Silva CG, Coutinho-Silva R. The P2X7 Receptor in Inflammatory Diseases: Angel or Demon? Front Pharmacol 2018; 9:52. [PMID: 29467654 PMCID: PMC5808178 DOI: 10.3389/fphar.2018.00052] [Citation(s) in RCA: 306] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 01/15/2018] [Indexed: 12/13/2022] Open
Abstract
Under physiological conditions, adenosine triphosphate (ATP) is present at low levels in the extracellular milieu, being massively released by stressed or dying cells. Once outside the cells, ATP and related nucleotides/nucleoside generated by ectonucleotidases mediate a high evolutionary conserved signaling system: the purinergic signaling, which is involved in a variety of pathological conditions, including inflammatory diseases. Extracellular ATP has been considered an endogenous adjuvant that can initiate inflammation by acting as a danger signal through the activation of purinergic type 2 receptors-P2 receptors (P2Y G-protein coupled receptors and P2X ligand-gated ion channels). Among the P2 receptors, the P2X7 receptor is the most extensively studied from an immunological perspective, being involved in both innate and adaptive immune responses. P2X7 receptor activation induces large-scale ATP release via its intrinsic ability to form a membrane pore or in association with pannexin hemichannels, boosting purinergic signaling. ATP acting via P2X7 receptor is the second signal to the inflammasome activation, inducing both maturation and release of pro-inflammatory cytokines, such as IL-1β and IL-18, and the production of reactive nitrogen and oxygen species. Furthermore, the P2X7 receptor is involved in caspases activation, as well as in apoptosis induction. During adaptive immune response, P2X7 receptor modulates the balance between the generation of T helper type 17 (Th17) and T regulatory (Treg) lymphocytes. Therefore, this receptor is involved in several inflammatory pathological conditions. In infectious diseases and cancer, P2X7 receptor can have different and contrasting effects, being an angel or a demon depending on its level of activation, cell studied, type of pathogen, and severity of infection. In neuroinflammatory and neurodegenerative diseases, P2X7 upregulation and function appears to contribute to disease progression. In this review, we deeply discuss P2X7 receptor dual function and its pharmacological modulation in the context of different pathologies, and we also highlight the P2X7 receptor as a potential target to treat inflammatory related diseases.
Collapse
Affiliation(s)
- Luiz E B Savio
- Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Paola de Andrade Mello
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, United States
| | - Cleide Gonçalves da Silva
- Division of Vascular Surgery, Department of Surgery, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
| | - Robson Coutinho-Silva
- Laboratory of Immunophysiology, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| |
Collapse
|
|
20
|
Zhang H, Yang N, Wang T, Dai B, Shang Y. Vitamin D reduces inflammatory response in asthmatic mice through HMGB1/TLR4/NF‑κB signaling pathway. Mol Med Rep 2018; 17:2915-2920. [PMID: 29257249 PMCID: PMC5783507 DOI: 10.3892/mmr.2017.8216] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 11/22/2017] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate the effects of vitamin D (VD) on inflammatory responses in asthmatic mice and the underlying mechanism, providing a theoretical basis for clinical application of targeted drug therapy, and the development of novel drugs against asthma. Mouse models of asthma were established. Hematoxylin‑eosin staining was performed to observe the pathological changes of the lung tissue. Pulmonary function tests were conducted to determine airway resistance in asthmatic mice. ELISA was performed to measure the serum levels of inflammatory factors. Western blot analysis and reverse transcription‑quantitative polymerase chain reaction were performed to determine the changes in apoptosis‑inducing factors, and high mobility group box 1 protein (HMGB1)/Toll‑like receptor‑4 (TLR4)/nuclear factor (NF)‑κB signaling pathway‑related proteins. VD reduced infiltrated inflammatory factors, attenuated the airway resistance of asthmatic mice, decreased serum levels of interleukin (IL)‑1β, IL‑6, tumor necrosis factor (TNF)‑α, increased serum levels of IL‑10, decreased apoptotic factor Bcl‑2‑associated X and caspase‑3 expression, downregulated HMGB1 and TLR4, NF‑κB and phosphorylated‑NF‑κB p65 expression. When TLR4 expression was inhibited, the anti‑inflammatory effects of VD were attenuated, and HMGB1, TLR4, NF‑κB and p‑NF‑κB p65 expression was increased. VD was able reduce the inflammatory response of asthmatic mice and apoptosis in lung tissue through the HMGB1/TLR4/NF‑κB signaling pathway.
Collapse
Affiliation(s)
- Han Zhang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Nan Yang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Tianyue Wang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Bing Dai
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| | - Yunxiao Shang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, P.R. China
| |
Collapse
|
|
21
|
Evaluation of the transcription of interleukin-12 in the intestinal mucosa of mice subjected to experimental toxocariasis and supplemented with Saccharomyces boulardii. Vet Parasitol 2017; 242:59-62. [PMID: 28606326 DOI: 10.1016/j.vetpar.2017.05.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Revised: 02/01/2017] [Accepted: 05/19/2017] [Indexed: 11/23/2022]
|
|
22
|
Aarts SABM, Seijkens TTP, Kusters PJH, van der Pol SMA, Zarzycka B, Heijnen PDAM, Beckers L, den Toom M, Gijbels MJJ, Boon L, Weber C, de Vries HE, Nicolaes GAF, Dijkstra CD, Kooij G, Lutgens E. Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation. J Neuroinflammation 2017; 14:105. [PMID: 28494768 PMCID: PMC5427621 DOI: 10.1186/s12974-017-0875-9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 04/26/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The influx of leukocytes into the central nervous system (CNS) is a key hallmark of the chronic neuro-inflammatory disease multiple sclerosis (MS). Strategies that aim to inhibit leukocyte migration across the blood-brain barrier (BBB) are therefore regarded as promising therapeutic approaches to combat MS. As the CD40L-CD40 dyad signals via TNF receptor-associated factor 6 (TRAF6) in myeloid cells to induce inflammation and leukocyte trafficking, we explored the hypothesis that specific inhibition of CD40-TRAF6 interactions can ameliorate neuro-inflammation. METHODS Human monocytes were treated with a small molecule inhibitor (SMI) of CD40-TRAF6 interactions (6877002), and migration capacity across human brain endothelial cells was measured. To test the therapeutic potential of the CD40-TRAF6-blocking SMI under neuro-inflammatory conditions in vivo, Lewis rats and C57BL/6J mice were subjected to acute experimental autoimmune encephalomyelitis (EAE) and treated with SMI 6877002 for 6 days (rats) or 3 weeks (mice). RESULTS We here show that a SMI of CD40-TRAF6 interactions (6877002) strongly and dose-dependently reduces trans-endothelial migration of human monocytes. Moreover, upon SMI treatment, monocytes displayed a decreased production of ROS, tumor necrosis factor (TNF), and interleukin (IL)-6, whereas the production of the anti-inflammatory cytokine IL-10 was increased. Disease severity of EAE was reduced upon SMI treatment in rats, but not in mice. However, a significant reduction in monocyte-derived macrophages, but not in T cells, that had infiltrated the CNS was eminent in both models. CONCLUSIONS Together, our results indicate that SMI-mediated inhibition of the CD40-TRAF6 pathway skews human monocytes towards anti-inflammatory cells with reduced trans-endothelial migration capacity, and is able to reduce CNS-infiltrated monocyte-derived macrophages during neuro-inflammation, but minimally ameliorates EAE disease severity. We therefore conclude that SMI-mediated inhibition of the CD40-TRAF6 pathway may represent a beneficial treatment strategy to reduce monocyte recruitment and macrophage activation in the CNS and has the potential to be used as a co-treatment to combat MS.
Collapse
Affiliation(s)
- Suzanne A. B. M. Aarts
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Tom T. P. Seijkens
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Pascal J. H. Kusters
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Susanne M. A. van der Pol
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Barbara Zarzycka
- Department of Biochemistry, University of Maastricht, 6200 MD Maastricht, The Netherlands
| | - Priscilla D. A. M. Heijnen
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Linda Beckers
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Myrthe den Toom
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
| | - Marion J. J. Gijbels
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
- Department of Pathology and Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, Maastricht, The Netherlands
| | - Louis Boon
- Bioceros, 3584 CM Utrecht, The Netherlands
| | - Christian Weber
- Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University (LMU), Pettenkoferstraße 9, 80336 Munich, Germany
| | - Helga E. de Vries
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Gerry A. F. Nicolaes
- Department of Biochemistry, University of Maastricht, 6200 MD Maastricht, The Netherlands
| | - Christine D. Dijkstra
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Gijs Kooij
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands
| | - Esther Lutgens
- Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands
- Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University (LMU), Pettenkoferstraße 9, 80336 Munich, Germany
| |
Collapse
|
|
23
|
Cheifetz AS, Gianotti R, Luber R, Gibson PR. Complementary and Alternative Medicines Used by Patients With Inflammatory Bowel Diseases. Gastroenterology 2017; 152:415-429.e15. [PMID: 27743873 DOI: 10.1053/j.gastro.2016.10.004] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 10/03/2016] [Accepted: 10/06/2016] [Indexed: 02/06/2023]
Abstract
Patients and physicians often have many questions regarding the role of complementary and alternative medicines (CAMs), or nonallopathic therapies, for inflammatory bowel diseases (IBDs). CAMs of various forms are used by more than half of patients with IBD during some point in their disease course. We summarize the available evidence for the most commonly used and discussed CAMs. We discuss evidence for the effects of herbs (such as cannabis and curcumin), probiotics, acupuncture, exercise, and mind-body therapy. There have been few controlled studies of these therapies, which have been limited by their small sample sizes; most studies have been uncontrolled. In addition, there has been a lack of quality control for herbal preparations. It has been a challenge to design rigorous, randomized, placebo-controlled trials, in part owing to problems of adequate blinding for psychological interventions, acupuncture, and exercise. These barriers have limited the acceptance of CAMs by physicians. However, such therapies might be used to supplement conventional therapies and help ease patient symptoms. We conclude that physicians should understand the nature of and evidence for CAMs for IBD so that rational advice can be offered to patients who inquire about their use. CAMs have the potential to aid in the treatment of IBD, but further research is needed to validate these approaches.
Collapse
Affiliation(s)
- Adam S Cheifetz
- Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Robert Gianotti
- Department of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Raphael Luber
- Department of Gastroenterology, Alfred Hospital and Monash University, Melbourne, Australia
| | - Peter R Gibson
- Department of Gastroenterology, Alfred Hospital and Monash University, Melbourne, Australia.
| |
Collapse
|
|
24
|
Williams AR, Klaver EJ, Laan LC, Ramsay A, Fryganas C, Difborg R, Kringel H, Reed JD, Mueller-Harvey I, Skov S, van Die I, Thamsborg SM. Co-operative suppression of inflammatory responses in human dendritic cells by plant proanthocyanidins and products from the parasitic nematode Trichuris suis. Immunology 2016; 150:312-328. [PMID: 27905107 DOI: 10.1111/imm.12687] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 10/29/2016] [Accepted: 11/01/2016] [Indexed: 12/20/2022] Open
Abstract
Interactions between dendritic cells (DCs) and environmental, dietary and pathogen antigens play a key role in immune homeostasis and regulation of inflammation. Dietary polyphenols such as proanthocyanidins (PAC) may reduce inflammation, and we therefore hypothesized that PAC may suppress lipopolysaccharide (LPS) -induced responses in human DCs and subsequent T helper type 1 (Th1) -type responses in naive T cells. Moreover, we proposed that, because DCs are likely to be exposed to multiple stimuli, the activity of PAC may synergise with other bioactive molecules that have anti-inflammatory activity, e.g. soluble products from the helminth parasite Trichuris suis (TsSP). We show that PAC are endocytosed by monocyte-derived DCs and selectively induce CD86 expression. Subsequently, PAC suppress the LPS-induced secretion of interleukin-6 (IL-6) and IL-12p70, while enhancing secretion of IL-10. Incubation of DCs with PAC did not affect lymphocyte proliferation; however, subsequent interferon-γ production was markedly suppressed, while IL-4 production was unaffected. The activity of PAC was confined to oligomers (degree of polymerization ≥ 4). Co-pulsing DCs with TsSP and PAC synergistically reduced secretion of tumour necrosis factor-α, IL-6 and IL-12p70 while increasing IL-10 secretion. Moreover, both TsSP and PAC alone induced Th2-associated OX40L expression in DCs, and together synergized to up-regulate OX40L. These data suggest that PAC induce an anti-inflammatory phenotype in human DCs that selectively down-regulates Th1 response in naive T cells, and that they also act cooperatively with TsSP. Our results indicate a novel interaction between dietary compounds and parasite products to influence immune function, and may suggest that combinations of PAC and TsSP can have therapeutic potential for inflammatory disorders.
Collapse
Affiliation(s)
- Andrew R Williams
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Elsenoor J Klaver
- Department of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands
| | - Lisa C Laan
- Department of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands
| | - Aina Ramsay
- Chemistry and Biochemistry Laboratory, University of Reading, Reading, UK
| | - Christos Fryganas
- Chemistry and Biochemistry Laboratory, University of Reading, Reading, UK
| | - Rolf Difborg
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Helene Kringel
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Jess D Reed
- Department of Animal Science, University of Wisconsin-Madison, Madison, WI, USA
| | | | - Søren Skov
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Irma van Die
- Department of Molecular Cell Biology and Immunology, VU University Medical Centre, Amsterdam, the Netherlands
| | - Stig M Thamsborg
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| |
Collapse
|
|
25
|
Laan LC, Williams AR, Stavenhagen K, Giera M, Kooij G, Vlasakov I, Kalay H, Kringel H, Nejsum P, Thamsborg SM, Wuhrer M, Dijkstra CD, Cummings RD, van Die I. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells. FASEB J 2016; 31:719-731. [PMID: 27806992 DOI: 10.1096/fj.201600841r] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 10/24/2016] [Indexed: 12/11/2022]
Abstract
Clinical trials have shown that administration of the nematode Trichuris suis can be beneficial in treating various immune disorders. To provide insight into the mechanisms by which this worm suppresses inflammatory responses, an active component was purified from T. suis soluble products (TsSPs) that suppress---- TNF and IL-12 secretion from LPS-activated human dendritic cells (DCs). Analysis by liquid chromatography tandem mass spectrometry identified this compound as prostaglandin (PG)E2. The purified compound showed similar properties compared with TsSPs and commercial PGE2 in modulating LPS-induced expression of many cytokines and chemokines and in modulating Rab7B and P2RX7 expression in human DCs. Furthermore, the TsSP-induced reduction of TNF secretion from DCs is reversed by receptor antagonists for EP2 and EP4, indicating PGE2 action. T. suis secretes extremely high amounts of PGE2 (45-90 ng/mg protein) within their excretory/secretory products but few related lipid mediators as established by metabololipidomic analysis. Culture of T. suis with several cyclooxygenase (COX) inhibitors that inhibit mammalian prostaglandin synthesis affected the worm's motility but did not inhibit PGE2 secretion, suggesting that the worms can synthesize PGE2 via a COX-independent pathway. We conclude that T. suis secretes PGE2 to suppress proinflammatory responses in human DCs, thereby modulating the host's immune response.-Laan, L. C., Williams, A. R., Stavenhagen, K., Giera, M., Kooij, G., Vlasakov, I., Kalay, H., Kringel, H., Nejsum, P., Thamsborg, S. M., Wuhrer, M., Dijkstra, C. D., Cummings, R. D., van Die, I. The whipworm (Trichuris suis) secretes prostaglandin E2 to suppress proinflammatory properties in human dendritic cells.
Collapse
Affiliation(s)
- Lisa C Laan
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Andrew R Williams
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Kathrin Stavenhagen
- Division of BioAnalytical Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.,Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Martin Giera
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Gijs Kooij
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands.,Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; and
| | - Iliyan Vlasakov
- Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; and
| | - Hakan Kalay
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Helene Kringel
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Peter Nejsum
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Stig M Thamsborg
- Section for Parasitology, Health, and Development, Department of Veterinary Disease Biology, University of Copenhagen, Denmark
| | - Manfred Wuhrer
- Division of BioAnalytical Chemistry, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.,Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Christine D Dijkstra
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Richard D Cummings
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School Center for Glycosciences, Boston, Massachusetts, USA
| | - Irma van Die
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, Vrije Universiteit Medical Center Amsterdam, Amsterdam, The Netherlands;
| |
Collapse
|
|
26
|
Abstract
Inflammatory bowel disease is a complex, chronic, multifactorial inflammatory disorder of the digestive tract. Standard therapies include immunosuppressive and biological treatments, but there is increasing interest in the potential benefit of complementary and alternative medicine for the treatment of inflammatory bowel disease. Given the high prevalence of use of complementary and alternative medicine among inflammatory bowel disease patients, gastroenterologists must remain knowledgeable regarding the risks and benefits of these treatment options. This article reviews the updated scientific data on the use of biologically based complementary and alternative therapies for the treatment of inflammatory bowel disease.
Collapse
|
|
27
|
Zakeri A, Borji H, Haghparast A. Interaction Between Helminths and Toll-Like Receptors: Possibilities and Potentials for Asthma Therapy. Int Rev Immunol 2016; 35:219-48. [PMID: 27120222 DOI: 10.3109/08830185.2015.1096936] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Toll-like receptors (TLRs) are essential components of the innate immune system. They play an important role in the pathogenesis of allergic diseases, especially asthma. Since TLRs significantly orchestrate innate and adaptive immune response, their manipulation has widely been considered as a potential approach to control asthma symptoms. It is well established that helminths have immunoregulatory effects on host immune responses, especially innate immunity. They release bioactive molecules such as excretory-secretory (ES) products manipulating TLRs expression and signaling. Thus, given the promising results derived from preclinical studies, harnessing helminth-derived molecules affecting TLRs can be considered as a potential biological therapy for allergic diseases. Prospectively, the data that are available at present suggest that, in the near future, it is possible that helminth antigens will offer new therapeutic strategies and druggable targets for fighting allergic diseases. This review describes the interactions between helminths and TLRs and discusses the potential possibilities for asthma therapy. In this opinion paper, the authors aimed to review the updated literatures on the interplay between helminths, TLRs, and asthma with a view to proposing helminth-based asthma therapy.
Collapse
Affiliation(s)
- Amin Zakeri
- a Parasitology Section, Department of Pathobiology , Faculty of Veterinary Medicine, Ferdowsi University of Mashhad , Mashhad , Iran.,b Immunology Sections, Department of Pathobiology, Faculty of Veterinary Medicine , Faculty of Veterinary Medicine, Ferdowsi University of Mashhad , Mashhad , Iran
| | - Hassan Borji
- a Parasitology Section, Department of Pathobiology , Faculty of Veterinary Medicine, Ferdowsi University of Mashhad , Mashhad , Iran
| | - Alireza Haghparast
- b Immunology Sections, Department of Pathobiology, Faculty of Veterinary Medicine , Faculty of Veterinary Medicine, Ferdowsi University of Mashhad , Mashhad , Iran.,c Biotechnology Section, Department of Pathobiology , Faculty of Veterinary Medicine, Ferdowsi University of Mashhad , Mashhad , Iran
| |
Collapse
|
|
28
|
Hoeksema MA, Laan LC, Postma JJ, Cummings RD, de Winther MPJ, Dijkstra CD, van Die I, Kooij G. Treatment with Trichuris suis soluble products during monocyte-to-macrophage differentiation reduces inflammatory responses through epigenetic remodeling. FASEB J 2016; 30:2826-36. [PMID: 27095802 DOI: 10.1096/fj.201600343r] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2016] [Accepted: 04/12/2016] [Indexed: 01/09/2023]
Abstract
Helminths have strong immunoregulatory properties that may be exploited in treatment of chronic immune disorders, such as multiple sclerosis and inflammatory bowel disease. Essential players in the pathogenesis of these diseases are proinflammatory macrophages. We present evidence that helminths modulate the function and phenotype of these innate immune cells. We found that soluble products derived from the Trichuris suis (TsSP) significantly affect the differentiation of monocytes into macrophages and their subsequent polarization. TsSPs reduce the expression and production of inflammatory cytokines, including IL-6 and TNF, in human proinflammatory M1 macrophages. TsSPs induce a concomitant anti-inflammatory M2 signature, with increased IL-10 production. Furthermore, they suppress CHIT activity and enhance secretion of matrix metalloproteinase 9. Short-term triggering of monocytes with TsSPs early during monocyte-to-macrophage differentiation imprinted these phenotypic alterations, suggesting long-lasting epigenetic changes. The TsSP-induced effects in M1 macrophages were completely reversed by inhibiting histone deacetylases, which corresponded with decreased histone acetylation at the TNF and IL6 promoters. These results demonstrate that TsSPs have a potent and sustained immunomodulatory effect on human macrophage differentiation and polarization through epigenetic remodeling and provide new insights into the mechanisms by which helminths modulate human immune responses.-Hoeksema, M. A., Laan, L. C., Postma, J. J., Cummings, R. D., de Winther, M. P. J., Dijkstra, C. D., van Die, I., Kooij, G. Treatment with Trichuris suis soluble products during monocyte-to-macrophage differentiation reduces inflammatory responses through epigenetic remodeling.
Collapse
Affiliation(s)
- Marten A Hoeksema
- Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands
| | - Lisa C Laan
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; and
| | - Juliette J Postma
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; and
| | - Richard D Cummings
- National Center for Functional Glycomics, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Menno P J de Winther
- Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands
| | - Christine D Dijkstra
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; and
| | - Irma van Die
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; and
| | - Gijs Kooij
- Department of Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; and
| |
Collapse
|
|
29
|
Legaki E, Gazouli M. Influence of environmental factors in the development of inflammatory bowel diseases. World J Gastrointest Pharmacol Ther 2016; 7:112-125. [PMID: 26855817 PMCID: PMC4734944 DOI: 10.4292/wjgpt.v7.i1.112] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 10/20/2015] [Accepted: 12/03/2015] [Indexed: 02/06/2023] Open
Abstract
Idiopathic inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial diseases that are manifested after disruption of a genetic predisposed individual and its intestinal microflora through an environmental stimulus. Urbanization and industrialization are associated with IBD. Epidemiological data, clinical observations and family/immigrants studies indicate the significance of environmental influence in the development of IBD. Some environmental factors have a different effect on the subtypes of IBD. Smoking and appendectomy is negatively associated with UC, but they are aggravating factors for CD. A westernized high fat diet, full of refined carbohydrates is strongly associated with the development of IBD, contrary to a high in fruit, vegetables and polyunsaturated fatty acid-3 diet that is protective against these diseases. High intake of nonsteroidal antiinflammatory drug and oral contraceptive pills as well as the inadequacy of vitamin D leads to an increased risk for IBD and a more malignant course of disease. Moreover, other factors such as air pollution, psychological factors, sleep disturbances and exercise influence the development and the course of IBD. Epigenetic mechanism like DNA methylation, histone modification and altered expression of miRNAS could explain the connection between genes and environmental factors in triggering the development of IBD.
Collapse
|
|
30
|
Kooij G, Braster R, Koning JJ, Laan LC, van Vliet SJ, Los T, Eveleens AM, van der Pol SMA, Förster-Waldl E, Boztug K, Belot A, Szilagyi K, van den Berg TK, van Buul JD, van Egmond M, de Vries HE, Cummings RD, Dijkstra CD, van Die I. Trichuris suis induces human non-classical patrolling monocytes via the mannose receptor and PKC: implications for multiple sclerosis. Acta Neuropathol Commun 2015. [PMID: 26205402 PMCID: PMC4513676 DOI: 10.1186/s40478-015-0223-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Introduction The inverse correlation between prevalence of auto-immune disorders like the chronic neuro-inflammatory disease multiple sclerosis (MS) and the occurrence of helminth (worm) infections, suggests that the helminth-trained immune system is protective against auto-immunity. As monocytes are regarded as crucial players in the pathogenesis of auto-immune diseases, we explored the hypothesis that these innate effector cells are prime targets for helminths to exert their immunomodulatory effects. Results Here we show that soluble products of the porcine nematode Trichuris suis (TsSP) are potent in changing the phenotype and function of human monocytes by skewing classical monocytes into anti-inflammatory patrolling cells, which exhibit reduced trans-endothelial migration capacity in an in vitro model of the blood–brain barrier. Mechanistically, we identified the mannose receptor as the TsSP-interacting monocyte receptor and we revealed that specific downstream signalling occurs via protein kinase C (PKC), and in particular PKCδ. Conclusion This study provides comprehensive mechanistic insight into helminth-induced immunomodulation, which can be therapeutically exploited to combat various auto-immune disorders. Electronic supplementary material The online version of this article (doi:10.1186/s40478-015-0223-1) contains supplementary material, which is available to authorized users.
Collapse
|
|
31
|
Hansen EP, Kringel H, Williams AR, Nejsum P. Secretion of RNA-Containing Extracellular Vesicles by the Porcine Whipworm,Trichuris suis. J Parasitol 2015; 101:336-40. [DOI: 10.1645/14-714.1] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
|
|
32
|
Klaver EJ, van der Pouw Kraan TCTM, Laan LC, Kringel H, Cummings RD, Bouma G, Kraal G, van Die I. Trichuris suis soluble products induce Rab7b expression and limit TLR4 responses in human dendritic cells. Genes Immun 2015; 16:378-87. [PMID: 25996526 DOI: 10.1038/gene.2015.18] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 03/19/2015] [Accepted: 04/17/2015] [Indexed: 01/02/2023]
Abstract
Inflammatory immune disorders such as inflammatory bowel disease and multiple sclerosis are major health problems. Currently, the intestinal whipworm Trichuris suis is being explored in clinical trials to reduce inflammation in these diseases; however, the mechanisms by which the parasite affects the host immune system are not known. Here we determined the effects of T. suis soluble products (SPs) on Toll-like receptor-4 (TLR4)-stimulated human dendritic cells (DCs) using Illumina bead chip gene arrays. Pathway analysis of lipopolysaccharide-stimulated DCs with or without T. suis treatment showed that co-stimulation with T. suis SPs resulted in a downregulation of both the myeloid differentiation primary response gene 88-dependent and the TIR-domain-containing adaptor-inducing interferon-β-dependent signalling pathways triggered by TLR4. These data were verified using quantitative real-time PCR of several key genes within these pathways and/or defining their protein levels. In addition, T. suis SPs induce Rab7b, a negative regulator of TLR4 signalling that interferes with its trafficking, which coincided with a reduced surface expression of TLR4. These data indicate that the mechanism by which T. suis SPs reduce inflammatory responses is through suppression of both TLR4 signalling and surface expression on DCs.
Collapse
Affiliation(s)
- E J Klaver
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - T C T M van der Pouw Kraan
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - L C Laan
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - H Kringel
- Section for Parasitology, Health and Development, Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark
| | - R D Cummings
- Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA
| | - G Bouma
- Department of Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands
| | - G Kraal
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| | - I van Die
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands
| |
Collapse
|
|
33
|
Vogel DYS, Kooij G, Heijnen PDAM, Breur M, Peferoen LAN, van der Valk P, de Vries HE, Amor S, Dijkstra CD. GM-CSF promotes migration of human monocytes across the blood brain barrier. Eur J Immunol 2015; 45:1808-19. [PMID: 25756873 DOI: 10.1002/eji.201444960] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 02/13/2015] [Accepted: 03/06/2015] [Indexed: 12/22/2022]
Abstract
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Infiltration of monocytes into the CNS is crucial for disease onset and progression. Animal studies indicate that granulocyte-macrophages colony-stimulating factor (GM-CSF) may play an essential role in this process, possibly by acting on the migratory capacities of myeloid cells across the blood-brain barrier. This study describes the effect of GM-CSF on human monocytes, macrophages, and microglia. Furthermore, the expression of GM-CSF and its receptor was investigated in the CNS under healthy and pathological conditions. We show that GM-CSF enhances monocyte migration across human blood-brain barrier endothelial cells in vitro. Next, immunohistochemical analysis on human brain tissues revealed that GM-CSF is highly expressed by microglia and macrophages in MS lesions. The GM-CSF receptor is expressed by neurons in the rim of combined gray/white matter lesions and astrocytes. Finally, the effect of GM-CSF on human macrophages was determined, revealing an intermediate activation status, with a phenotype similar to that observed in active MS lesions. Together our data indicate that GM-CSF is a powerful stimulator of monocyte migration, and is abundantly present in the inflamed CNS where it may act as an activator of macrophages and microglia.
Collapse
Affiliation(s)
- Daphne Y S Vogel
- Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, Neuroscience Campus, Amsterdam, The Netherlands.,Department of Pathology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Gijs Kooij
- Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, Neuroscience Campus, Amsterdam, The Netherlands
| | - Priscilla D A M Heijnen
- Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, Neuroscience Campus, Amsterdam, The Netherlands
| | - Marjolein Breur
- Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, Neuroscience Campus, Amsterdam, The Netherlands
| | - Laura A N Peferoen
- Department of Pathology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Paul van der Valk
- Department of Pathology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands
| | - Helga E de Vries
- Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, Neuroscience Campus, Amsterdam, The Netherlands
| | - Sandra Amor
- Department of Pathology, VU University Medical Center Amsterdam, Amsterdam, The Netherlands.,Department of Neuroimmunology Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK
| | - Christine D Dijkstra
- Department of Molecular Cell Biology and Immunology, VU University Medical Center Amsterdam, Neuroscience Campus, Amsterdam, The Netherlands
| |
Collapse
|