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Lian X, Li Y, Wang W, Zuo J, Yu T, Wang L, Song L. The Modification of H3K4me3 Enhanced the Expression of CgTLR3 in Hemocytes to Increase CgIL17-1 Production in the Immune Priming of Crassostrea gigas. Int J Mol Sci 2024; 25:1036. [PMID: 38256110 PMCID: PMC10816183 DOI: 10.3390/ijms25021036] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 01/04/2024] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
Increasing evidence confirms that histone modification plays a critical role in preserving long-term immunological memory. Immune priming is a novel form of immunological memory recently verified in invertebrates. Toll-like receptor (TLR) signaling and cytokines have been reported to be involved in the immune priming of the Pacific oyster Crassostrea gigas. In the present study, the expression of Toll-like receptor 3 (CgTLR3), myeloid differentiation factor 88-2 (CgMyd88-2) and interleukin 17-1 (CgIL17-1) was found to be elevated in the hemocytes of C. gigas at 6 h after the secondary stimulation with Vibrio splendidus, which was significantly higher than that at 6 h after the primary stimulation (p < 0.05). A significant increase in histone H3 lysine 4 trimethylation (H3K4me3) enrichment was detected in the promoter region of the CgTLR3 gene at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05). After the treatment with a histone methyltransferase inhibitor (5'-methylthioadenosine, MTA), the level of H3K4me3 at the promoter of the CgTLR3 gene decreased significantly at 7 d after the primary stimulation with inactivated V. splendidus (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was significantly repressed at 6 h after the secondary stimulation with V. splendidus (p < 0.05). Conversely, the treatment with monomethyl fumarate (MEF, an inhibitor of histone demethylases) resulted in a significant increase in H3K4me3 enrichment levels at the CgTLR3 promoter at 7 d after the primary stimulation (p < 0.05), and the expression of CgTLR3, CgMyD88-2 and CgIL17-1 was observed to increase significantly at 6 h after the secondary stimulation (p < 0.05). These results suggested that H3K4me3 regulated MyD88-dependent TLR signaling in the hemocytes of C. gigas, which defined the role of histone modifications in invertebrate immune priming.
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Affiliation(s)
- Xingye Lian
- School of Life Science, Liaoning Normal University, Dalian 116029, China; (X.L.); (Y.L.)
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China; (W.W.); (J.Z.); (T.Y.)
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
- Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
- Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian 116023, China
| | - Yinan Li
- School of Life Science, Liaoning Normal University, Dalian 116029, China; (X.L.); (Y.L.)
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China; (W.W.); (J.Z.); (T.Y.)
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
- Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
- Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian 116023, China
| | - Weilin Wang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China; (W.W.); (J.Z.); (T.Y.)
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
- Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
- Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian 116023, China
| | - Jiajun Zuo
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China; (W.W.); (J.Z.); (T.Y.)
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
- Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
- Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian 116023, China
| | - Tianqi Yu
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China; (W.W.); (J.Z.); (T.Y.)
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
- Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
- Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian 116023, China
| | - Lingling Wang
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China; (W.W.); (J.Z.); (T.Y.)
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
- Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
- Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian 116023, China
| | - Linsheng Song
- Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian 116023, China; (W.W.); (J.Z.); (T.Y.)
- Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai), Zhuhai 519000, China
- Laboratory of Marine Fisheries Science and Food Production Process, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266235, China
- Dalian Key Laboratory of Aquatic Animal Disease Prevention and Control, Dalian Ocean University, Dalian 116023, China
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Kouroumalis E, Tsomidis I, Voumvouraki A. Viral Liver Disease and Intestinal Gut–Liver Axis. GASTROINTESTINAL DISORDERS 2024; 6:64-93. [DOI: 10.3390/gidisord6010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The intestinal microbiota is closely related to liver diseases via the intestinal barrier and bile secretion to the gut. Impairment of the barrier can translocate microbes or their components to the liver where they can contribute to liver damage and fibrosis. The components of the barrier are discussed in this review along with the other elements of the so-called gut–liver axis. This bidirectional relation has been widely studied in alcoholic and non-alcoholic liver disease. However, the involvement of microbiota in the pathogenesis and treatment of viral liver diseases have not been extensively studied, and controversial data have been published. Therefore, we reviewed data regarding the integrity and function of the intestinal barrier and the changes of the intestinal microbioma that contribute to progression of Hepatitis B (HBV) and Hepatitis C (HCV) infection. Their consequences, such as cirrhosis and hepatic encephalopathy, were also discussed in connection with therapeutic interventions such as the effects of antiviral eradication and the use of probiotics that may influence the outcome of liver disease. Profound alterations of the microbioma with significant reduction in microbial diversity and changes in the abundance of both beneficial and pathogenic bacteria were found.
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Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Ioannis Tsomidis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
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Elbestawy A, Ellakany H, Sedeik M, Gado A, Abdel-Latif M, Noreldin A, Orabi A, Radwan I, El-Ghany WA. Superior Efficacy of Apathogenic Genotype I (V4) over Lentogenic Genotype II (LaSota) Live Vaccines against Newcastle Disease Virus Genotype VII.1.1 in Pathogen-Associated Molecular Pattern-H9N2 Vaccinated Broiler Chickens. Vaccines (Basel) 2023; 11:1638. [PMID: 38005970 PMCID: PMC10674370 DOI: 10.3390/vaccines11111638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 10/16/2023] [Accepted: 10/20/2023] [Indexed: 11/26/2023] Open
Abstract
A comparison of the efficacy of apathogenic genotype I (V4) and lentogenic genotype II (LaSota) strains of live Newcastle disease virus (NDV) vaccines was performed following vaccination with pathogen-associated molecular pattern (PAMP) H9N2 avian influenza vaccine and challenge with velogenic NDV genotype VII.1.1 (vNDV-VII.1.1). Eight groups (Gs) of day-old chicks were used (n = 25). Groups 1-4 received a single dose of PAMP-H9N2 subcutaneously, while Gs (1, 5) and (2, 6) received eye drops of V4 and LaSota, respectively, as two doses. All Gs, except for 4 and 8, were intramuscularly challenged with vNDV-VII.1.1 at 28 days of age. No signs were detected in Gs 1, 5, 4, and 8. The mortality rates were 0% in Gs 1, 4, 5, and 8; 40% in G2; 46.66% in G6; and 100% in Gs 3 and 7. Lesions were recorded as minimal in Gs 1 and 5, but mild to moderate in Gs 2 and 6. The lowest significant viral shedding was detected in Gs 1, 2, and 5. In conclusion, two successive vaccinations of broilers with a live V4 NDV vaccine provided higher protection against vNDV-VII.1.1 challenge than LaSota. PAMP-H9N2 with live NDV vaccines induced more protection than the live vaccine alone.
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Affiliation(s)
- Ahmed Elbestawy
- Department of Poultry and Fish Diseases, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt; (H.E.); (A.G.)
| | - Hany Ellakany
- Department of Poultry and Fish Diseases, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt; (H.E.); (A.G.)
| | - Mahmoud Sedeik
- Department of Poultry and Fish Diseases, Faculty of Veterinary Medicine, Alexandria University, Edfina 22758, Egypt;
| | - Ahmed Gado
- Department of Poultry and Fish Diseases, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt; (H.E.); (A.G.)
| | - Mervat Abdel-Latif
- Nutrition and Veterinary Clinical Nutrition Department, Faculty of Veterinary Medicine, Damanhour University, El-Beheira 22511, Egypt;
| | - Ahmed Noreldin
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Damanhour University, El-Beheira 22511, Egypt;
| | - Ahmed Orabi
- Department of Microbiology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt;
| | - Ismail Radwan
- Department of Bacteriology, Mycology and Immunology, Faculty of Veterinary Medicine, Beni-Suef University, Beni Suef 62511, Egypt;
| | - Wafaa Abd El-Ghany
- Department of Poultry Diseases, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt;
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Sadakane K, Ichinose T, Maki T, Nishikawa M. Co-exposure of peptidoglycan and heat-inactivated Asian sand dust exacerbates ovalbumin-induced allergic airway inflammation in mice. Inhal Toxicol 2022; 34:231-243. [PMID: 35698289 DOI: 10.1080/08958378.2022.2086650] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
AIMS Asian sand dust (ASD) comprises soil particles, microorganisms, and various chemical components. We examined whether peptidoglycan (PGN), a structural cell wall component of Gram-positive bacteria, exacerbates ASD-induced allergic airway inflammation in mice. METHODS The ASD (median diameter ∼4 µm) used was a certified reference material from the National Institute for Environmental Studies in Japan, derived from Gobi Desert surface soil collected in 2011. BALB/c mice were intratracheally exposed to PGN, heat-inactivated ASD (H-ASD), and ovalbumin (OVA), individually and in combination. Twenty-four hours after the final intratracheal administration, bronchoalveolar lavage fluid (BALF) and serum samples were collected. Inflammatory cell count, cytokine levels in the BALF, OVA-specific immunoglobulin levels in the serum, and pathological changes in the lungs were analyzed. RESULTS AND DISCUSSION After OVA + PGN + H-ASD treatment, the number of eosinophils, neutrophils, and macrophages in the BALF and of eosinophils in the lung tissue was significantly higher than that after OVA + PGN or OVA + H-ASD treatment. Moreover, levels of chemokines and cytokines associated with eosinophil recruitment and activation were significantly higher in the BALF of this group than in that of the OVA + PGN group, and tended to be higher than those in the OVA + H-ASD group. Pathological changes in the lungs were most severe in mice treated with OVA + PGN + H-ASD. CONCLUSIONS Our results indicate that PGN is involved in the exacerbation of ASD-induced allergic airway inflammation in mice. Thus, inhalation of ASD containing Gram-positive bacteria may trigger allergic bronchial asthma.
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Affiliation(s)
- Kaori Sadakane
- Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita, Japan
| | - Takamichi Ichinose
- Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita, Japan.,Department of Environmental Engineering, Graduate School of Engineering, Kyoto University, Kyoto, Japan
| | - Teruya Maki
- Department of Life Science, Kindai University, Osaka, Japan
| | - Masataka Nishikawa
- Environmental Standards Section, National Institute for Environmental Studies, Ibaraki, Japan
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Yu X, Wang L, Yang X, Zhang S, Li G, Zhang L, Li J, Wang X, Zhou H, Jiang Y, Cui W, Li Y, Tang L, Qiao X. Lactobacillus casei Ghosts as a Vehicle for the Delivery of DNA Vaccines Mediate Immune Responses. Front Immunol 2022; 13:849409. [PMID: 35711427 PMCID: PMC9193971 DOI: 10.3389/fimmu.2022.849409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 04/25/2022] [Indexed: 11/25/2022] Open
Abstract
We developed Lactobacillus casei bacterial ghosts (BGs) as vehicles for delivering DNA vaccines and analyzed their effects on immune responses. Uptake of the plasmids encoding the enhanced green fluorescent protein (pCI-EGFP) and BGs loaded with pCI-EGFP by macrophages was investigated using fluorescence microscopy and flow cytometry. The results showed that pCI-EGFP-loaded L. casei BGs were efficiently taken up by macrophages. Lactobacillus casei BGs loaded with plasmids encoding VP6 protein of PoRV (pCI-PoRV-VP6) significantly upregulated the mRNA expression of interleukin (IL)-1β, IL-10, tumor necrosis factor (TNF)-α, inducible nitric oxide synthase (iNOS), arginase-1 (Arg-1), Mannose receptor (CD206) toll-like receptor (TLR)-2, TLR4, and TLR9 in macrophages. The levels of markers of M1 polarization (IL-10 and TNF-α) and M2 polarization (Arg-1 and CD206) were increased in macrophages incubated with pCI-PoRV-VP6-loaded BGs compared with the control group. The results of the enzyme-linked immunosorbent assay showed that the secretion of IL-1β, IL-10, and TNF-α in macrophages was significantly upregulated compared with the control group. Flow cytometry demonstrated that L. casei BGs loaded with pCI-PoRV-VP6 promoted the maturation of dendritic cells (DCs). Following incubation with pCI-PoRV-VP6-loaded BGs, the mRNA expression levels of IL-1β, IL-6 and interferon (IFN)-γ in DCs were significantly increased. ELISA assay showed the secretion of the IL-1β, IL-6, IFN-γ IL-10 and TNF-α in DCs were upregulated significantly. Thus, L. casei BGs promoted the maturation and activation of DCs. We analyzed the stimulatory capacity of DCs in a mixed lymphocyte reaction with allogeneic T cells. T cell proliferation increased upon incubation with DCs stimulated by BGs. After immunizing mice with BGs loaded with pCI-PoRV-VP6, the specific IgG levels in the serum were higher than those elicited by BGs loaded with pCI-PoRV-VP6. BGs loaded with pCI-PoRV-VP6 on Th1 and Th2 cytokines polarized T cells into the Th1 type and increased the proportion of CD4+/CD8+ T cells. These results indicate L. casei BGs effectively mediate immune responses and can be used as delivery system for DNA vaccination.
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Affiliation(s)
- Xiaoli Yu
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Li Wang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Xinru Yang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Songsong Zhang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Guiwei Li
- Branch of Animal Husbandry and Veterinary, Heilongjiang Academy of Agricultural Sciences, Qiqihar, China
| | - Lanlan Zhang
- Heilongjiang Fishery Technology Extension Station , Harbin, China
| | - Jiaxuan Li
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Xiaona Wang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Han Zhou
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Yanping Jiang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Wen Cui
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Yijing Li
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Lijie Tang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
| | - Xinyuan Qiao
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development, Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
- *Correspondence: Xinyuan Qiao,
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Karasarides M, Cogdill AP, Robbins PB, Bowden M, Burton EM, Butterfield LH, Cesano A, Hammer C, Haymaker CL, Horak CE, McGee HM, Monette A, Rudqvist NP, Spencer CN, Sweis RF, Vincent BG, Wennerberg E, Yuan J, Zappasodi R, Lucey VMH, Wells DK, LaVallee T. Hallmarks of Resistance to Immune-Checkpoint Inhibitors. Cancer Immunol Res 2022; 10:372-383. [PMID: 35362046 PMCID: PMC9381103 DOI: 10.1158/2326-6066.cir-20-0586] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/15/2021] [Accepted: 01/24/2022] [Indexed: 01/29/2023]
Abstract
Immune-checkpoint inhibitors (ICI), although revolutionary in improving long-term survival outcomes, are mostly effective in patients with immune-responsive tumors. Most patients with cancer either do not respond to ICIs at all or experience disease progression after an initial period of response. Treatment resistance to ICIs remains a major challenge and defines the biggest unmet medical need in oncology worldwide. In a collaborative workshop, thought leaders from academic, biopharma, and nonprofit sectors convened to outline a resistance framework to support and guide future immune-resistance research. Here, we explore the initial part of our effort by collating seminal discoveries through the lens of known biological processes. We highlight eight biological processes and refer to them as immune resistance nodes. We examine the seminal discoveries that define each immune resistance node and pose critical questions, which, if answered, would greatly expand our notion of immune resistance. Ultimately, the expansion and application of this work calls for the integration of multiomic high-dimensional analyses from patient-level data to produce a map of resistance phenotypes that can be utilized to guide effective drug development and improved patient outcomes.
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Affiliation(s)
- Maria Karasarides
- Worldwide Medical Oncology, Bristol Myers Squibb, Princeton, New Jersey.,Corresponding Authors: Maria Karasarides, Worldwide Medical Oncology, Bristol-Myers Squibb, Boston, MA 021273401. E-mail: ; and Theresa LaVallee, 1 Letterman Drive, Suite D3500, San Francisco, CA 94129. Phone: 628-899-7593; E-mail:
| | - Alexandria P. Cogdill
- Immunai, New York, New York.,Department of Immunology, The University of Texas MD Anderson, Houston, Texas
| | | | - Michaela Bowden
- Translational Medicine, Bristol Myers Squibb, Cambridge, Massachusetts
| | - Elizabeth M. Burton
- Department of Surgical Oncology, The University of Texas MD Anderson, Houston, Texas
| | - Lisa H. Butterfield
- Parker Institute for Cancer Immunotherapy, San Francisco, California.,Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California
| | | | - Christian Hammer
- Department of Cancer Immunology, Genentech, South San Francisco, California.,Department of Human Genetics, Genentech, South San Francisco, California
| | - Cara L. Haymaker
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Christine E. Horak
- Global Drug Development, Bristol Myers Squibb, Lawrenceville, New Jersey
| | - Heather M. McGee
- Department of Radiation Oncology, City of Hope National Medical Center and Department of Immuno-Oncology, Beckmann Research Institute, City of Hope, Duarte, California
| | - Anne Monette
- Lady Davis Institute for Medical Research, Montréal, Québec, Canada
| | | | - Christine N. Spencer
- Department of Informatics, Parker Institute for Cancer Immunotherapy, San Francisco, California.,University of California San Francisco, San Francisco, California
| | - Randy F. Sweis
- Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.,Committee on Immunology, University of Chicago, Chicago, Illinois.,Comprehensive Cancer Center, University of Chicago, Chicago, Illinois
| | - Benjamin G. Vincent
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina
| | | | - Jianda Yuan
- Translational Oncology, Early Oncology Development Department, Merck Research Laboratories, Rahway, New Jersey
| | - Roberta Zappasodi
- Weill Cornell Medicine, New York, New York.,Ludwig Collaborative and Swim Across America Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York.,Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Daniel K. Wells
- Immunai, New York, New York.,Parker Institute for Cancer Immunotherapy, San Francisco, California
| | - Theresa LaVallee
- Parker Institute for Cancer Immunotherapy, San Francisco, California.,Corresponding Authors: Maria Karasarides, Worldwide Medical Oncology, Bristol-Myers Squibb, Boston, MA 021273401. E-mail: ; and Theresa LaVallee, 1 Letterman Drive, Suite D3500, San Francisco, CA 94129. Phone: 628-899-7593; E-mail:
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Kurago Z, Loveless J. Microbial Colonization and Inflammation as Potential Contributors to the Lack of Therapeutic Success in Oral Squamous Cell Carcinoma. FRONTIERS IN ORAL HEALTH 2022; 2:739499. [PMID: 35048056 PMCID: PMC8757816 DOI: 10.3389/froh.2021.739499] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 09/03/2021] [Indexed: 12/15/2022] Open
Abstract
This review discusses the microenvironment of evolving and established conventional oral squamous cell carcinoma, by far the most common oral cancer. The focus of this paper is mainly on the more recent data that describe the role of microorganisms, host-microbial interactions, and in particular, the contributions of cell-surface toll-like receptors on immune system cells and on normal and malignant epithelial cells to their functions that support carcinogenesis. Because carcinomas arising at various host surfaces share much in common, additional information available from studies of other carcinomas is included in the discussion. Accumulating evidence reveals the complex toll-like receptor-mediated tumor-supporting input into many aspects of carcinogenesis via malignant cells, stromal immune cells and non-immune cells, complicating the search for effective treatments.
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Affiliation(s)
- Zoya Kurago
- Augusta University Dental College of Georgia, Augusta, GA, United States.,Medical College of Georgia, Augusta, GA, United States.,Georgia Cancer Center, Augusta, GA, United States
| | - Jenni Loveless
- Augusta University Dental College of Georgia, Augusta, GA, United States
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Du L, Hou L, Yu X, Cheng H, Chen J, Zheng Q, Hou J. Pattern-Recognition Receptor Agonist-Containing Immunopotentiator CVC1302 Boosts High-Affinity Long-Lasting Humoral Immunity. Front Immunol 2021; 12:697292. [PMID: 34867941 PMCID: PMC8637734 DOI: 10.3389/fimmu.2021.697292] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 10/11/2021] [Indexed: 11/25/2022] Open
Abstract
Ideally, a vaccine should provide life-long protection following a single administered dose. In our previous study, the immunopotentiator CVC1302, which contains pattern- recognition receptor (PRR) agonists, was demonstrated to prolong the lifetime of the humoral immune response induced by killed foot-and-mouth disease virus (FMDV) vaccine. To elucidate the mechanism by which CVC1302 induces long-term humoral immunity, we used 4-hydroxy-3-nitrophenylacetyl (NP)-OVA as a pattern antigen and administered it to mice along with CVC1302, emulsified together with Marcol 52 mineral oil (NP-CVC1302). From the results of NP-specific antibody levels, we found that CVC1302 could induce not only higher levels of NP-specific antibodies but also high-affinity NP-specific antibody levels. To detect the resulting NP-specific immune cells, samples were taken from the injection sites, draining lymph nodes (LNs), and bone marrow of mice injected with NP-CVC1302. The results of these experiments show that, compared with mice injected with NP alone, those injected with NP-CVC1302 had higher percentages of NP+ antigen-presenting cells (APCs) at the injection sites and draining LNs, higher percentages of follicular helper T cells (TFH), germinal center (GC) B cells, and NP+ plasma-blasts in the draining LNs, as well as higher percentages of NP+ long-lived plasma cells (LLPCs) in the bone marrow. Additionally, we observed that the inclusion of CVC1302 in the immunization prolonged the lifetime of LLPCs in the bone marrow by improving the transcription expression of anti-apoptotic transcription factors such as Mcl-1, Bcl-2, BAFF, BCMA, Bax, and IRF-4. This research provides a blueprint for designing new generations of immunopotentiators.
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Affiliation(s)
- Luping Du
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing, China
| | - Liting Hou
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing, China
| | - Xiaoming Yu
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing, China
| | - Haiwei Cheng
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing, China
| | - Jin Chen
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing, China
| | - Qisheng Zheng
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing, China
| | - Jibo Hou
- Institute of Veterinary Immunology & Engineering, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- National Research Center of Engineering and Technology for Veterinary Biologicals, Jiangsu Academy of Agricultural Sciences, Nanjing, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, China
- Jiangsu Key Laboratory for Food Quality and Safety-State Key Laboratory Cultivation Base, Ministry of Science and Technology, Nanjing, China
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9
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Zheng X, Li S, Yang H. Roles of Toll-Like Receptor 3 in Human Tumors. Front Immunol 2021; 12:667454. [PMID: 33986756 PMCID: PMC8111175 DOI: 10.3389/fimmu.2021.667454] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 04/06/2021] [Indexed: 12/29/2022] Open
Abstract
Toll-like receptor 3 (TLR3) is an important member of the TLR family, which is an important group of pathogen-associated molecular patterns. TLR3 can recognize double-stranded RNA and induce activation of NF-κB and the production of type I interferons. In addition to its immune-associated role, TLR3 has also been detected in some tumors. However TLR3 can play protumor or antitumor roles in different tumors or cell lines. Here, we review the basic signaling associated with TLR3 and the pro- or antitumor roles of TLR3 in different types of tumors and discuss the possible reasons for the opposing roles of TLR3 in tumors.
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Affiliation(s)
- Xin Zheng
- Department of Neurosurgery, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Song Li
- Department of Neurosurgery, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Hui Yang
- Department of Neurosurgery, Xinqiao Hospital, Army Medical University, Chongqing, China
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10
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Jin YH, Kim CX, Huang J, Kim BS. Infection and Activation of B Cells by Theiler's Murine Encephalomyelitis Virus (TMEV) Leads to Autoantibody Production in an Infectious Model of Multiple Sclerosis. Cells 2020; 9:cells9081787. [PMID: 32727036 PMCID: PMC7465974 DOI: 10.3390/cells9081787] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 07/22/2020] [Accepted: 07/24/2020] [Indexed: 12/23/2022] Open
Abstract
Theiler’s murine encephalomyelitis virus (TMEV) induces immune-mediated inflammatory demyelinating disease in susceptible mice that is similar to human multiple sclerosis (MS). In light of anti-CD20 therapies for MS, the susceptibility of B cells to TMEV infection is particularly important. In our study, direct viral exposure to macrophages and lymphocytes resulted in viral replication and cellular stimulation in the order of DCs, macrophages, B cells, and T cells. Notably, B cells produced viral proteins and expressed elevated levels of CD69, an activation marker. Similarly, the expression of major histocompatibility complex class II and costimulatory molecules in B cells was upregulated. Moreover, TMEV-infected B cells showed elevated levels of antigen-presenting function and antibody production. TMEV infection appeared to polyclonally activate B cells to produce autoantibodies and further T cell stimulation. Thus, the viral infection might potentially affect the outcome of autoimmune diseases, and/or the development of other chronic infections, including the protection and/or pathogenesis of TMEV-induced demyelinating disease.
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Affiliation(s)
- Young-Hee Jin
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA;
- KM Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Korea
- Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
- Correspondence: (Y.-H.J.); (B.S.K.); Tel.: +82-42-610-8850 (Y.-H.J.); +1-312-503-8693 (B.S.K.)
| | - Charles X. Kim
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA;
- M Health Fairview Heart Clinic, University of Minnesota Health, Edina, MN 55435, USA
| | - Jocelin Huang
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA;
- M Health Cancer Care, University of Minnesota Health, Edina, MN 55435, USA
| | - Byung S. Kim
- Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA;
- Correspondence: (Y.-H.J.); (B.S.K.); Tel.: +82-42-610-8850 (Y.-H.J.); +1-312-503-8693 (B.S.K.)
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11
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Wu M, Li H, Chen X, Jiang Y, Jiang W. Studies on the clinical symptoms, virus distribution, and mRNA expression of several antiviral immunity-related genes in grass carp after infection with genotype II grass carp reovirus. Arch Virol 2020; 165:1599-1609. [PMID: 32399788 DOI: 10.1007/s00705-020-04654-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 04/09/2020] [Indexed: 01/05/2023]
Abstract
The viral hemorrhage disease caused by grass carp reovirus (GCRV) is a serious contagious disease of grass carp that mainly infects fingerlings and yearlings. Epidemiological studies have shown that GCRV genotype II is currently the prominent genotype. However, little is known about the histopathological characteristics, virus distribution, and expression of immunity-related genes in grass carp infected by GCRV genotype II. In this study, we found that grass carp infected by GCRV genotype II lost appetite, swam alone, and rolled, and their fins, eyes, operculum, oral cavity, abdomen, intestine, and muscles showed pronounced punctate hemorrhage. Congestion, swelling, deformation, thinning of membranes, dilatation and darkened color of nucleoli, cathepsis, erythrocyte infiltration, and vacuole formation were observed in some infected tissues. A qRT-PCR test showed that the 11 genome segments of GCRV had similar expression patterns in different tissues. The S8 segment, with unknown function and no homologous sequences, had the highest expression level, while the most conserved segment, L2, had the lowest expression level. GCRV particles were distributed in different tissues, especially in the intestine. In the infected intestine, the expression of various receptors and adaptor molecules was modulated at different levels. Pro-inflammatory cytokine interleukin-1β (IL-1β) expression was 2160.9 times higher than that in the control group. The upregulation of immunity-related genes activated the antiviral immunity pathways. Therefore, the intestine might play a dual role in mediating GCRV infection and the antiviral immune response. This study provides detailed information about the pathogenicity of GCRV and expression of immunity-related genes, laying the foundation for further research on virus control and treatment.
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Affiliation(s)
- Minglin Wu
- Fisheries Research Institute, Anhui Academy of Agricultural Sciences, No. 40 South Nongke Road, Luyang District, Hefei, 230031, Anhui, China.
- Anhui Province Key Laboratory of Aquaculture & Stock Enhancement, No. 40 South Nongke Road, Luyang District, Hefei, 230031, Anhui, China.
| | - Haiyang Li
- Fisheries Research Institute, Anhui Academy of Agricultural Sciences, No. 40 South Nongke Road, Luyang District, Hefei, 230031, Anhui, China
- Anhui Province Key Laboratory of Aquaculture & Stock Enhancement, No. 40 South Nongke Road, Luyang District, Hefei, 230031, Anhui, China
| | - Xiaowu Chen
- Shanghai Ocean University, No.999 Huchenghuan Road, Nanhui New City, 201306, Shanghai, China
| | - Yangyang Jiang
- Fisheries Research Institute, Anhui Academy of Agricultural Sciences, No. 40 South Nongke Road, Luyang District, Hefei, 230031, Anhui, China
- Anhui Province Key Laboratory of Aquaculture & Stock Enhancement, No. 40 South Nongke Road, Luyang District, Hefei, 230031, Anhui, China
| | - Wei Jiang
- Fisheries Research Institute, Anhui Academy of Agricultural Sciences, No. 40 South Nongke Road, Luyang District, Hefei, 230031, Anhui, China
- Anhui Province Key Laboratory of Aquaculture & Stock Enhancement, No. 40 South Nongke Road, Luyang District, Hefei, 230031, Anhui, China
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12
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Lalor R, O'Neill S. Bovine κ-casein induces a hypo-responsive DC population which exhibit a reduced capacity to elicit T-cell responses. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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13
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In Vitro Evaluation of the Potential Use of Propolis as a Multitarget Therapeutic Product: Physicochemical Properties, Chemical Composition, and Immunomodulatory, Antibacterial, and Anticancer Properties. BIOMED RESEARCH INTERNATIONAL 2019; 2019:4836378. [PMID: 31915694 PMCID: PMC6930758 DOI: 10.1155/2019/4836378] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 11/25/2019] [Indexed: 12/13/2022]
Abstract
Propolis is a resin that honeybees produce by mixing saliva and beeswax with exudate gathered from botanical sources. The present in vitro study investigated the potential use of propolis as a multitarget therapeutic product and the physicochemical properties, chemical composition, and immunomodulatory, antioxidant, antibacterial, and anticancer properties of a propolis extract from the northern Morocco region (PNM). Pinocembrin, chrysin, and quercetin were the main phenolic compounds of PNM as measured in HPLC. The PNM showed significant inhibitory effects against all tested Gram-positive and Gram-negative strains and showed high antioxidant activities by scavenging free radicals with IC50 (DPPH = 0.02, ABTS = 0.04, and FRAP = 0.04 mg/ml). In addition, PNM induced a dose-dependent cytostatic effect in MCF-7, HCT, and THP-1 cell lines at noncytotoxic concentrations with IC50 values of 479.22, 108.88, and 50.54 μg/ml, respectively. The production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) was decreased in a dose-dependent manner in LPS-stimulated human peripheral blood mononuclear cells (PBMNCs), whereas the production of the anti-inflammatory interleukin-10 (IL-10) was increased in a dose-dependent manner reaching 15-fold compared to the levels measured in untreated PBMNCs. Overall, the results showed that the traditionally known multitarget therapeutic properties of the PNM seem to be mediated, at least in part, through cytostatic, antibacterial, and immunomodulatory effects.
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14
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Alqarni AM, Niwasabutra K, Sahlan M, Fearnley H, Fearnley J, Ferro VA, Watson DG. Propolis Exerts an Anti-Inflammatory Effect on PMA-Differentiated THP-1 Cells via Inhibition of Purine Nucleoside Phosphorylase. Metabolites 2019; 9:metabo9040075. [PMID: 30995826 PMCID: PMC6523283 DOI: 10.3390/metabo9040075] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/09/2019] [Accepted: 04/15/2019] [Indexed: 12/13/2022] Open
Abstract
Previous research has shown that propolis has immunomodulatory activity. Propolis extracts from different geographic origins were assessed for their anti-inflammatory activities by investigating their ability to alter the production of tumour necrosis factor-α (TNF-α) and the cytokines interleukin-1β (IL-1β), IL-6 and IL-10 in THP-1-derived macrophage cells co-stimulated with lipopolysaccharide (LPS). All the propolis extracts suppressed the TNF-α and IL-6 LPS-stimulated levels. Similar suppression effects were detected for IL-1β, but the release of this cytokine was synergised by propolis samples from Ghana and Indonesia when compared with LPS. Overall, the Cameroonian propolis extract (P-C) was the most active and this was evaluated for its effects on the metabolic profile of unstimulated macrophages or macrophages activated by LPS. The levels of 81 polar metabolites were identified by liquid chromatography (LC) coupled with mass spectrometry (MS) on a ZIC-pHILIC column. LPS altered the energy, amino acid and nucleotide metabolism in THP-1 cells, and interpretation of the metabolic pathways showed that P-C reversed some of the effects of LPS. Overall, the results showed that propolis extracts exert an anti-inflammatory effect by inhibition of pro-inflammatory cytokines and by metabolic reprogramming of LPS activity in macrophage cells, suggesting an immunomodulatory effect.
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Affiliation(s)
- Abdulmalik M Alqarni
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
- Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University (University of Dammam), Dammam 31441, Saudi Arabia.
| | - Kanidta Niwasabutra
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
| | - Muhamad Sahlan
- Faculty of Engineering, Universitas Indonesia Campus UI, Depok 16424, Indonesia.
| | - Hugo Fearnley
- Apiceutical Research Centre, 6 Hunter Street, Whitby, North Yorkshire YO21 3DA, UK.
| | - James Fearnley
- Apiceutical Research Centre, 6 Hunter Street, Whitby, North Yorkshire YO21 3DA, UK.
| | - Valerie A Ferro
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
| | - David G Watson
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0RE, UK.
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15
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Pinaud S, Portet A, Allienne JF, Belmudes L, Saint-Beat C, Arancibia N, Galinier R, Du Pasquier L, Duval D, Gourbal B. Molecular characterisation of immunological memory following homologous or heterologous challenges in the schistosomiasis vector snail, Biomphalaria glabrata. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2019; 92:238-252. [PMID: 30529491 DOI: 10.1016/j.dci.2018.12.001] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 11/30/2018] [Accepted: 12/01/2018] [Indexed: 05/16/2023]
Abstract
Invertebrate immune response may be primed by a current infection in a sustained manner, leading to the failure of a secondary infection with the same pathogen. The present study focuses on the Schistosomiasis vector snail Biomphalaria glabrata, in which a specific genotype-dependent immunological memory was demonstrated as a shift from a cellular to a humoral immune response. Herein, we investigate the complex molecular bases associated with this genotype-dependant immunological memory response. We demonstrate that Biomphalaria regulates a polymorphic set of immune recognition molecules and immune effector repertoires to respond to different strains of Schistosoma parasites. These results suggest a combinatorial usage of pathogen recognition receptors (PRRs) that distinguish different strains of parasites during the acquisition of immunological memory. Immunizations also show that snails become resistant after exposure to parasite extracts. Hemolymph transfer and a label-free proteomic analysis proved that circulating hemolymph compounds can be produced and released to more efficiently kill the newly encountered parasite of the same genetic lineage.
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Affiliation(s)
- Silvain Pinaud
- Univ. Perpignan Via Domitia, Interactions Hôtes Pathogènes Environments UMR 5244, CNRS, IFREMER, Univ. Montpellier, F-66860, Perpignan, France.
| | - Anaïs Portet
- Univ. Perpignan Via Domitia, Interactions Hôtes Pathogènes Environments UMR 5244, CNRS, IFREMER, Univ. Montpellier, F-66860, Perpignan, France.
| | - Jean-François Allienne
- Univ. Perpignan Via Domitia, Interactions Hôtes Pathogènes Environments UMR 5244, CNRS, IFREMER, Univ. Montpellier, F-66860, Perpignan, France.
| | - Lucid Belmudes
- CEA-Grenoble, Exploring the Dynamics of Proteomes (EDyP), F-38054, Grenoble, Cedex 9, France.
| | - Cécile Saint-Beat
- Univ. Perpignan Via Domitia, Interactions Hôtes Pathogènes Environments UMR 5244, CNRS, IFREMER, Univ. Montpellier, F-66860, Perpignan, France.
| | - Nathalie Arancibia
- Univ. Perpignan Via Domitia, Interactions Hôtes Pathogènes Environments UMR 5244, CNRS, IFREMER, Univ. Montpellier, F-66860, Perpignan, France.
| | - Richard Galinier
- Univ. Perpignan Via Domitia, Interactions Hôtes Pathogènes Environments UMR 5244, CNRS, IFREMER, Univ. Montpellier, F-66860, Perpignan, France.
| | - Louis Du Pasquier
- University of Basel, Zoological Institute, Department of Zoology and Evolutionary Biology Vesalgasse 1, Basel, Switzerland.
| | - David Duval
- Univ. Perpignan Via Domitia, Interactions Hôtes Pathogènes Environments UMR 5244, CNRS, IFREMER, Univ. Montpellier, F-66860, Perpignan, France.
| | - Benjamin Gourbal
- Univ. Perpignan Via Domitia, Interactions Hôtes Pathogènes Environments UMR 5244, CNRS, IFREMER, Univ. Montpellier, F-66860, Perpignan, France.
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16
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Cai J, Wang H, Wang D, Li Y. Improving Cancer Vaccine Efficiency by Nanomedicine. ACTA ACUST UNITED AC 2019; 3:e1800287. [PMID: 32627400 DOI: 10.1002/adbi.201800287] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 12/11/2018] [Indexed: 12/21/2022]
Abstract
Cancer vaccines, which have been widely investigated in the past few decades, are one of the most attractive strategies for cancer immunotherapy. Through the precise delivery of antigens and adjuvants to lymphoid organs or lymphocytes via nanotechnology, innate and adaptive immunity can be boosted to prevent the growth and relapse of malignant tumors. Indeed, nanomedicine offers great opportunities to improve the efficiency of vaccines. Various functional platforms are used to deliver small molecules, peptides, nucleic acids, and even whole cell antigens to the target area of interest, achieving enhanced antitumor immunity and durable therapeutic benefits. Herein, the recent progress in cancer vaccines based on nanotechnology is summarized. Novel platforms used for delivering tumor antigens, promoting adjuvant functions, and combining other therapeutic strategies are discussed. Moreover, possible striving directions and major challenges of nanomedicine for vaccination are also reviewed.
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Affiliation(s)
- Junyu Cai
- State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, 201203, Shanghai, China.,China State Institute of Pharmaceutical Industry, 285 Gebaini Road, 201203, Shanghai, China
| | - Hao Wang
- China State Institute of Pharmaceutical Industry, 285 Gebaini Road, 201203, Shanghai, China
| | - Dangge Wang
- State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, 201203, Shanghai, China
| | - Yaping Li
- State Key Laboratory of Drug Research and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, 201203, Shanghai, China
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17
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Aloor JJ, Azzam KM, Guardiola JJ, Gowdy KM, Madenspacher JH, Gabor KA, Mueller GA, Lin WC, Lowe JM, Gruzdev A, Henderson MW, Draper DW, Merrick BA, Fessler MB. Leucine-rich repeats and calponin homology containing 4 (Lrch4) regulates the innate immune response. J Biol Chem 2018; 294:1997-2008. [PMID: 30523158 DOI: 10.1074/jbc.ra118.004300] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 11/27/2018] [Indexed: 01/07/2023] Open
Abstract
Toll-like receptors (TLRs) are pathogen-recognition receptors that trigger the innate immune response. Recent reports have identified accessory proteins that provide essential support to TLR function through ligand delivery and receptor trafficking. Herein, we introduce leucine-rich repeats (LRRs) and calponin homology containing 4 (Lrch4) as a novel TLR accessory protein. Lrch4 is a membrane protein with nine LRRs in its predicted ectodomain. It is widely expressed across murine tissues and has two expression variants that are both regulated by lipopolysaccharide (LPS). Predictive modeling indicates that Lrch4 LRRs conform to the horseshoe-shaped structure typical of LRRs in pathogen-recognition receptors and that the best structural match in the protein database is to the variable lymphocyte receptor of the jawless vertebrate hagfish. Silencing Lrch4 attenuates cytokine induction by LPS and multiple other TLR ligands and dampens the in vivo innate immune response. Lrch4 promotes proper docking of LPS in lipid raft membrane microdomains. We provide evidence that this is through regulation of lipid rafts as Lrch4 silencing reduces cell surface gangliosides, a metric of raft abundance, as well as expression and surface display of CD14, a raft-resident LPS co-receptor. Taken together, we identify Lrch4 as a broad-spanning regulator of the innate immune response and a potential molecular target in inflammatory disease.
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Affiliation(s)
- Jim J Aloor
- From the Immunity, Inflammation and Disease Laboratory
| | | | | | | | | | | | | | - Wan-Chi Lin
- From the Immunity, Inflammation and Disease Laboratory
| | - Julie M Lowe
- From the Immunity, Inflammation and Disease Laboratory
| | | | | | | | - B Alex Merrick
- National Toxicology Program, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709
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18
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Sabetian S, Nezafat N, Dorosti H, Zarei M, Ghasemi Y. Exploring dengue proteome to design an effective epitope-based vaccine against dengue virus. J Biomol Struct Dyn 2018; 37:2546-2563. [PMID: 30035699 DOI: 10.1080/07391102.2018.1491890] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Dengue, a mosquito-borne disease, is caused by four known dengue serotypes. This infection causes a range of symptoms from a mild fever to a sever homorganic fever and death. It is a serious public health problem in subtropical and tropical countries. There is no specific vaccine currently available for clinical use and study on this issue is ongoing. In this study, bioinformatics approaches were used to predict antigenic, immunogenic, non-allergenic, and conserved B and T-cell epitopes as promising targets to design an effective peptide-based vaccine against dengue virus. Molecular docking analysis indicated the deep binding of the identified epitopes in the binding groove of the most popular human MHC I allele (human leukocyte antigens [HLA] A*0201). The final vaccine construct was created by conjugating the B and T-cell identified epitopes using proper linkers and adding an appropriate adjuvant at the N-terminal. The characteristics of the new subunit vaccine demonstrated that the epitope-based vaccine was antigenic, non-toxic, stable, and soluble. Other physicochemical properties of the new designed construct including isoelectric point value, aliphatic index, and grand average of hydropathicity were biologically considerable. Molecular docking of the engineered vaccine with Toll-like receptor 2 (TLR2) model revealed the hydrophobic interaction between the adjuvant and the ligand binding regions in the hydrophobic channel of TLR2. The study results indicated the high potential capability of the new multi-epitope vaccine to induce cellular and humoral immune responses against the dengue virus. Further experimental tests are required to investigate the immune protection capacity of the new vaccine construct in animal models. Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Soudabeh Sabetian
- a Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences , Shiraz , Iran
| | - Navid Nezafat
- a Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences , Shiraz , Iran.,b Department of Pharmaceutical Biotechnology, School of Pharmacy , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Hesam Dorosti
- a Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences , Shiraz , Iran.,b Department of Pharmaceutical Biotechnology, School of Pharmacy , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Mahboubeh Zarei
- a Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences , Shiraz , Iran.,b Department of Pharmaceutical Biotechnology, School of Pharmacy , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Younes Ghasemi
- a Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences , Shiraz , Iran.,b Department of Pharmaceutical Biotechnology, School of Pharmacy , Shiraz University of Medical Sciences , Shiraz , Iran.,c Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies , Shiraz University of Medical Sciences , Shiraz , Iran.,d Biotechnology Research Center, Shiraz University of Medical Sciences , Shiraz , Iran
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19
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Effects of cigarette smoke on immunity, neuroinflammation and multiple sclerosis. J Neuroimmunol 2018; 329:24-34. [PMID: 30361070 DOI: 10.1016/j.jneuroim.2018.10.004] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 09/30/2018] [Accepted: 10/05/2018] [Indexed: 12/18/2022]
Abstract
Cigarette smoking is the most prominent significant cause of death and morbidity. It is recognised as a risk factor for a number of immune mediated, inflammatory diseases including multiple sclerosis (MS). Here, we review the complex immunological effects of smoking on the immune system, which include enhancement of inflammatory responses with a parallel reduction of some immune defences, resulting in an increased susceptibility to infection and a persistent proinflammatory environment. We discuss the effect of smoking on the susceptibility, clinical course, disability, and mortality in MS, the likely benefits of smoking cessation, and the specific immunological effects of smoking in MS. In conclusion, smoking is an important environmental risk factor for MS occurrence and outcome, and it acts in significant part through immunological mechanisms.
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20
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Che CY, Yuan KL, Zhao GQ, Li C, Lin J, Zhu GQ, Liu M. Regulation of lipoxygenase-1 and Dectin-1 on interleukin-10 in mouse Aspergillus fumigatus keratitis. Int J Ophthalmol 2018; 11:905-909. [PMID: 29977799 DOI: 10.18240/ijo.2018.06.02] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 02/28/2018] [Indexed: 01/24/2023] Open
Abstract
AIM To investigate the regulation of lipoxygenase (LOX)-1 and Dectin-1 on interleukin-10 (IL-10) production in mice with Aspergillus fumigatus (A. fumigatus) keratitis. METHODS The corneas of C57BL/6 mice were pretreated with LOX-1 inhibitor Poly(I) or Dectin-1 siRNA separately before the infection of A. fumigatus. Polymerase chain reaction (PCR) and Western blot were used to detect the expression of IL-10. RESULTS The mRNA and protein expressions of IL-10 were significantly increased in mice with A. fumigatus keratitis. Compared with the group pretreated with sterile water before infection, Poly(I) pretreatment suppressed IL-10 expression significantly. Compared with the group pretreated with scrambled siRNA before infection, Dectin-1 siRNA pretreatment significantly reduced IL-10 expression in response to A. fumigatus infection. CONCLUSION LOX-1 and Dectin-1 regulate IL-10 production in mouse A. fumigatus keratitis.
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Affiliation(s)
- Cheng-Ye Che
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Ke-Lan Yuan
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Gui-Qiu Zhao
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Cui Li
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Jing Lin
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Guo-Qiang Zhu
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Min Liu
- Department of Ophthalmology, the Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
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Sasaki Y, Iwai K. Crucial Role of Linear Ubiquitin Chain Assembly Complex-Mediated Inhibition of Programmed Cell Death in TLR4-Mediated B Cell Responses and B1b Cell Development. THE JOURNAL OF IMMUNOLOGY 2018; 200:3438-3449. [PMID: 29654209 DOI: 10.4049/jimmunol.1701526] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 03/21/2018] [Indexed: 01/27/2023]
Abstract
Linear ubiquitin chain assembly complex (LUBAC)-mediated linear polyubiquitin plays crucial roles in thymus-dependent and -independent type II Ab responses and B1 cell development. In this study, we analyzed the role of LUBAC in TLR-mediated B cell responses. A mouse strain in which LUBAC activity was ablated specifically in B cells (B-HOIPΔlinear mice) showed defective Ab responses to a type I thymus-independent Ag, NP-LPS. B cells from B-HOIPΔlinear mice (HOIPΔlinear B cells) underwent massive cell death in response to stimulation of TLR4, but not TLR9. TLR4 stimulation induced caspase-8 activation in HOIPΔlinear B cells; this phenomenon, as well as TLR4-induced cell death, was suppressed by ablation of TRIF, a signal inducer specific for TLR4. In addition, LPS-induced survival, proliferation, and differentiation into Ab-producing cells of HOIPΔlinear B cells were substantially restored by inhibition of caspases together with RIP3 deletion, but not by RIP3 deletion alone, suggesting that LPS stimulation kills HOIPΔlinear B cells by apoptosis elicited via the TRIF pathway. Further examination of the roles of cell death pathways in B-HOIPΔlinear mice revealed that deletion of RIP3 increased the number of B1 cells, particularly B1b cells, in B-HOIPΔlinear mice, indicating that B1b cell homeostasis is controlled via LUBAC-mediated suppression of necroptosis. Taken together, the data show that LUBAC regulates TLR4-mediated B cell responses and B1b cell development and/or maintenance by inhibiting programmed cell death.
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Affiliation(s)
- Yoshiteru Sasaki
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Kazuhiro Iwai
- Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
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22
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Sahan AZ, Hazra TK, Das S. The Pivotal Role of DNA Repair in Infection Mediated-Inflammation and Cancer. Front Microbiol 2018; 9:663. [PMID: 29696001 PMCID: PMC5904280 DOI: 10.3389/fmicb.2018.00663] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Accepted: 03/21/2018] [Indexed: 12/19/2022] Open
Abstract
Pathogenic and commensal microbes induce various levels of inflammation and metabolic disease in the host. Inflammation caused by infection leads to increased production of reactive oxygen species (ROS) and subsequent oxidative DNA damage. These in turn cause further inflammation and exacerbation of DNA damage, and pose a risk for cancer development. Helicobacter pylori-mediated inflammation has been implicated in gastric cancer in many previously established studies, and Fusobacterium nucleatum presence has been observed with greater intensity in colorectal cancer patients. Despite ambiguity in the exact mechanism, infection-mediated inflammation may have a link to cancer development through an accumulation of potentially mutagenic DNA damage in surrounding cells. The multiple DNA repair pathways such as base excision, nucleotide excision, and mismatch repair that are employed by cells are vital in the abatement of accumulated mutations that can lead to carcinogenesis. For this reason, understanding the role of DNA repair as an important cellular mechanism in combatting the development of cancer will be essential to characterizing the effect of infection on DNA repair proteins and to identifying early cancer biomarkers that may be targeted for cancer therapies and treatments.
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Affiliation(s)
- Ayse Z Sahan
- Department of Pathology, University of California, San Diego, San Diego, CA, United States
| | - Tapas K Hazra
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, United States
| | - Soumita Das
- Department of Pathology, University of California, San Diego, San Diego, CA, United States
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Adachi K, Tamada K. Microbial biomarkers for immune checkpoint blockade therapy against cancer. J Gastroenterol 2018; 53:999-1005. [PMID: 30003334 PMCID: PMC6132931 DOI: 10.1007/s00535-018-1492-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 06/29/2018] [Indexed: 02/04/2023]
Abstract
Three major standard treatments, i.e., surgery, chemotherapy, and radiotherapy, were traditionally applied to the treatment of cancer and saved many patients. Meanwhile, clinical studies as well as basic research of immunotherapy are being actively conducted for intractable or advanced malignancies that cannot be cured by the conventional standard treatments. Remarkable therapeutic efficacies have been recently reported in clinical trials on some cancer types, and immunotherapy is now being recognized as the "fourth" standard therapy against cancer. In particular, immune checkpoint inhibitor therapy (ICI) has demonstrated the effectiveness of immunotherapy through large-scale randomized clinical trials, leading to the paradigm-shift in cancer treatment. Immune checkpoint molecules transduce co-inhibitory signals to immunocompetent cells including T cells, and crucially contribute to the formation of an immunosuppressive microenvironment in tumor tissues, which intrinsically confers the treatment resistance. Programmed death-1 (PD-1, CD279) is one of the typical immune checkpoint molecules. Anti-tumor therapies targeting PD-1 and its ligands had been developed and approved in many countries, and various studies utilizing clinical specimens are currently progressing. In this review, we provide an overview of the biomarkers based on the analysis of enteric microbiota that correlate with the clinical efficacy/inefficacy of PD-1-based therapy.
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Affiliation(s)
- Keishi Adachi
- 0000 0001 0660 7960grid.268397.1Department of Immunology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505 Japan
| | - Koji Tamada
- 0000 0001 0660 7960grid.268397.1Department of Immunology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505 Japan
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Lee B, Ko E, Lee J, Jo Y, Hwang H, Goh TS, Joo M, Hong C. Soluble common gamma chain exacerbates COPD progress through the regulation of inflammatory T cell response in mice. Int J Chron Obstruct Pulmon Dis 2017; 12:817-827. [PMID: 28331303 PMCID: PMC5352154 DOI: 10.2147/copd.s123405] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Cigarette smoking (CS) is a major cause of considerable morbidity and mortality by inducing lung cancer and COPD. COPD, a smoking-related disorder, is closely related to the alteration of immune system and inflammatory processes that are specifically mediated by T cells. Soluble common gamma chain (sγc) has recently been identified as a critical regulator of the development and differentiation of T cells. We examined the effects of sγc in a cigarette smoke extract (CSE) mouse model. The sγc level in CSE mice serum is significantly downregulated, and the cellularity of lymph node (LN) is systemically reduced in the CSE group. Overexpression of sγc enhances the cellularity and IFNγ production of CD8 T cells in LN and also enhances Th1 and Th17 differentiation of CD4 T cells in the respiratory tract. Mechanistically, the downregulation of sγc expression mediated by CSE is required to prevent excessive inflammatory T cell responses. Therefore, our data suggest that sγc may be one of the target molecules for the control of immunopathogenic progresses in COPD.
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Affiliation(s)
- Byunghyuk Lee
- Department of Anatomy and Cell Biology, Pusan National University School of Medicine
| | - Eunhee Ko
- Department of Anatomy and Cell Biology, Pusan National University School of Medicine
| | - Jiyeon Lee
- Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan
| | - Yuna Jo
- Department of Anatomy and Cell Biology, Pusan National University School of Medicine
| | - Hyunju Hwang
- Department of Anatomy and Cell Biology, Pusan National University School of Medicine
| | - Tae Sik Goh
- Department of Anatomy and Cell Biology, Pusan National University School of Medicine; Department of Orthopedic Surgery, Medical Research Institute, Pusan National University School of Medicine, Busan, South Korea
| | - Myungsoo Joo
- Division of Applied Medicine, School of Korean Medicine, Pusan National University, Yangsan
| | - Changwan Hong
- Department of Anatomy and Cell Biology, Pusan National University School of Medicine
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25
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Czaja AJ. Factoring the intestinal microbiome into the pathogenesis of autoimmune hepatitis. World J Gastroenterol 2016; 22:9257-9278. [PMID: 27895415 PMCID: PMC5107691 DOI: 10.3748/wjg.v22.i42.9257] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Revised: 10/07/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023] Open
Abstract
The intestinal microbiome is a reservoir of microbial antigens and activated immune cells. The aims of this review were to describe the role of the intestinal microbiome in generating innate and adaptive immune responses, indicate how these responses contribute to the development of systemic immune-mediated diseases, and encourage investigations that improve the understanding and management of autoimmune hepatitis. Alterations in the composition of the intestinal microflora (dysbiosis) can disrupt intestinal and systemic immune tolerances for commensal bacteria. Toll-like receptors within the intestine can recognize microbe-associated molecular patterns and shape subsets of T helper lymphocytes that may cross-react with host antigens (molecular mimicry). Activated gut-derived lymphocytes can migrate to lymph nodes, and gut-derived microbial antigens can translocate to extra-intestinal sites. Inflammasomes can form within hepatocytes and hepatic stellate cells, and they can drive the pro-inflammatory, immune-mediated, and fibrotic responses. Diet, designer probiotics, vitamin supplements, re-colonization methods, antibiotics, drugs that decrease intestinal permeability, and molecular interventions that block signaling pathways may emerge as adjunctive regimens that complement conventional immunosuppressive management. In conclusion, investigations of the intestinal microbiome are warranted in autoimmune hepatitis and promise to clarify pathogenic mechanisms and suggest alternative management strategies.
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A structure-function approach to optimizing TLR4 ligands for human vaccines. Clin Transl Immunology 2016; 5:e108. [PMID: 27990284 PMCID: PMC5133366 DOI: 10.1038/cti.2016.63] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 09/15/2016] [Accepted: 09/15/2016] [Indexed: 12/31/2022] Open
Abstract
Adjuvants are combined with vaccine antigens to enhance and modify immune responses, and have historically been primarily crude, undefined entities. Introducing toll-like receptor (TLR) ligands has led to a new generation of adjuvants, with TLR4 ligands being the most extensively used in human vaccines. The TLR4 crystal structures demonstrate extensive contact with their ligands and provide clues as to how they discriminate a broad array of molecules and activate or attenuate innate, as well as adaptive, responses resulting from these interactions. Leveraging this discerning ability, we made subtle chemical alterations to the structure of a synthetic monophosphoryl lipid-A molecule to produce SLA, a designer TLR4 ligand that had a number of desirable adjuvant effects. The SLA molecule stimulated human TLR4 and induced Th1 biasing cytokines and chemokines. On human cells, the activity of SLA plateaued at lower concentrations than the lipid A comparator, and induced cytokine profiles distinct from other known TLR4 agonists, indicating the potential for superior adjuvant performance. SLA was formulated in an oil-in-water emulsion, producing an adjuvant that elicited potent Th1-biased adaptive responses. This was verified using a recombinant Leishmania vaccine antigen, first in mice, then in a clinical study in which the antigen-specific Th1-biased responses observed in mice were recapitulated in humans. These results demonstrated that using structure-based approaches one can predictably design and produce modern adjuvant formulations for safe and effective human vaccines.
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Sadakane K, Ichinose T, Nishikawa M, Takano H, Shibamoto T. Co-exposure to zymosan A and heat-inactivated Asian sand dust exacerbates ovalbumin-induced murine lung eosinophilia. Allergy Asthma Clin Immunol 2016; 12:48. [PMID: 27766108 PMCID: PMC5057426 DOI: 10.1186/s13223-016-0153-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 09/20/2016] [Indexed: 01/19/2023] Open
Abstract
Background Epidemiological studies have implicated Asian sand dust (ASD) in the increased prevalence of respiratory disorders, including asthma. It has been observed that fungal elements such as β-glucan can be adsorbed onto ASD. In the present study, the exacerbating effect of the combined exposure to zymosan A (ZymA) containing yeast β-glucan and heat-inactivated ASD on ovalbumin (OVA)-induced murine lung eosinophilia was investigated. Methods BALB/c mice were repeatedly instilled intratracheally with one of eight immunogenic formulations consisting of various combinations of (1) ZymA, (2) ASD that was briefly heated to remove organic substances (H-ASD), and (3) OVA in normal saline, or each of the above alone. Pathologic changes, cytological alterations in bronchoalveolar lavage fluid (BALF), changes in inflammatory cytokines and chemokines in BALF, and OVA-specific IgE and IgG1 antibodies in serum were investigated. Results Exposure to ZymA with or without OVA had no effect on most indicators of lung inflammation. Exposure to H-ASD with OVA increased the recruitment of inflammatory cells to the lungs and the serum levels of OVA-specific IgE and IgG1. The combination OVA + ZymA + H-ASD induced a marked recruitment of eosinophils and upregulation of T helper 2 (Th2) cytokines (interleukin [IL]-4 and IL-13), IL-6, eotaxin/CCL11, and monocyte chemotactic protein (MCP)-3/CCL7 in BALF and OVA-specific IgE in serum. This treatment also induced the most severe pathological changes in the lungs of mice. ZymA was found to boost the effects of H-ASD, thereby exacerbating the OVA-induced allergic inflammation, even though ZymA alone did not have such effect. Conclusions The results suggest that fungal elements such as β-1,3-glucan aggravate the allergic inflammation caused by ASD. Our findings may facilitate prophylaxis of some allergic diseases in Asia.
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Affiliation(s)
- Kaori Sadakane
- Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita, 870-1201 Japan
| | - Takamichi Ichinose
- Department of Health Sciences, Oita University of Nursing and Health Sciences, Oita, 870-1201 Japan
| | - Masataka Nishikawa
- Environmental Chemistry Division, National Institute for Environmental Studies, Tsukuba, Ibaraki 305-8506 Japan
| | - Hirohisa Takano
- Environmental Health Division, Department of Environmental Engineering, Graduate School of Engineering, Kyoto University, Kyoto, 615-8530 Japan
| | - Takayuki Shibamoto
- Department of Environmental Toxicology, University of California, Davis, CA 95616 USA
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Sun H, Zhang J, Chen F, Chen X, Zhou Z, Wang H. Activation of RAW264.7 macrophages by the polysaccharide from the roots of Actinidia eriantha and its molecular mechanisms. Carbohydr Polym 2015; 121:388-402. [DOI: 10.1016/j.carbpol.2014.12.023] [Citation(s) in RCA: 161] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 10/08/2014] [Accepted: 12/03/2014] [Indexed: 12/25/2022]
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Giraldo DM, Hernandez JC, Urcuqui Inchima S. Impact of in vitro Costimulation with TLR2, TLR4 and TLR9 Agonists and HIV-1 on Antigen-Presenting Cell Activation. Intervirology 2015; 58:122-9. [DOI: 10.1159/000371765] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 12/26/2014] [Indexed: 11/19/2022] Open
Abstract
Objective: HIV-1 infects several immune cells including dendritic cells (DCs) and monocytes, which contributes in both to dissemination of HIV-1 infection and induction of antiviral immunity. These cells produce high amounts of type I IFN and proinflammatory cytokines upon Toll-like receptor (TLR) stimulation. During HIV-1 infection, an altered production of proinflammatory cytokines has been reported. However, the mechanisms underlying cytokine modulation have not been well described. Here, we evaluated the production of proinflammatory cytokines and activation of myeloid and plasmacytoid DCs and monocytes costimulated in vitro with TLR agonists and HIV-1. Methods: Changes in cytokine expression by real-time PCR and activation of DCs and monocytes by flow cytometry were evaluated after costimulation with HIV-1 and TLR agonists. Results: We observed an upregulation of TNF-α expression after TLR4 stimulation, but a downregulation of IL-6 when TLR2/TLR9 were stimulated. Interestingly, the expression of CD80 and CD86 costimulatory molecules in monocytes and DCs were significantly increased in cells challenged with HIV-1 and TLR2/TLR4/TLR9 agonists. Conclusion: This regulation of TNF-α and IL-6 production and changes in the expression of costimulatory molecules can be critical in the context of HIV-1 infection, by favoring the antigen-presenting cell activation through the stimulation of TLRs.
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Possible involvement of Toll-like receptor 7 in the development of type 1 autoimmune pancreatitis. J Gastroenterol 2015; 50:435-44. [PMID: 25005350 DOI: 10.1007/s00535-014-0977-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Accepted: 06/14/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND High serum immunoglobulin G4 (IgG4) levels and IgG4-positive plasma cell infiltration are characteristic of type 1 autoimmune pancreatitis (AIP). It is unclear whether innate immunity is a cause of type 1 AIP; the possible involvement of microbial infection has been suggested in its pathogenesis. To clarify the pathogenesis of type 1 AIP, we investigated Toll-like receptors (TLRs) in type 1 AIP patients. METHODS We studied nine cases of type 1 AIP with ten cases of alcoholic chronic pancreatitis (ACP) and three of the samples from non-tumorous lesion of neuroendocrine tumor (NET) as control subjects. We counted the number of TLR1-11-positive cells immunohistochemically stained with anti-TLR1-11 antibodies. To identify TLR-positive cells in pancreata from type 1 AIP patients, we used a double-immunofluorescence method and counted the numbers of identifiable CD68-, CD163-, CD123-, and CD20-positive cells. RESULTS In type 1 AIP, TLR7 (8.815 ± 1.755), TLR8 (3.852 ± 1.489), and TLR10 (3.852 ± 0.921) were highly expressed. Only the ratio of TLR7 per monocyte was significantly higher in type 1 AIP (0.053 ± 0.012) than in ACP (0.007 ± 0.004; p < 0.01) and non-tumorous lesion of NET (0.000 ± 0.000; p < 0.01). In type 1 AIP, the CD163 to TLR7 ratio (0.789 ± 0.031) was significantly higher both than that of CD123 to TLR7 ratio (0.034 ± 0.006; p < 0.001) and CD20 to TLR7 ratio (0.029 ± 0.010; p < 0.001). CONCLUSIONS TLR7 might be key pattern-recognition receptors involved in the development of type 1 AIP.
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Toll-like receptor mediated modulation of T cell response by commensal intestinal microbiota as a trigger for autoimmune arthritis. J Immunol Res 2015; 2015:527696. [PMID: 25802876 PMCID: PMC4352938 DOI: 10.1155/2015/527696] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 09/23/2014] [Indexed: 12/17/2022] Open
Abstract
In autoimmune diseases, a disturbance of the balance between T helper 17 (Th17) and regulatory T cells (Tregs) is often observed. This disturbed balance is also the case in rheumatoid arthritis (RA). Genetic predisposition to RA confers the presence of several polymorphisms mainly regulating activation of T lymphocytes. However, the presence of susceptibility factors is neither necessary nor sufficient to explain the disease development, emphasizing the importance of environmental factors. Multiple studies have shown that commensal gut microbiota is of great influence on immune homeostasis and can trigger the development of autoimmune diseases by favoring induction of Th17 cells over Tregs. However the mechanism by which intestinal microbiota influences the Th cell balance is not completely understood. Here we review the current evidence supporting the involvement of commensal intestinal microbiota in rheumatoid arthritis, along with a potential role of Toll-like receptors (TLRs) in modulating the relevant Th cell responses to trigger autoimmunity. A better understanding of TLR triggering by intestinal microbiota and subsequent T cell activation might offer new perspectives for manipulating the T cell response in RA patients and may lead to the discovery of new therapeutic targets or even preventive measures.
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Karki K, Pande D, Negi R, Khanna S, Khanna RS, Khanna HD. Linking Toll-Like Receptors Signaling to Oxidative Damage: Potential Role in Cancer Therapy. FREE RADICALS IN HUMAN HEALTH AND DISEASE 2015:323-334. [DOI: 10.1007/978-81-322-2035-0_20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Wang X, Zhao YR, Liu HL, Ma XH, Zhang Y. In vitro immunomodulatory activity of interferon alpha on toll-like receptor 9 signaling pathway in chronic hepatitis B. J Interferon Cytokine Res 2014; 35:385-91. [PMID: 25535670 DOI: 10.1089/jir.2014.0182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Interferon alpha (IFN-α) is registered for chronic hepatitis B (CHB) treatment. However, the antiviral mechanism of IFN-α and the biological function of many IFN-α responsive genes have not been fully elucidated. We investigated to determine the regulative effect of IFN-α on toll-like receptor (TLR) 9 signaling in peripheral blood mononuclear cells (PBMCs) from CHB patients in vitro. We examined the changes of expression and function of TLR9 signaling pathway in the PBMCs with different treatment methods and investigated the synergism of IFN-α and TLR9 ligand on antiviral cytokine secretions in vitro. The data showed that, for the TLR9 signaling pathway, IFN-α not only augmented the expressions of TLR9 signal transduction molecules but also activated the TLR9 signal function. This study has clearly demonstrated that the TLR9 ligand could stimulate PBMCs that have been pretreated with IFN-α. Furthermore, the quantity of antiviral cytokines secreted by the pretreated PBMCs was greater than those without pretreatment. The interaction between IFN-α and TLR9 ligand appears to be synergistic. Data revealed IFN-α could influence TLR9 signaling transduction and synergistically improve the immune efficacy of TLR9 ligand against CHB. The present study suggests a potential novel mechanism for the antiviral activity against hepatitis B virus and a new individualized antiviral strategy.
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Affiliation(s)
- Xin Wang
- 1 Department of Infectious Diseases, The First Affiliated Hospital of Medical College of Xi'an Jiaotong University , Xi'an, P.R. China
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Quayle K, Coy C, Standish L, Lu H. The TLR2 agonist in polysaccharide-K is a structurally distinct lipid which acts synergistically with the protein-bound β-glucan. J Nat Med 2014; 69:198-208. [PMID: 25510899 DOI: 10.1007/s11418-014-0879-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Accepted: 11/19/2014] [Indexed: 01/21/2023]
Abstract
Protein-bound polysaccharide-K (Krestin; PSK) is a hot-water extract of Trametes versicolor with immune stimulatory activity. It has been used for the past 30 years and has demonstrated anti-tumor efficacy in multiple types of cancer. The ability of PSK to activate dendritic cells and T cells is dependent on its ability to stimulate Toll-like receptor 2 (TLR2), yet it remains unknown which structural component within PSK activates TLR2. The purpose of this study was to identify the TLR2 agonist within PSK and understand its role in the overall mechanism of PSK's immunogenic activity. TLR2 activity was eliminated by treatment with lipoprotein lipase but not by trypsin or lyticase. Rapid centrifugation of PSK can separate the fraction with TLR2 agonist activity from the soluble β-glucan fraction. To study the potential interaction between the β-glucan component and the lipid component, we labeled the soluble β-glucan with fluorescein. Uptake of the labeled β-glucan by J774A macrophages and JAWSII dendritic cells was inhibited by anti-Dectin-1 antibody but not by anti-TLR2 antibody, confirming that Dectin-1 is the receptor for β-glucan. Interestingly, pre-treatment of JAWSII cells with the TLR2-active lipid fraction significantly enhanced the uptake of the soluble β-glucan, indicating the synergy between the TLR2 agonist component and the β-glucan component. Altogether, these results present evidence that PSK has two active components-the well-characterized protein-bound β-glucan and a previously unreported lipid-which work synergistically via the Dectin-1 and TLR2 receptors.
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Affiliation(s)
- Kenneth Quayle
- Tumor Vaccine Group, Department of Medicine, University of Washington, 850 Republican Street, Seattle, WA, 98109, USA,
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35
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Fontes FL, Pinheiro DML, Oliveira AHSD, Oliveira RKDM, Lajus TBP, Agnez-Lima LF. Role of DNA repair in host immune response and inflammation. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2014; 763:246-57. [PMID: 25795123 DOI: 10.1016/j.mrrev.2014.11.004] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 11/06/2014] [Accepted: 11/07/2014] [Indexed: 12/28/2022]
Abstract
In recent years, the understanding of how DNA repair contributes to the development of innate and acquired immunity has emerged. The DNA damage incurred during the inflammatory response triggers the activation of DNA repair pathways, which are required for host-cell survival. Here, we reviewed current understanding of the mechanism by which DNA repair contributes to protection against the oxidized DNA damage generated during infectious and inflammatory diseases and its involvement in innate and adaptive immunity. We discussed the functional role of DNA repair enzymes in the immune activation and the relevance of these processes to: transcriptional regulation of cytokines and other genes involved in the inflammatory response; V(D)J recombination; class-switch recombination (CSR); and somatic hypermutation (SHM). These three last processes of DNA damage repair are required for effective humoral adaptive immunity, creating genetic diversity in developing T and B cells. Furthermore, viral replication is also dependent on host DNA repair mechanisms. Therefore, the elucidation of the pathways of DNA damage and its repair that activate innate and adaptive immunity will be important for a better understanding of the immune and inflammatory disorders and developing new therapeutic interventions for treatment of these diseases and for improving their outcome.
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Affiliation(s)
- Fabrícia Lima Fontes
- Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, RN, Brazil.
| | - Daniele Maria Lopes Pinheiro
- Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, RN, Brazil.
| | - Ana Helena Sales de Oliveira
- Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, RN, Brazil.
| | | | - Tirzah Braz Petta Lajus
- Departamento de Biologia Celular e Genética, Universidade Federal do Rio Grande do Norte, UFRN, Natal, RN, Brazil; Liga Contra o Cancer, Natal, RN, Brazil.
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Manoharan I, Hong Y, Suryawanshi A, Angus-Hill ML, Sun Z, Mellor AL, Munn DH, Manicassamy S. TLR2-dependent activation of β-catenin pathway in dendritic cells induces regulatory responses and attenuates autoimmune inflammation. THE JOURNAL OF IMMUNOLOGY 2014; 193:4203-13. [PMID: 25210120 DOI: 10.4049/jimmunol.1400614] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Dendritic cells (DCs) sense microbes via multiple innate receptors. Signals from different innate receptors are coordinated and integrated by DCs to generate specific innate and adaptive immune responses against pathogens. Previously, we have shown that two pathogen recognition receptors, TLR2 and dectin-1, which recognize the same microbial stimulus (zymosan) on DCs, induce mutually antagonistic regulatory or inflammatory responses, respectively. How diametric signals from these two receptors are coordinated in DCs to regulate or incite immunity is not known. In this study, we show that TLR2 signaling via AKT activates the β-catenin/T cell factor 4 pathway in DCs and programs them to drive T regulatory cell differentiation. Activation of β-catenin/T cell factor 4 was critical to induce regulatory molecules IL-10 (Il-10) and vitamin A metabolizing enzyme retinaldehyde dehydrogenase 2 (Aldh1a2) and to suppress proinflammatory cytokines. Deletion of β-catenin in DCs programmed them to drive Th17/Th1 cell differentiation in response to zymosan. Consistent with these findings, activation of the β-catenin pathway in DCs suppressed chronic inflammation and protected mice from Th17/Th1-mediated autoimmune neuroinflammation. Thus, activation of β-catenin in DCs via the TLR2 receptor is a novel mechanism in DCs that regulates autoimmune inflammation.
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Affiliation(s)
- Indumathi Manoharan
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | - Yuan Hong
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | - Amol Suryawanshi
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | | | - Zuoming Sun
- Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, CA 91010
| | - Andrew L Mellor
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and
| | - David H Munn
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912
| | - Santhakumar Manicassamy
- Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; and
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Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants. Proc Natl Acad Sci U S A 2014; 111:12294-9. [PMID: 25136133 DOI: 10.1073/pnas.1400478111] [Citation(s) in RCA: 229] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Innate immunity confers an immediate nonspecific mechanism of microbial recognition through germ line-encoded pattern recognition receptors (PRRs). Of these, Toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) have shaped our current understanding of innate regulation of adaptive immunity. It is now recognized that PRRs are paramount in instructing an appropriate adaptive immune response. Their ligands have been the focus of adjuvant research with the goal of generating modern vaccine combinations tailored to specific pathogens. In this review we will highlight the recent findings in the field of adjuvant research with a particular focus on the potential of TLR and NLR ligands as adjuvants and their influence on adaptive immune responses.
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Fornuskova A, Bryja J, Vinkler M, Macholán M, Piálek J. Contrasting patterns of polymorphism and selection in bacterial-sensing toll-like receptor 4 in two house mouse subspecies. Ecol Evol 2014; 4:2931-44. [PMID: 25165529 PMCID: PMC4130449 DOI: 10.1002/ece3.1137] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Revised: 05/09/2014] [Accepted: 05/14/2014] [Indexed: 02/02/2023] Open
Abstract
Detailed investigation of variation in genes involved in pathogen recognition is crucial for understanding co-evolutionary processes between parasites and their hosts. Triggering immediate innate response to invading microbes, Toll-like receptors (TLRs) belong presently among the best-studied receptors of vertebrate immunity. TLRs exhibit remarkable interspecific variation and also intraspecific polymorphism is well documented. In humans and laboratory mice, several studies have recently shown that single amino acid substitution may significantly alter receptor function. Unfortunately, data concerning polymorphism in free-living species are still surprisingly scarce. In this study, we analyzed the polymorphism of Toll-like receptor 4 (Tlr4) over the Palearctic range of house mouse (Mus musculus). Our results reveal contrasting evolutionary patterns between the two recently (0.5 million years ago) diverged house mouse subspecies: M. m. domesticus (Mmd) and M. m. musculus (Mmm). Comparison with cytochrome b indicates strong directional selection in Mmd Tlr4. Throughout the whole Mmd western Palaearctic region, a single variant of the ligand-binding region is spread, encoded mainly by one dominant haplotype (71% of Mmd). In contrast, Tlr4 in Mmm is much more polymorphic with several haplotypes at intermediate frequencies. Moreover, we also found clear signals of recombination between two principal haplogroups in Mmm, and we identified eight sites under positive selection in our dataset. Our results suggest that observed differences in Tlr4 diversity may be attributed to contrasting parasite-mediated selection acting in the two subspecies.
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Affiliation(s)
- Alena Fornuskova
- Institute of Vertebrate Biology, Academy of Sciences of the Czech Republic Brno, Czech Republic ; Department of Botany and Zoology, Faculty of Science, Masaryk University Brno, Czech Republic ; Centre de Biologie pour la Gestion des Populations (CBGP), Institut National de la Recherche Agronomique (INRA), Campus International de Baillarguet Montferrier-sur-Lez, France
| | - Josef Bryja
- Institute of Vertebrate Biology, Academy of Sciences of the Czech Republic Brno, Czech Republic ; Department of Botany and Zoology, Faculty of Science, Masaryk University Brno, Czech Republic
| | - Michal Vinkler
- Department of Zoology, Faculty of Science, Charles University in Prague Prague, Czech Republic
| | - Miloš Macholán
- Laboratory of Mammalian Evolutionary Genetics, Institute of Animal Physiology and Genetics, Academy of Sciences of the Czech Republic Brno, Czech Republic
| | - Jaroslav Piálek
- Institute of Vertebrate Biology, Academy of Sciences of the Czech Republic Brno, Czech Republic
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Crane-Godreau MA, Maccani MA, Eszterhas SK, Warner SL, Jukosky JA, Fiering S. Exposure to Cigarette Smoke Disrupts CCL20-Mediated Antimicrobial Activity in Respiratory Epithelial Cells. ACTA ACUST UNITED AC 2014; 2:86-93. [PMID: 19966927 DOI: 10.2174/1874226200902010086] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Cigarette smoke (CS) exposure is known to increase infection rates, but the mechanisms are not well understood. These studies tested the hypothesis that CS exposure would impair antimicrobial activity of apical conditioned media from human airway (BEAS-2B) cultures by reducing induction and release of the antimicrobial peptide CCL20. BEAS-2B cultures were exposed to CS extract and assayed for temporal and physical characteristics of release as well as for antimicrobial activity. E. coli were exposed to Beas-2B-conditioned media (BCM) and subsequent bacterial colonies were enumerated. In time course studies TLR-agonist-induced CCL20 transcription and release were rapid, of short duration and release was consistently targeted to the apical/luminal compartment. Cells treated with CS extract had diminished release of CCL20 under both constitutive and toll-like receptor (TLR) agonist stimulating conditions. Exposure of the cells to CS significantly reduced the antimicrobial activity in BCM and neutralizing antibodies to CCL20 brought antibacterial activity back to baseline levels demonstrating that antimicrobial activity in this culture system was primarily attributable to CCL20. These studies add to the understanding of CCL20 as a mucosal antimicrobial and improve insight into a likely mechanism linking infection to CS exposure.
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Affiliation(s)
- Mardi A Crane-Godreau
- Department of Microbiology & Immunology, Dartmouth Medical School, Lebanon, NH 03756, USA
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An ITAM-Syk-CARD9 signalling axis triggers contact hypersensitivity by stimulating IL-1 production in dendritic cells. Nat Commun 2014; 5:3755. [DOI: 10.1038/ncomms4755] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Accepted: 03/28/2014] [Indexed: 12/14/2022] Open
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Kokatla HP, Sil D, Tanji H, Ohto U, Malladi SS, Fox LM, Shimizu T, David SA. Structure-based design of novel human Toll-like receptor 8 agonists. ChemMedChem 2014; 9:719-23. [PMID: 24474703 PMCID: PMC4105021 DOI: 10.1002/cmdc.201300573] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Indexed: 12/12/2022]
Abstract
Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds might be promising candidate vaccine adjuvants. Recently, a C2-butyl furo[2,3-c]quinoline was reported with purely TLR8 agonistic activity. This compound was successfully co-crystallized with the human TLR8 ectodomain, and the co-crystal structure revealed ligand-induced reorganization of the binding pocket of TLR8. The loss of a key hydrogen bond between the oxygen atom of the furanyl ring of the agonist and Thr 574 in TLR8 suggested that the furan ring is dispensable. Employing a disconnection strategy, 3- and 4-substituted aminoquinolines were investigated. Focused structure-based ligand design studies led to the identification of 3-pentyl-quinoline-2-amine as a novel, structurally simple, and highly potent human TLR8-specific agonist (EC50 =0.2 μM). Preliminary evaluation of this compound in ex vivo human blood assay systems revealed that it retains prominent cytokine-inducing activity. Together, these results indicate the suitability of this compound as a novel vaccine adjuvant, warranting further investigation.
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Affiliation(s)
- Hari Prasad Kokatla
- Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence KS 66047, USA
| | - Diptesh Sil
- Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence KS 66047, USA
| | - Hiromi Tanji
- Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, and CREST, JST., Japan
| | - Umeharu Ohto
- Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, and CREST, JST., Japan
| | - Subbalakshmi S. Malladi
- Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence KS 66047, USA
| | - Lauren M. Fox
- Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence KS 66047, USA
| | - Toshiyoki Shimizu
- Graduate School of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, and CREST, JST., Japan
| | - Sunil A. David
- Department of Medicinal Chemistry, University of Kansas, Multidisciplinary Research Building, Room 320D, 2030 Becker Drive, Lawrence KS 66047, USA
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Ma J, Wang H, Zheng X, Xue X, Wang B, Wu H, Zhang K, Fan S, Wang T, Li N, Zhao Y, Gao Y, Yang S, Xia X. CpG/Poly (I:C) mixed adjuvant priming enhances the immunogenicity of a DNA vaccine against eastern equine encephalitis virus in mice. Int Immunopharmacol 2014; 19:74-80. [PMID: 24440303 DOI: 10.1016/j.intimp.2014.01.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2013] [Revised: 01/06/2014] [Accepted: 01/06/2014] [Indexed: 12/26/2022]
Abstract
Eastern equine encephalitis virus (EEEV) poses a serious public health threat in many countries. Therefore, developing efficient vaccine against EEEV remains an important challenge in the field of disease control. To identify immunogenic proteins in EEEV, we constructed an expression vector containing the protein coding genes C, E3, E2, 6k, and E1 (pcDNA3.1-C-E). After verifying the target gene expression in 293 T cells, we immunized BALB/c mice with the pcDNA3.1-C-E vector as a DNA vaccine in conjunction with either CpG or poly (I:C) or a mixture of both adjuvants and monitored various aspects of the immune response. After two immunizations, the mice vaccinated with antigen plus mixed CpG/poly (I:C) adjuvant exhibited significantly stronger IFN-gamma responses and generated high-level CD4(+) cell responses for the cytokines IL-2, IL-4, and IFN-γ and CD8(+) T cell responses for the cytokines IL-2 and IFN-γ compared to the mice vaccinated with the corresponding antigen plus CpG or poly(I:C) alone. In addition, the higher antibody titers against EEEV effectively neutralized the EEEV pseudoviruses in the group immunized with antigen plus mixed CpG/poly (I:C) adjuvant after tertiary immunization. This study demonstrates that the pcDNA3.1-C-E plasmids in conjunction with mixed CpG/poly (I:C) adjuvant priming maximize the cellular immune response and specific antibody generation in mice. Moreover, this mixed adjuvant priming provides a promising strategy for enhancing the immune effectiveness of a DNA vaccine against EEEV.
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Affiliation(s)
- JinZhu Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, Heilongjiang Province, China; The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China; College of Life Science and Biotechnology, Heilongjiang Bayi Agricultural University, Daqing 163319, Heilongjiang Province, China
| | - HuaLei Wang
- The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China
| | - XueXing Zheng
- The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China
| | - XiangHong Xue
- The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China
| | - BeiYan Wang
- College of Life Science and Biotechnology, Heilongjiang Bayi Agricultural University, Daqing 163319, Heilongjiang Province, China
| | - HongXia Wu
- The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China
| | - Kun Zhang
- The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China
| | - ShengTao Fan
- The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China
| | - TieCheng Wang
- The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China
| | - Nan Li
- The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China
| | - YongKun Zhao
- The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China
| | - YuWei Gao
- The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China
| | - SongTao Yang
- The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China.
| | - XianZhu Xia
- College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, Heilongjiang Province, China; The Military Veterinary Institute, Academy of Military Medical Science of PLA, Changchun 130122, Jilin Province, China.
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Tolouei S, Hejazi SH, Ghaedi K, Khamesipour A, Hasheminia SJ. TLR2 and TLR4 in cutaneous leishmaniasis caused by Leishmania major. Scand J Immunol 2014; 78:478-84. [PMID: 23980810 DOI: 10.1111/sji.12105] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2013] [Accepted: 08/16/2013] [Indexed: 12/18/2022]
Abstract
Cutaneous leishmaniasis (CL) is a self-healing skin disease which rarely for unknown reason(s) the lesion develops to a non-healing form. It seems that the initial contact of Leishmania parasites with the host innate immune system is an important step in the outcome of the disease. Recent studies suggested that toll-like receptors (TLRs) play a role in Leishmania recognition. In this study, the level of TLR2 and TLR4 was checked in patients with healing form of lesion and compared with that of patients with non-healing form of lesion caused by Leishmania major. Gene expression of TLR2 and TLR4 in peripheral blood-derived macrophages, before and after stimulation with live L. major promastigotes, was evaluated using quantitative real-time reverse transcription PCR and flow cytometry. The results showed that the mean relative gene expression and difference membrane expression of TLR2 in macrophages of patients with healing form of lesion were significantly higher than patients with non-healing form of lesion (P < 0.0001 and P = 0.0034), respectively, and the mean relative gene expression and difference in protein expression of TLR4 in macrophages of patients with healing form of lesion were significantly higher than that of patients with non-healing form of lesion (P = 0.021 and P = 0.002), respectively. The data suggested a possible role for TLR2 and TLR4 in the outcome of CL lesion. Further studies are needed to understand more about the detail role of the immune factors in leishmaniasis.
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Affiliation(s)
- S Tolouei
- Department of Parasitology and Mycology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Uropathogenic Escherichia coli modulates innate immunity to suppress Th1-mediated inflammatory responses during infectious epididymitis. Infect Immun 2013; 82:1104-11. [PMID: 24366252 DOI: 10.1128/iai.01373-13] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Infectious epididymitis in men, a frequent entity in urological outpatient settings, is commonly caused by bacteria originating from the anal region ascending the genitourinary tract. One of the most prevalent pathogens associated with epididymitis is Escherichia coli. In our previous study, we showed that semen quality is compromised in men following epididymitis associated with specific E. coli pathovars. Thus, our aim was to investigate possible differences in immune responses elicited during epididymitis following infection with the uropathogenic E. coli (UPEC) strain CFT073 and the nonpathogenic enteric E. coli (NPEC) strain 470. Employing an in vivo experimental epididymitis model, C57BL/6 mice were infected with UPEC CFT073, NPEC 470, or phosphate-buffered saline (PBS) as a sham control for up to 7 days. After infection with NPEC 470, the expression of proinflammatory cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha in the epididymis was significantly increased. Conversely, UPEC CFT073-challenged mice displayed inflammatory gene expression at levels comparable to sham PBS-treated animals. Moreover, by day 7 only NPEC-infected animals showed activation of adaptive immunity evident by a substantial influx of CD3+ and F4/80+ cells in the epididymal interstitium. This correlated with enhanced production of Th1-associated cytokines IL-2 and gamma interferon (IFN-γ). Furthermore, splenocytes isolated from UPEC-infected mice exhibited diminished T-cell responses with significantly reduced secretion of IL-2 and IFN-γ in contrast to NPEC-infected animals. Overall, these findings provide new insights into understanding pathogen-specific modulation of host immunity during acute phases of epididymitis, which may influence severity of disease and clinical outcomes.
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Elsayh KI, Zahran AM, Lotfy Mohamad I, Aly SS. Dendritic cells in childhood sepsis. J Crit Care 2013; 28:881.e7-13. [DOI: 10.1016/j.jcrc.2013.05.007] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 04/18/2013] [Accepted: 05/10/2013] [Indexed: 12/01/2022]
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Callol A, Roher N, Amaro C, MacKenzie S. Characterization of PAMP/PRR interactions in European eel (Anguilla anguilla) macrophage-like primary cell cultures. FISH & SHELLFISH IMMUNOLOGY 2013; 35:1216-1223. [PMID: 23911651 DOI: 10.1016/j.fsi.2013.07.037] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 07/18/2013] [Accepted: 07/24/2013] [Indexed: 06/02/2023]
Abstract
The eel (Anguilla anguilla) has been identified as a vulnerable species with stocks dramatically declining over the past decade. In an effort to support the species from overfishing of wild stocks increased interest in eel aquaculture has been notable. In order to expand the scarce knowledge concerning the biology of this species significant research efforts are required in several fields of biology. The development of cell culture systems to study the immune response is a key step towards an increased understanding of the immune response and to develop resources to support further study in this threatened species. Macrophages are one of the most important effector cells of the innate immune system. The capacity to engulf pathogens and orchestrate the immune response relies on the existence of different surface receptors, such as scavenger receptors and toll-like receptors. We have developed and described an eel macrophage-like in vitro model and studied its functional and transcriptomic responses. Macrophage-like cells from both head kidney and purified peripheral blood leukocytes were obtained and phagocytic activity measured for different whole bacteria and yeast. Moreover, based on PAMP-PRR association the innate immune response of both head kidney and PBL derived macrophage-like cells was evaluated against different pathogen-associated molecular patterns (PAMPs). Results highlight that peptidoglycan stimulation strongly induces inflammatory mRNA expression reflected in the up-regulation of pro-inflammatory genes IL1β and IL18 in PBL derived cells whereas IL8 is upregulated in head kidney derived cells. Furthermore TLR2 mRNA abundance is regulated by all stimuli supporting a multifunctional role for this pathogen recognition receptor (PRR) in eel macrophage-like cells.
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Affiliation(s)
- A Callol
- Departamento de Microbiología y Ecología, Universidad de Valencia, 46100 Burjassot, Valencia, Spain
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Contrasted evolutionary histories of two Toll-like receptors (Tlr4 and Tlr7) in wild rodents (MURINAE). BMC Evol Biol 2013; 13:194. [PMID: 24028551 PMCID: PMC3848458 DOI: 10.1186/1471-2148-13-194] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Accepted: 09/06/2013] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND In vertebrates, it has been repeatedly demonstrated that genes encoding proteins involved in pathogen-recognition by adaptive immunity (e.g. MHC) are subject to intensive diversifying selection. On the other hand, the role and the type of selection processes shaping the evolution of innate-immunity genes are currently far less clear. In this study we analysed the natural variation and the evolutionary processes acting on two genes involved in the innate-immunity recognition of Microbe-Associated Molecular Patterns (MAMPs). RESULTS We sequenced genes encoding Toll-like receptor 4 (Tlr4) and 7 (Tlr7), two of the key bacterial- and viral-sensing receptors of innate immunity, across 23 species within the subfamily Murinae. Although we have shown that the phylogeny of both Tlr genes is largely congruent with the phylogeny of rodents based on a comparably sized non-immune sequence dataset, we also identified several potentially important discrepancies. The sequence analyses revealed that major parts of both Tlrs are evolving under strong purifying selection, likely due to functional constraints. Yet, also several signatures of positive selection have been found in both genes, with more intense signal in the bacterial-sensing Tlr4 than in the viral-sensing Tlr7. 92% and 100% of sites evolving under positive selection in Tlr4 and Tlr7, respectively, were located in the extracellular domain. Directly in the Ligand-Binding Region (LBR) of TLR4 we identified two rapidly evolving amino acid residues and one site under positive selection, all three likely involved in species-specific recognition of lipopolysaccharide of gram-negative bacteria. In contrast, all putative sites of LBRTLR7 involved in the detection of viral nucleic acids were highly conserved across rodents. Interspecific differences in the predicted 3D-structure of the LBR of both Tlrs were not related to phylogenetic history, while analyses of protein charges clearly discriminated Rattini and Murini clades. CONCLUSIONS In consequence of the constraints given by the receptor protein function purifying selection has been a dominant force in evolution of Tlrs. Nevertheless, our results show that episodic diversifying parasite-mediated selection has shaped the present species-specific variability in rodent Tlrs. The intensity of diversifying selection was higher in Tlr4 than in Tlr7, presumably due to structural properties of their ligands.
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TLR7/TLR8 Activation Restores Defective Cytokine Secretion by Myeloid Dendritic Cells but Not by Plasmacytoid Dendritic Cells in HIV-Infected Pregnant Women and Newborns. PLoS One 2013; 8:e67036. [PMID: 23826189 PMCID: PMC3694931 DOI: 10.1371/journal.pone.0067036] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Accepted: 05/14/2013] [Indexed: 11/30/2022] Open
Abstract
Mother-to-child transmission (MTCT) of HIV-1 has been significantly reduced with the use of antiretroviral therapies, resulting in an increased number of HIV-exposed uninfected infants. The consequences of HIV infection on the innate immune system of both mother-newborn are not well understood. In this study, we analyzed peripheral blood and umbilical cord blood (CB) collected from HIV-1-infected and uninfected pregnant women. We measured TNF-α, IL-10 and IFN-α secretion after the stimulation of the cells with agonists of both extracellular Toll-like receptors (TLRs) (TLR2, TLR4 and TLR5) and intracellular TLRs (TLR7, TLR7/8 and TLR9). Moreover, as an indicator of the innate immune response, we evaluated the responsiveness of myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) to TLRs that are associated with the antiviral response. Our results showed that peripheral blood mononuclear cells (PBMCs) from HIV-1-infected mothers and CB were defective in TNF-α production after activation by TLR2, TLR5, TLR3 and TLR7. However, the TNF-α response was preserved after TLR7/8 (CL097) stimulation, mainly in the neonatal cells. Furthermore, only CL097 activation was able to induce IL-10 and IFN-α secretion in both maternal and CB cells in the infected group. An increase in IFN-α secretion was observed in CL097-treated CB from HIV-infected mothers compared with control mothers. The effectiveness of CL097 stimulation was confirmed by observation of similar mRNA levels of interferon regulatory factor-7 (IRF-7), IFN-α and TNF-α in PBMCs of both groups. The function of both mDCs and pDCs was markedly compromised in the HIV-infected group, and although TLR7/TLR8 activation overcame the impairment in TNF-α secretion by mDCs, such stimulation was unable to reverse the dysfunctional type I IFN response by pDCs in the HIV-infected samples. Our findings highlight the dysfunction of innate immunity in HIV-infected mother-newborn pairs. The activation of the TLR7/8 pathway could function as an adjuvant to improve maternal-neonatal innate immunity.
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Esmaeili A, Dadkhahfar S, Fadakar K, Rezaei N. Post-stroke immunodeficiency: effects of sensitization and tolerization to brain antigens. Int Rev Immunol 2013; 31:396-409. [PMID: 23083348 DOI: 10.3109/08830185.2012.723078] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Acute onset of cerebrovascular diseases seems to be related to a number of immunological alternations. After the initial pro-inflammatory response to brain ischemia accompanied by systemic inflammatory response syndrome, stroke interferes with function of the innate and the adaptive immune cells, resulting in systemic immunosuppression. Although post-stroke immunodeficiency could predispose patients to life-threatening infections, it could potentially protect brain via reducing autoimmune reaction to the brain antigens. In this paper, we review current knowledge on the immunological alterations after brain ischemia, particularly effects of infection for stimulation of autoimmune response against brain antigens.
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Affiliation(s)
- Arash Esmaeili
- Brain and Spinal Injuries Repair Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Zhou Q, Zhu K, Cheng H. Toll-like receptors in human papillomavirus infection. Arch Immunol Ther Exp (Warsz) 2013; 61:203-15. [PMID: 23435874 DOI: 10.1007/s00005-013-0220-7] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Accepted: 02/13/2013] [Indexed: 01/02/2023]
Abstract
Infection with human papillomaviruses (HPVs) often causes cutaneous benign lesions, cervical cancer, and a number of other tumors. The mechanisms of host immune system to prevent and control HPV infection still remain poorly understood. Toll-like receptors (TLRs) are specific pattern recognition molecules that bind to microbial components to trigger innate immunity and direct adaptive immunity in the face of immunological danger. TLRs have been established to play an essential role in sensing and initiating antiviral immune responses. Recent accumulating evidence demonstrated that HPVs modulate TLR expression and interfere with TLR signaling pathways, leading to persistent viral infection and carcinogenesis. This review summarizes current knowledge on the roles of TLR during HPV infection, focusing on TLR recognition, modulation of TLR expression and signaling, regulatory receptors involved in TLR signaling, and cross-talk of TLRs with antimicrobial peptides. Immunotherapeutic strategies based on TLR agonists have emerged to be one of the novel promising avenues in treatment of HPV-associated diseases in the future.
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Affiliation(s)
- Qiang Zhou
- Department of Dermatology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3 Qingchun Road East, Hangzhou 310016, People's Republic of China
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