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1
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Alghazali T, Ahmed AT, Hussein UAR, Sanghvi G, Uthirapathy S, Edan RT, Lal M, Shit D, Naidu KS, Al-Hamairy AK. Noncoding RNA (ncRNA)-mediated regulation of TLRs: critical regulator of inflammation in tumor microenvironment. Med Oncol 2025; 42:144. [PMID: 40163200 DOI: 10.1007/s12032-025-02690-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/13/2025] [Indexed: 04/02/2025]
Abstract
Toll-like receptors (TLRs) are central components of the innate immune system as they recognize molecular patterns associated with pathogens and cellular damage and initiate immune responses using MyD88- and TRIF-dependent pathways. In contrast to being very useful for immune defense, dysregulated TLR signaling may be involved in diseases, such as cancer and autoimmune conditions. In cancer, TLRs create an environment that supports tumorigenesis and growth. In addition to this, a class of multifunctional noncoding RNAs (ncRNAs), including miRNAs, lncRNAs, and circRNAs, regulate gene expression without encoding proteins. MiRNAs regulate gene expression in a fine-tuned manner, while lncRNAs and circRNAs do so via diverse mechanisms. Notably, these ncRNAs interact, where lncRNAs and circRNAs function as competing endogenous RNAs and ceRNA, affecting miRNA activity. This interaction has a vital role in cancer pathology, in influencing that of various oncogenes and tumor suppressors in the tumor microenvironment; hence, modulation of ncRNAs could also be a great promising therapeutic approach. In this context, interplay between TLRs and ncRNAs is of paramount importance as they influence various parameters of the tumor microenvironment. TLR signaling works upon the expression of ncRNAs, while ncRNAs work back to regulate TLR signaling in return. An example of this includes miRNA targeting of components of the TLR; lncRNAs induced by TLR signaling possibly would favor tumor progression. Pharmacological interventions directed toward inhibiting these TLR pathways could be the model to halt malignancy by hampering pro-tumor inflammation and boosting immune responses against neoplasms. Hence, the review will highlight the complicated contrast of ncRNAs and TLRs within human cancer. By connecting the mechanisms, the researchers may study more about tumorigenesis and gather up new, innovative notions regarding therapeutic targeting.
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Affiliation(s)
| | | | | | - Gaurav Sanghvi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India
| | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Reem Turki Edan
- Department of Medical Laboratories Technology, AL-Nisour University College, Baghdad, Iraq
| | - Madan Lal
- Department of Medicine, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India
| | - Debasish Shit
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | - K Satyam Naidu
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Ahmed Khudhair Al-Hamairy
- Anesthesia Techniques Department, College of Health and Medical Techniques, Al-Mustaqbal University, 51001, Babylon, Iraq
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2
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Luo R, Yao Y, Chen Z, Sun X. An examination of the LPS-TLR4 immune response through the analysis of molecular structures and protein-protein interactions. Cell Commun Signal 2025; 23:142. [PMID: 40102851 PMCID: PMC11921546 DOI: 10.1186/s12964-025-02149-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 03/10/2025] [Indexed: 03/20/2025] Open
Abstract
The LPS-TLR4 immune response is a critical mechanism in the body's defense against Gram-negative bacterial infections, yet its dysregulation can lead to severe inflammatory diseases. Lipopolysaccharide (LPS), a pivotal pathogen-associated molecular pattern (PAMP) on the surface of gram-negative bacteria, is recognized by Toll-like receptor 4 (TLR4), initiating a complex cascade of immune responses. This review delves into the intricate molecular structures and protein-protein interactions that underpin the LPS-TLR4 signaling pathway, offering a comprehensive analysis of both extracellular recognition and intracellular signal transduction. We explore the roles of key molecules such as LBP, CD14, MD-2, and TLR4 in the initial recognition of LPS, followed by the downstream signaling pathways mediated by MyD88-dependent and MyD88-independent mechanisms. The MyD88-dependent pathway primarily activates NF-κB and AP-1, leading to macrophage M1 polarization and the release of pro-inflammatory cytokines, while the MyD88-independent pathway triggers IRF activation and type-I interferon production. By elucidating the structural basis and functional interactions of these signaling molecules, this review not only enhances our understanding of the LPS-TLR4 immune response but also highlights its implications in both infectious and non-infectious diseases. Our findings underscore the potential of targeting this pathway for therapeutic interventions, offering new avenues for the treatment of inflammatory and immune-related disorders.
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Affiliation(s)
- Ruiqin Luo
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, China
- Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China
| | - Yuexin Yao
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, China
- Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China
| | - Zhuo Chen
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, China.
- Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China.
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China.
| | - Xiaoming Sun
- School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, 442000, China.
- Biomedical Research Institute, Hubei University of Medicine, Shiyan, 442000, China.
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, 442000, China.
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3
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Sakuma C, Takenouchi T, Sato M. Impaired LPS Signaling in Macrophages Overexpressing the P2X7 C-Terminal Domain or Anti-P2X7 C-Terminal Domain Intrabody. Int J Mol Sci 2025; 26:1178. [PMID: 39940947 PMCID: PMC11818346 DOI: 10.3390/ijms26031178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/20/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
The P2X7 receptor is involved in innate immune responses, with its intracellular C-terminal domain capable of interacting with signaling molecules to regulate immune cell activation; however, the mechanisms underlying the signaling complexes remain unclear. To elucidate the function of the P2X7 C-terminal domain, we established bone marrow-derived macrophage (BMDM) cell lines from transgenic (Tg) mice overexpressing the C-terminal domain of P2X7 or anti-P2X7 C-terminal domain single-chain variable fragment (scFv) intrabody. In contrast to wild-type mouse BMDMs, the Tg BMDMs showed impairment of inflammatory responses induced by lipopolysaccharide (LPS) stimulation, such as NF-κB activation and subsequent TNF-α, IL-1β, and IL-6 expression. Furthermore, P2X7 was specifically associated with myeloid differentiation primary response gene 88 (MyD88) in wild-type BMDMs; its specific interaction was strongly interfered with by overexpression of the P2X7 C-terminal domain or anti-P2X7 C-terminal domain scFv in Tg BMDMs. These observations strongly suggest that P2X7 may have pivotal roles in LPS signaling cascades and could modulate macrophage inflammatory responses through its C-terminal domain.
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Affiliation(s)
- Chisato Sakuma
- Silkworm Research Group, Division of Silk-Producing Insect Biotechnology, Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Ibaraki 305-8634, Japan;
| | - Takato Takenouchi
- Animal Model Development Group, Division of Biomaterial Sciences, Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Ibaraki 305-8634, Japan;
| | - Mitsuru Sato
- Silkworm Research Group, Division of Silk-Producing Insect Biotechnology, Institute of Agrobiological Sciences, National Agriculture and Food Research Organization, Tsukuba, Ibaraki 305-8634, Japan;
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4
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Elliott ER, Cooper RL. Fluoxetine antagonizes the acute response of LPS: Blocks K2P channels. Comp Biochem Physiol C Toxicol Pharmacol 2025; 287:110045. [PMID: 39307514 DOI: 10.1016/j.cbpc.2024.110045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/21/2024] [Accepted: 09/19/2024] [Indexed: 09/26/2024]
Abstract
The channels responsible for maintaining resting membrane potential are known as K2P (two-P-domain K+ subunit) channels, a subset of which are known to be blocked by Fluoxetine. In this experiment, the compound's effects on the membrane potential were examined on muscles in larval Drosophila overexpressing a subtype of K2P channel (known in Drosophila as dORKA1 or ORKA1) and compared to larvae without overexpression. The compound was also observed in sequence and/or combination with a form of lipopolysaccharide (LPS) that transiently activates K2P channels. Different concentrations of Fluoxetine were tested, and it was also examined in cocktail with the LPS. At 25 μM Fluoxetine exposure, muscle in control larvae underwent depolarization, while muscles overexpressing K2P channels hyperpolarized; at 50 μM, however, much more variable responses were observed. The LPS caused hyperpolarization in both larval strains, but the effect was more transient in the Canton-S line than in the K2P overexpressors. Finally, LPS continued to cause hyperpolarization even in the presence of Fluoxetine, while Fluoxetine quickly depolarized the muscle during exposure to LPS. The cocktail showed a smaller effect on muscles overexpressing ORKA1 as compared to the controls, indicating that Fluoxetine does not block the ORKA1 subtype. This study is significant because it demonstrates how overexpression of K2P channels alters membrane response to LPS and Fluoxetine exposure.
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Affiliation(s)
| | - Robin L Cooper
- Department of Biology, University of Kentucky, Lexington 40506, KY, USA.
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Rughetti A, Bharti S, Savai R, Barmpoutsi S, Weigert A, Atre R, Siddiqi F, Sharma R, Khabiya R, Hirani N, Baig MS. Imperative role of adaptor proteins in macrophage toll-like receptor signaling pathways. Future Sci OA 2024; 10:2387961. [PMID: 39248050 PMCID: PMC11385170 DOI: 10.1080/20565623.2024.2387961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 07/30/2024] [Indexed: 09/10/2024] Open
Abstract
Macrophages are integral part of the body's defense against pathogens and serve as vital regulators of inflammation. Adaptor molecules, featuring diverse domains, intricately orchestrate the recruitment and transmission of inflammatory responses through signaling cascades. Key domains involved in macrophage polarization include Toll-like receptors (TLRs), Src Homology2 (SH2) and other small domains, alongside receptor tyrosine kinases, crucial for pathway activation. This review aims to elucidate the enigmatic role of macrophage adaptor molecules in modulating macrophage activation, emphasizing their diverse roles and potential therapeutic and investigative avenues for further exploration.
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Affiliation(s)
- Aurelia Rughetti
- Laboratory of Tumor Immunology & Cell Therapy, Department of Experimental Medicine, Policlinico Umberto I, University of Rome "Sapienza", Rome, Italy
| | - Shreya Bharti
- Department of Biosciences & Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Rajkumar Savai
- Lung Microenvironmental Niche in Cancerogenesis, Institute for Lung Health (ILH), Justus Liebig University, Giessen, D-35390, Germany
- Max Planck Institute for Heart & Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, D-61231, Germany
- Institute of Biochemistry, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, D-60590, Germany
| | - Spyridoula Barmpoutsi
- Lung Microenvironmental Niche in Cancerogenesis, Institute for Lung Health (ILH), Justus Liebig University, Giessen, D-35390, Germany
- Max Planck Institute for Heart & Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Bad Nauheim, D-61231, Germany
| | - Andreas Weigert
- Institute of Biochemistry, Faculty of Medicine, Goethe University Frankfurt, Frankfurt, D-60590, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt, D-60323, Germany
| | - Rajat Atre
- Department of Biosciences & Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Faaiza Siddiqi
- Department of Biosciences & Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Rahul Sharma
- Department of Biosciences & Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Rakhi Khabiya
- Department of Biosciences & Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
| | - Nik Hirani
- MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, EH164TJ, UK
| | - Mirza S Baig
- Department of Biosciences & Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Indore, India
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6
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Kumar P, Schroder EA, Rajaram MVS, Harris EN, Ganesan LP. The Battle of LPS Clearance in Host Defense vs. Inflammatory Signaling. Cells 2024; 13:1590. [PMID: 39329771 PMCID: PMC11430141 DOI: 10.3390/cells13181590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/17/2024] [Accepted: 09/18/2024] [Indexed: 09/28/2024] Open
Abstract
Lipopolysaccharide (LPS) in blood circulation causes endotoxemia and is linked to various disease conditions. Current treatments focus on preventing LPS from interacting with its receptor Toll-like receptor 4 (TLR4) and reducing inflammation. However, our body has a natural defense mechanism: reticuloendothelial cells in the liver rapidly degrade and inactivate much of the circulating LPS within minutes. But this LPS clearance mechanism is not perfect. Excessive LPS that escape this clearance mechanism cause systemic inflammatory damage through TLR4. Despite its importance, the role of reticuloendothelial cells in LPS elimination is not well-studied, especially regarding the specific cells, receptors, and mechanisms involved. This gap hampers the development of effective therapies for endotoxemia and related diseases. This review consolidates the current understanding of LPS clearance, narrates known and explores potential mechanisms, and discusses the relationship between LPS clearance and LPS signaling. It also aims to highlight key insights that can guide the development of strategies to reduce circulating LPS by way of bolstering host defense mechanisms. Ultimately, we seek to provide a foundation for future research that could lead to innovative approaches for enhancing the body's natural ability to clear LPS and thereby lower the risk of endotoxin-related inflammatory diseases, including sepsis.
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Affiliation(s)
- Pankaj Kumar
- Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA;
| | - Evan A. Schroder
- Department of Biochemistry, University of Nebraska, Lincoln, NE 68588, USA; (E.A.S.); (E.N.H.)
| | - Murugesan V. S. Rajaram
- Department of Microbial Infection and Immunity, College of Medicine, The Ohio State University, Columbus, OH 43210, USA;
| | - Edward N. Harris
- Department of Biochemistry, University of Nebraska, Lincoln, NE 68588, USA; (E.A.S.); (E.N.H.)
| | - Latha P. Ganesan
- Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH 43210, USA;
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7
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Toshchakov VY. Peptide-Based Inhibitors of the Induced Signaling Protein Interactions: Current State and Prospects. BIOCHEMISTRY. BIOKHIMIIA 2024; 89:784-798. [PMID: 38880642 DOI: 10.1134/s000629792405002x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 02/29/2024] [Accepted: 03/12/2024] [Indexed: 06/18/2024]
Abstract
Formation of the transient protein complexes in response to activation of cellular receptors is a common mechanism by which cells respond to external stimuli. This article presents the concept of blocking interactions of signaling proteins by the peptide inhibitors, and describes the progress achieved to date in the development of signaling inhibitors that act by blocking the signal-dependent protein interactions.
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Affiliation(s)
- Vladimir Y Toshchakov
- Sirius University of Science and Technology, Sirius Federal Territory, Krasnodar Region, 354340, Russia.
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8
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Zhang FY, Lian N, Li M. Macrophage pyroptosis induced by Candida albicans. Pathog Dis 2024; 82:ftae003. [PMID: 38499444 PMCID: PMC11162155 DOI: 10.1093/femspd/ftae003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 10/21/2023] [Accepted: 03/15/2024] [Indexed: 03/20/2024] Open
Abstract
Candida albicans (C. albicans) is a prevalent opportunistic pathogen that causes mucocutaneous and systemic infections, particularly in immunocompromised individuals. Macrophages play a crucial role in eliminating C. albicans in local and bloodstream contexts, while also regulating antifungal immune responses. However, C. albicans can induce macrophage lysis through pyroptosis, a type of regulated cell death. This process can enable C. albicans to escape from immune cells and trigger the release of IL-1β and IL-18, which can impact both the host and the pathogen. Nevertheless, the mechanisms by which C. albicans triggers pyroptosis in macrophages and the key factors involved in this process remain unclear. In this review, we will explore various factors that may influence or trigger pyroptosis in macrophages induced by C. albicans, such as hypha, ergosterol, cell wall remodeling, and other virulence factors. We will also examine the possible immune response following macrophage pyroptosis.
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Affiliation(s)
- Feng-yuan Zhang
- Hospital for Skin Diseases, Institute of Dermatology,Chinese Academy of Medical Sciences & Peking Union Medical College, 12th. JiangWangmiao street, Nanjing, 210042, China
| | - Ni Lian
- Hospital for Skin Diseases, Institute of Dermatology,Chinese Academy of Medical Sciences & Peking Union Medical College, 12th. JiangWangmiao street, Nanjing, 210042, China
| | - Min Li
- Hospital for Skin Diseases, Institute of Dermatology,Chinese Academy of Medical Sciences & Peking Union Medical College, 12th. JiangWangmiao street, Nanjing, 210042, China
- Center for Global Health, School of Public Health, Nanjing Medical University, 101st. LongMian Avenue, Nanjing, 211166, China
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9
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Yue C, Zhang K, Liu Z, Lü W, Guo H, Zhao L, Song X, Fang JKH. The Role of the TLR4-MyD88 Signaling Pathway in the Immune Response of the Selected Scallop Strain "Hongmo No. 1" to Heat Stress. Animals (Basel) 2024; 14:497. [PMID: 38338140 PMCID: PMC10854496 DOI: 10.3390/ani14030497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 01/23/2024] [Accepted: 01/30/2024] [Indexed: 02/12/2024] Open
Abstract
The innate immunity of marine bivalves is challenged upon exposure to heat stress, especially with increases in the frequency and intensity of heat waves. TLR4 serves a classical pattern recognition receptor in recognizing pathogenic microorganisms and activating immune responses. In this study, three genes, HMTLR4, HMMyD88 and HMTRAF6, were characterized as homologs of genes in the TLR4-MyD88 signaling pathway in the selected scallop strain "Hongmo No. 1". According to RT-PCR, acute heat stress (32 °C) inhibited genes in the TLR4-MyD88 signaling pathway, and LPS stimulation-induced activation of TLR4-MyD88 signal transduction was also negatively affected at 32 °C. ELISA showed LPS-induced tumor necrosis factor alpha (TNF-α) or lysozyme (LZM) activity, but this was independent of temperature. RNA interference (RNAi) confirmed that HMTLR4 silencing suppressed the expression of its downstream gene, whether at 24 °C or at 32 °C. The level of TNF-α and the activity of LZM also decreased after injection with dsRNA, indicating a negative effect on the innate immunity of scallops. Additionally, acute heat stress affected the suppression of downstream gene expression when compared with that at 24 °C, which led us to the hypothesis that heat stress directly influences the downstream targets of HMTLR4. These results enrich the knowledge of scallop immunity under heat stress and can be beneficial for the genetic improvement of new scallop strains with higher thermotolerance.
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Affiliation(s)
- Chenyang Yue
- Guangdong Marine Invertebrates Science and Technology Innovation Center, Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China; (K.Z.); (W.L.); (H.G.); (L.Z.); (X.S.)
- Guangdong Provincial Engineering Laboratory for Mariculture Organism Breeding, Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
| | - Kexin Zhang
- Guangdong Marine Invertebrates Science and Technology Innovation Center, Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China; (K.Z.); (W.L.); (H.G.); (L.Z.); (X.S.)
| | - Zhigang Liu
- Guangdong Marine Invertebrates Science and Technology Innovation Center, Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China; (K.Z.); (W.L.); (H.G.); (L.Z.); (X.S.)
| | - Wengang Lü
- Guangdong Marine Invertebrates Science and Technology Innovation Center, Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China; (K.Z.); (W.L.); (H.G.); (L.Z.); (X.S.)
| | - Hui Guo
- Guangdong Marine Invertebrates Science and Technology Innovation Center, Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China; (K.Z.); (W.L.); (H.G.); (L.Z.); (X.S.)
- Key Laboratory of Marine Ecology and Aquaculture Environment of Zhanjiang, Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
| | - Liqiang Zhao
- Guangdong Marine Invertebrates Science and Technology Innovation Center, Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China; (K.Z.); (W.L.); (H.G.); (L.Z.); (X.S.)
| | - Xinyu Song
- Guangdong Marine Invertebrates Science and Technology Innovation Center, Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China; (K.Z.); (W.L.); (H.G.); (L.Z.); (X.S.)
| | - James Kar-Hei Fang
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Hong Kong 999077, China;
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Yang W, Cui X, Sun D, Sun G, Yan Z, Wei M, Wang Z, Yu W. POU5F1 promotes the proliferation, migration, and invasion of gastric cancer cells by reducing the ubiquitination level of TRAF6. Cell Death Dis 2023; 14:802. [PMID: 38062041 PMCID: PMC10703809 DOI: 10.1038/s41419-023-06332-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 11/15/2023] [Accepted: 11/23/2023] [Indexed: 12/18/2023]
Abstract
POU5F1 plays an important role in maintaining the cancer stem cell (CSC) -like properties of gastric cancer (GC) cells. The impact of POU5F1 on the proliferation and metastasis of GC was examined, along with the potential of ATRA as a specific therapeutic agent for GC. The dysregulation of POU5F1 expression in GC tissues was analyzed using public databases and bioinformatics techniques, and the disparity in POU5F1 expression between normal gastric tissues and GC tissues was further assessed through western blot, RT-qPCR, and immunohistochemistry. The present study aimed to investigate the impact of POU5F1 on the proliferation, migration, and invasion of GC cells through both in vivo and in vitro experiments. Additionally, the effects of ATRA on the proliferation, migration, and invasion of GC cells were examined using in vivo and in vitro approaches. Our findings revealed a significant upregulation of POU5F1 in GC tissues, which was found to be associated with a poorer prognosis in patients with GC. Moreover, POU5F1 was observed to enhance the proliferation, migration, and invasion of GC cells in vitro, as well as promote subcutaneous tumor growth and lung metastasis of GC cells in vivo. The overexpression of POU5F1 mechanistically triggers the process of Epithelial-mesenchymal transition (EMT) by down-regulating E-Cadherin and up-regulating N-Cadherin and VIM. POU5F1 hinders the ubiquitination of TRAF6 through negative regulation of TRIM59, thereby facilitating the activation of the NF-κB pathway. Furthermore, the administration of ATRA effectively impedes the proliferation, migration, and invasion of GC cells by suppressing the expression of POU5F1. The upregulation of POU5F1 elicits EMT, fosters the initiation of the NF-κB signaling pathway in GC cells, and stimulates the proliferation, invasion, and metastasis of GC cells. All-trans retinoic acid (ATRA) can impede these POU5F1-induced effects, thereby potentially serving as an adjunctive therapeutic approach for GC.
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Affiliation(s)
- Wenshuo Yang
- Department of General Surgery, Qilu Hospital of Shandong University, 250012, Jinan, Shandong, China
| | - Xiaohan Cui
- Department of General Surgery, Qilu Hospital of Shandong University, 250012, Jinan, Shandong, China
| | - Danping Sun
- Department of General Surgery, Qilu Hospital of Shandong University, 250012, Jinan, Shandong, China
| | - Guorui Sun
- Department of General Surgery, Qilu Hospital of Shandong University, 250012, Jinan, Shandong, China
| | - Zhibo Yan
- Department of General Surgery, Qilu Hospital of Shandong University, 250012, Jinan, Shandong, China
| | - Meng Wei
- Department of General Surgery, Qilu Hospital of Shandong University, 250012, Jinan, Shandong, China
| | - Zuoyang Wang
- Department of General Surgery, Qilu Hospital of Shandong University, 250012, Jinan, Shandong, China
| | - Wenbin Yu
- Department of General Surgery, Qilu Hospital of Shandong University, 250012, Jinan, Shandong, China.
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11
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Nilsen KE, Zhang B, Skjesol A, Ryan L, Vagle H, Bøe MH, Orning P, Kim H, Bakke SS, Elamurugan K, Mestvedt IB, Stenvik J, Husebye H, Lien E, Espevik T, Yurchenko M. Peptide derived from SLAMF1 prevents TLR4-mediated inflammation in vitro and in vivo. Life Sci Alliance 2023; 6:e202302164. [PMID: 37788908 PMCID: PMC10547912 DOI: 10.26508/lsa.202302164] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 09/21/2023] [Accepted: 09/22/2023] [Indexed: 10/05/2023] Open
Abstract
Inflammation plays a crucial role in the development and progression of many diseases, and is often caused by dysregulation of signalling from pattern recognition receptors, such as TLRs. Inhibition of key protein-protein interactions is an attractive target for treating inflammation. Recently, we demonstrated that the signalling lymphocyte activation molecule family 1 (SLAMF1) positively regulates signalling downstream of TLR4 and identified the interaction interface between SLAMF1 and the TLR4 adaptor protein TRIF-related adapter molecule (TRAM). Based on these findings, we developed a SLAMF1-derived peptide, P7, which is linked to a cell-penetrating peptide for intracellular delivery. We found that P7 peptide inhibits the expression and secretion of IFNβ and pro-inflammatory cytokines (TNF, IL-1β, IL-6) induced by TLR4, and prevents death in mice subjected to LPS shock. The mechanism of action of P7 peptide is based on interference with several intracellular protein-protein interactions, including TRAM-SLAMF1, TRAM-Rab11FIP2, and TIRAP-MyD88 interactions. Overall, P7 peptide has a unique mode of action and demonstrates high efficacy in inhibiting TLR4-mediated signalling in vitro and in vivo.
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Affiliation(s)
- Kaja Elisabeth Nilsen
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Boyao Zhang
- Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Astrid Skjesol
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Liv Ryan
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Hilde Vagle
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Maren Helene Bøe
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Pontus Orning
- Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Hera Kim
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Siril Skaret Bakke
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Kirusika Elamurugan
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Ingvild Bergdal Mestvedt
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Jørgen Stenvik
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Infectious Diseases, Clinic of Medicine, St. Olavs Hospital HF, Trondheim University Hospital, Trondheim, Norway
| | - Harald Husebye
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Egil Lien
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Terje Espevik
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Infectious Diseases, Clinic of Medicine, St. Olavs Hospital HF, Trondheim University Hospital, Trondheim, Norway
| | - Maria Yurchenko
- Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Infectious Diseases, Clinic of Medicine, St. Olavs Hospital HF, Trondheim University Hospital, Trondheim, Norway
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12
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Panzer B, Kopp CW, Neumayer C, Koppensteiner R, Jozkowicz A, Poledniczek M, Gremmel T, Jilma B, Wadowski PP. Toll-like Receptors as Pro-Thrombotic Drivers in Viral Infections: A Narrative Review. Cells 2023; 12:1865. [PMID: 37508529 PMCID: PMC10377790 DOI: 10.3390/cells12141865] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/12/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
Toll-like receptors (TLRs) have a critical role in the pathogenesis and disease course of viral infections. The induced pro-inflammatory responses result in the disturbance of the endovascular surface layer and impair vascular homeostasis. The injury of the vessel wall further promotes pro-thrombotic and pro-coagulatory processes, eventually leading to micro-vessel plugging and tissue necrosis. Moreover, TLRs have a direct role in the sensing of viruses and platelet activation. TLR-mediated upregulation of von Willebrand factor release and neutrophil, as well as macrophage extra-cellular trap formation, further contribute to (micro-) thrombotic processes during inflammation. The following review focuses on TLR signaling pathways of TLRs expressed in humans provoking pro-thrombotic responses, which determine patient outcome during viral infections, especially in those with cardiovascular diseases.
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Affiliation(s)
- Benjamin Panzer
- Department of Cardiology, Wilhelminenspital, 1090 Vienna, Austria
| | - Christoph W Kopp
- Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria
| | - Christoph Neumayer
- Division of Vascular Surgery, Department of Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Renate Koppensteiner
- Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria
| | - Alicja Jozkowicz
- Faculty of Biophysics, Biochemistry and Biotechnology, Department of Medical Biotechnology, Jagiellonian University, 30-387 Krakow, Poland
| | - Michael Poledniczek
- Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria
| | - Thomas Gremmel
- Institute of Cardiovascular Pharmacotherapy and Interventional Cardiology, Karl Landsteiner Society, 3100 St. Pölten, Austria
- Department of Internal Medicine I, Cardiology and Intensive Care Medicine, Landesklinikum Mistelbach-Gänserndorf, 2130 Mistelbach, Austria
| | - Bernd Jilma
- Department of Clinical Pharmacology, Medical University of Vienna, 1090 Vienna, Austria
| | - Patricia P Wadowski
- Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria
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13
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Papadakos SP, Arvanitakis K, Stergiou IE, Lekakis V, Davakis S, Christodoulou MI, Germanidis G, Theocharis S. The Role of TLR4 in the Immunotherapy of Hepatocellular Carcinoma: Can We Teach an Old Dog New Tricks? Cancers (Basel) 2023; 15:2795. [PMID: 37345131 PMCID: PMC10216531 DOI: 10.3390/cancers15102795] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 05/12/2023] [Accepted: 05/15/2023] [Indexed: 06/23/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is a leading cause of cancer-related death worldwide. Immunotherapy has emerged as the mainstay treatment option for unresectable HCC. Toll-like receptor 4 (TLR4) plays a crucial role in the innate immune response by recognizing and responding primarily to bacterial lipopolysaccharides. In addition to its role in the innate immune system, TLR4 has also been implicated in adaptive immunity, including specific anti-tumor immune responses. In particular, the TLR4 signaling pathway seems to be involved in the regulation of several cancer hallmarks, such as the continuous activation of cellular pathways that promote cell division and growth, the inhibition of programmed cell death, the promotion of several invasion and metastatic mechanisms, epithelial-to-mesenchymal transition, angiogenesis, drug resistance, and epigenetic modifications. Emerging evidence further suggests that TLR4 signaling holds promise as a potential immunotherapeutic target in HCC. The aim of this review was to explore the multilayer aspects of the TLR4 signaling pathway, regarding its role in liver diseases and HCC, as well as its potential utilization as an immunotherapy target for HCC.
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Affiliation(s)
- Stavros P. Papadakos
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Konstantinos Arvanitakis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Ioanna E. Stergiou
- Pathophysiology Department, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Vasileios Lekakis
- Department of Gastroenterology, Laiko General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Spyridon Davakis
- First Department of Surgery, Laiko General Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Maria-Ioanna Christodoulou
- Tumor Immunology and Biomarkers Laboratory, Basic and Translational Cancer Research Center, Department of Life Sciences, European University Cyprus, Nicosia 2404, Cyprus;
| | - Georgios Germanidis
- First Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
- Basic and Translational Research Unit (BTRU), Special Unit for Biomedical Research and Education (BRESU), Faculty of Health Sciences, School of Medicine, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece
| | - Stamatios Theocharis
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece;
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14
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Rajpoot S, Kumar A, Gaponenko V, Thurston TL, Mehta D, Faisal SM, Zhang KY, Jha HC, Darwhekar GN, Baig MS. Dorzolamide suppresses PKCδ -TIRAP-p38 MAPK signaling axis to dampen the inflammatory response. Future Med Chem 2023. [PMID: 37129027 DOI: 10.4155/fmc-2022-0260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2023] Open
Abstract
Background: Sepsis is a syndrome due to microbial infection causing impaired multiorgan function. Its underlying cause is immune dysfunction and macrophages play an essential role. Methods: TIRAP interaction with PKCδ in macrophage was studied, revealing downstream signaling by Western blot and quantitative reverse transcriptase PCR. Dorzolamide (DZD) disrupting TIRAP-PKCδ interaction was identified by virtual screening and validated in vitro and in septic mice. Results: The study highlights the indispensable role of TIRAP-PKCδ in p38 MAPK-activation, NF-κB- and AP-1-mediated proinflammatory cytokines expression, whereas DZD significantly attenuated the signaling. Conclusion: Targeting TIRAP-PKCδ interaction by DZD is a novel therapeutic approach for treating sepsis.
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Affiliation(s)
- Sajjan Rajpoot
- Department of Biosciences & Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, 453552, India
| | - Ashutosh Kumar
- Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Tsurumi, Yokohama, Kanagawa, 230-0045, Japan
| | - Vadim Gaponenko
- Department of Biochemistry & Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Teresa Lm Thurston
- MRC Centre for Molecular Bacteriology & Infection, Imperial College London, London, SW7 2AZ, UK
| | - Dolly Mehta
- Department of Pharmacology & Center for Lung & Vascular Biology, College of Medicine, The University of Illinois, Chicago, IL 60612, USA
| | - Syed M Faisal
- National Institute of Animal Biotechnology, Hyderabad, 500032, India
| | - Kam Yj Zhang
- Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Tsurumi, Yokohama, Kanagawa, 230-0045, Japan
| | - Hem C Jha
- Department of Biosciences & Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, 453552, India
| | - Gajanan N Darwhekar
- Acropolis Institute of Pharmaceutical Education & Research, Indore, 453771, India
| | - Mirza S Baig
- Department of Biosciences & Biomedical Engineering, Indian Institute of Technology Indore, Simrol, Indore, 453552, India
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15
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Yu B, Li B, Chen T, Yang J, Wang X, Peng B, Hu Q. A NF-κB-Based High-Throughput Screening for Immune Adjuvants and Inhibitors. Inflammation 2023; 46:598-611. [PMID: 36306023 DOI: 10.1007/s10753-022-01758-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 09/19/2022] [Accepted: 10/12/2022] [Indexed: 11/05/2022]
Abstract
The nuclear factor-κB (NF-κB) family is crucial for regulating immune and inflammatory responses. The activation of the immune cell signaling pathway usually activates NF-κB, causing a protective immune response. NF-κB can also cause excessive inflammatory responses by activating a cascade reaction of pro-inflammatory mediators such as cytokines. In this study, we used an NF-κB luciferase reporter gene system. Out of more than 800 compounds screened, four NF-κB agonists were identified with strong activity at nontoxic concentrations. Subsequently, the adjuvant effect was verified on mouse bone marrow-derived dendritic cells (BMDCs) and macrophages RAW264.7. It was found that fostamatinib (R788) disodium increased the production of IL-6, IL-12p40, and TNF-α, indicating that R788 disodium could induce the maturation of antigen-presenting cells (APCs). In addition, three compounds were screened to significantly inhibit NF-κB at nontoxic doses, including dehydrocostus lactone (DHL)-a known NF-κB inhibitor. The results showed that DHL significantly reduced the release of LPS-induced inflammatory cytokines (including TNF-α, IL-6, and IL-12). Our findings indicate that the NF-κB-based high-throughput screening can be used to discover potential immune adjuvants and anti-inflammatory molecules.
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Affiliation(s)
- Boyang Yu
- The Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing University of Technology, Beijing, 100124, China
| | - Boye Li
- Civil Aviation Medicine Center, Civil Aviation Administration of China, Beijing, 100123, China
| | - Tian Chen
- The Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing University of Technology, Beijing, 100124, China
| | - Jinning Yang
- The Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing University of Technology, Beijing, 100124, China
| | - Xiaoli Wang
- The Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, China
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing University of Technology, Beijing, 100124, China
| | - Bo Peng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Qin Hu
- The Faculty of Environment and Life, Beijing University of Technology, Beijing, 100124, China.
- Beijing International Science and Technology Cooperation Base of Antivirus Drug, Beijing University of Technology, Beijing, 100124, China.
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16
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Yim HCH, Chakrabarti A, Kessler S, Morimoto H, Wang D, Sooraj D, Ahmed AU, de la Motte C, Silverman RH, Williams BRG, Sadler AJ. The protein kinase R modifies gut physiology to limit colitis. Front Immunol 2023; 14:1106737. [PMID: 36875104 PMCID: PMC9981792 DOI: 10.3389/fimmu.2023.1106737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Accepted: 02/03/2023] [Indexed: 02/19/2023] Open
Abstract
Here we investigate the function of the innate immune molecule protein kinase R (PKR) in intestinal inflammation. To model a colitogenic role of PKR, we determine the physiological response to dextran sulfate sodium (DSS) of wild-type and two transgenic mice strains mutated to express either a kinase-dead PKR or to ablate expression of the kinase. These experiments recognize kinase-dependent and -independent protection from DSS-induced weight loss and inflammation, against a kinase-dependent increase in the susceptibility to DSS-induced injury. We propose these effects arise through PKR-dependent alteration of gut physiology, evidenced as altered goblet cell function and changes to the gut microbiota at homeostasis that suppresses inflammasome activity by controlling autophagy. These findings establish that PKR functions as both a protein kinase and a signaling molecule in instituting immune homeostasis in the gut.
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Affiliation(s)
- Howard Chi Ho Yim
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Arindam Chakrabarti
- Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, United States
| | - Sean Kessler
- Department of Pathobiology, Lerner Research Institute, Cleveland, OH, United States
| | - Hiroyuki Morimoto
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Anatomy, School of Medicine, the University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan
| | - Die Wang
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Dhanya Sooraj
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Afsar U. Ahmed
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Carol de la Motte
- Department of Pathobiology, Lerner Research Institute, Cleveland, OH, United States
| | - Robert H. Silverman
- Department of Cancer Biology, Lerner Research Institute, Cleveland, OH, United States
| | - Bryan RG. Williams
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
| | - Anthony J. Sadler
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
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17
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Pereira M, Gazzinelli RT. Regulation of innate immune signaling by IRAK proteins. Front Immunol 2023; 14:1133354. [PMID: 36865541 PMCID: PMC9972678 DOI: 10.3389/fimmu.2023.1133354] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 01/30/2023] [Indexed: 02/16/2023] Open
Abstract
The Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1R) families are of paramount importance in coordinating the early immune response to pathogens. Signaling via most TLRs and IL-1Rs is mediated by the protein myeloid differentiation primary-response protein 88 (MyD88). This signaling adaptor forms the scaffold of the myddosome, a molecular platform that employs IL-1R-associated kinase (IRAK) proteins as main players for transducing signals. These kinases are essential in controlling gene transcription by regulating myddosome assembly, stability, activity and disassembly. Additionally, IRAKs play key roles in other biologically relevant responses such as inflammasome formation and immunometabolism. Here, we summarize some of the key aspects of IRAK biology in innate immunity.
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Affiliation(s)
- Milton Pereira
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States,*Correspondence: Milton Pereira, ; Ricardo T. Gazzinelli,
| | - Ricardo T. Gazzinelli
- Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, United States,Centro de Tecnologia de Vacinas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil,Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, MG, Brazil,Plataforma de Medicina Translacional, Fundação Oswaldo Cruz, Ribeirão Preto, SP, Brazil,*Correspondence: Milton Pereira, ; Ricardo T. Gazzinelli,
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18
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Taban Q, Ahmad SM, Mumtaz PT, Bhat B, Haq E, Magray S, Saleem S, Shabir N, Muhee A, Kashoo ZA, Zargar MH, Malik AA, Ganai NA, Shah RA. Scavenger receptor B1 facilitates the endocytosis of Escherichia coli via TLR4 signaling in mammary gland infection. Cell Commun Signal 2023; 21:3. [PMID: 36604713 PMCID: PMC9813905 DOI: 10.1186/s12964-022-01014-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 12/11/2022] [Indexed: 01/06/2023] Open
Abstract
SCARB1 belongs to class B of Scavenger receptors (SRs) that are known to be involved in binding and endocytosis of various pathogens. SRs have emerging role in regulating innate immunity and host-pathogen interactions by acting in co-ordination with Toll-like receptors.Query Little is known about the function of SCARB1 in milk-derived mammary epithelial cells (MECs). This study reports the role of SCARB1 in infection and its potential association in TLR4 signaling on bacterial challenge in Goat mammary epithelial cells (GMECs). The novelty in the establishment of MEC culture lies in the method that aims to enhance the viability of the cells with intact characteristics upto a higher passage number. We represent MEC culture to be used as a potential infection model for deeper understanding of animal physiology especially around the mammary gland. On E.coli challenge the expression of SCARB1 was significant in induced GMECs at 6 h. Endoribonuclease-esiRNA based silencing of SCARB1 affects the expression of TLR4 and its pathways i.e. MyD88 and TRIF pathways on infection. Knockdown also affected the endocytosis of E.coli in GMECs demonstrating that E.coli uses SCARB1 function to gain entry in cells. Furthermore, we predict 3 unique protein structures of uncharacterized SCARB1 (Capra hircus) protein. Overall, we highlight SCARB1 as a main participant in host defence and its function in antibacterial advances to check mammary gland infections. Video Abstract.
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Affiliation(s)
- Qamar Taban
- Division of Animal Biotechnology, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, FV.Sc and A.H, Shuhama, Jammu and Kashmir, India
- Department of Biotechnology, University of Kashmir, Hazratbal Srinagar, Jammu and Kashmir, India
| | - Syed Mudasir Ahmad
- Division of Animal Biotechnology, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, FV.Sc and A.H, Shuhama, Jammu and Kashmir, India.
| | | | - Basharat Bhat
- Division of Animal Biotechnology, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, FV.Sc and A.H, Shuhama, Jammu and Kashmir, India
| | - Ehtishamul Haq
- Department of Biotechnology, University of Kashmir, Hazratbal Srinagar, Jammu and Kashmir, India
| | - Suhail Magray
- Division of Animal Biotechnology, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, FV.Sc and A.H, Shuhama, Jammu and Kashmir, India
| | - Sahar Saleem
- Division of Animal Biotechnology, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, FV.Sc and A.H, Shuhama, Jammu and Kashmir, India
| | - Nadeem Shabir
- Division of Animal Biotechnology, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, FV.Sc and A.H, Shuhama, Jammu and Kashmir, India
| | - Amatul Muhee
- Department of Clinical Veterinary Medicine, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, FV.Sc and A.H, Shuhama, Jammu and Kashmir, India
| | - Zahid Amin Kashoo
- Department of Veterinary Microbiology & Immunology, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, FV.Sc and A.H, Shuhama, Jammu and Kashmir, India
| | - Mahrukh Hameed Zargar
- Department of Advanced Centre for Human Genetics, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
| | - Abrar A Malik
- Division of Animal Biotechnology, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, FV.Sc and A.H, Shuhama, Jammu and Kashmir, India
| | - Nazir A Ganai
- Division of Animal Biotechnology, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, FV.Sc and A.H, Shuhama, Jammu and Kashmir, India
| | - Riaz A Shah
- Division of Animal Biotechnology, Sher-E-Kashmir University of Agricultural Sciences and Technology of Kashmir, FV.Sc and A.H, Shuhama, Jammu and Kashmir, India
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19
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TIRAP, TRAM, and Toll-Like Receptors: The Untold Story. Mediators Inflamm 2023; 2023:2899271. [PMID: 36926280 PMCID: PMC10014160 DOI: 10.1155/2023/2899271] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 01/30/2023] [Accepted: 02/06/2023] [Indexed: 03/09/2023] Open
Abstract
Toll-like receptors (TLRs) are the most studied receptors among the pattern recognition receptors (PRRs). They act as microbial sensors, playing major roles in the regulation of the innate immune system. TLRs mediate their cellular functions through the activation of MyD88-dependent or MyD88-independent signaling pathways. Myd88, or myeloid differentiation primary response 88, is a cytosolic adaptor protein essential for the induction of proinflammatory cytokines by all TLRs except TLR3. While the crucial role of Myd88 is well described, the contribution of other adaptors in mediating TLR signaling and function has been underestimated. In this review, we highlight important results demonstrating that TIRAP and TRAM adaptors are also required for full signaling activity and responses induced by most TLRs.
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20
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Trachsel T, Prader S, Steindl K, Pachlopnik Schmid J. Case report: ETS1 gene deletion associated with a low number of recent thymic emigrants in three patients with Jacobsen syndrome. Front Immunol 2022; 13:867206. [PMID: 36341443 PMCID: PMC9634179 DOI: 10.3389/fimmu.2022.867206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 10/10/2022] [Indexed: 11/30/2022] Open
Abstract
Jacobsen syndrome is a rare genetic disorder associated with a terminal deletion in chromosome 11. The clinical presentation is variable. Although immunodeficiency has been described in patients with Jacobsen syndrome, a clear genotype-phenotype correlation has not yet been established. Here, we report on the immunologic phenotypes of four patients with Jacobsen syndrome. All four patients showed one or more atypical immunologic features. One patient suffered from recurrent viral infections, two patients had experienced a severe bacterial infection and one had received antibiotic prophylaxis since early childhood. One patient had experienced severe, transient immune dysregulation. Hypogammaglobulinemia and low B cell counts were found in two patients, while the number of recent thymic emigrants (CD31+CD45RA+ CD4 cells) was abnormally low in three. When considering the six immune-related genes located within the affected part of chromosome 11 (ETS1, TIRAP, FLI1, NFRKB, THYN1, and SNX19), only the ETS1 gene was found be deleted in the three patients with low numbers of recent thymic emigrants and non-switched memory B cells. Our findings support the hypothesis whereby Jacobsen syndrome is associated with a combined immunodeficiency with variable presentation. Further investigations of potential genotype-phenotype correlations are warranted and might help to personalize patient management in individuals lacking immune-related genes. In addition, we recommend immunologic follow-up for all patients with Jacobsen syndrome, as immune abnormalities may develop over time.
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Affiliation(s)
- Tina Trachsel
- Division of Immunology, University Children’s Hospital Zurich, Zurich, Switzerland
| | - Seraina Prader
- Division of Immunology, University Children’s Hospital Zurich, Zurich, Switzerland
| | - Katharina Steindl
- Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland
| | - Jana Pachlopnik Schmid
- Division of Immunology, University Children’s Hospital Zurich, Zurich, Switzerland
- Pediatric Immunology, University of Zurich, Zurich, Switzerland
- *Correspondence: Jana Pachlopnik Schmid,
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21
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Kusiak A, Brady G. Bifurcation of signalling in human innate immune pathways to NF-kB and IRF family activation. Biochem Pharmacol 2022; 205:115246. [PMID: 36088989 DOI: 10.1016/j.bcp.2022.115246] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 09/01/2022] [Accepted: 09/02/2022] [Indexed: 11/28/2022]
Abstract
The human innate immune response can be activated through a wide range of stimuli. This multi-faceted system can be triggered by a range of immunostimulants including pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). These stimuli drive intracellular signalling pathways that branch off downstream to activate several distinct transcription factors. The two most impactful of which in innate immune outcomes are the NF-κB and the IRF family members. Both transcription factor families play defining roles in driving inflammation as well as the antiviral response. Pathways leading to their simultaneous activation share common upstream components but eventually distinct regulators which directly facilitate their activation. This review will discuss the current state of knowledge about what is known about how these pathways bifurcate to activate NF-κB and IRF family members.
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Affiliation(s)
- Aleksandra Kusiak
- Trinity Translational Medicine Institute, St James' Campus, Trinity College Dublin, D08 W9RT Dublin, Ireland.
| | - Gareth Brady
- Trinity Translational Medicine Institute, St James' Campus, Trinity College Dublin, D08 W9RT Dublin, Ireland.
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22
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Nilsen KE, Skjesol A, Frengen Kojen J, Espevik T, Stenvik J, Yurchenko M. TIRAP/Mal Positively Regulates TLR8-Mediated Signaling via IRF5 in Human Cells. Biomedicines 2022; 10:biomedicines10071476. [PMID: 35884781 PMCID: PMC9312982 DOI: 10.3390/biomedicines10071476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/09/2022] [Accepted: 06/17/2022] [Indexed: 11/21/2022] Open
Abstract
Toll-like receptor 8 (TLR8) recognizes single-stranded RNA of viral and bacterial origin as well as mediates the secretion of pro-inflammatory cytokines and type I interferons by human monocytes and macrophages. TLR8, as other endosomal TLRs, utilizes the MyD88 adaptor protein for initiation of signaling from endosomes. Here, we addressed the potential role of the Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP) in the regulation of TLR8 signaling in human primary monocyte-derived macrophages (MDMs). To accomplish this, we performed TIRAP gene silencing, followed by the stimulation of cells with synthetic ligands or live bacteria. Cytokine-gene expression and secretion were analyzed by quantitative PCR or Bioplex assays, respectively, while nuclear translocation of transcription factors was addressed by immunofluorescence and imaging, as well as by cell fractionation and immunoblotting. Immunoprecipitation and Akt inhibitors were also used to dissect the signaling mechanisms. Overall, we show that TIRAP is recruited to the TLR8 Myddosome signaling complex, where TIRAP contributes to Akt-kinase activation and the nuclear translocation of interferon regulatory factor 5 (IRF5). Recruitment of TIRAP to the TLR8 signaling complex promotes the expression and secretion of the IRF5-dependent cytokines IFNβ and IL-12p70 as well as, to a lesser degree, TNF. These findings reveal a new and unconventional role of TIRAP in innate immune defense.
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Affiliation(s)
- Kaja Elisabeth Nilsen
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway; (K.E.N.); (A.S.); (J.F.K.); (T.E.); (J.S.)
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway
| | - Astrid Skjesol
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway; (K.E.N.); (A.S.); (J.F.K.); (T.E.); (J.S.)
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway
| | - June Frengen Kojen
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway; (K.E.N.); (A.S.); (J.F.K.); (T.E.); (J.S.)
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway
| | - Terje Espevik
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway; (K.E.N.); (A.S.); (J.F.K.); (T.E.); (J.S.)
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway
| | - Jørgen Stenvik
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway; (K.E.N.); (A.S.); (J.F.K.); (T.E.); (J.S.)
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway
- Department of Infectious Diseases, Clinic of Medicine, St. Olavs Hospital HF, Trondheim University Hospital, NO-7006 Trondheim, Norway
| | - Maria Yurchenko
- Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway; (K.E.N.); (A.S.); (J.F.K.); (T.E.); (J.S.)
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, NO-7491 Trondheim, Norway
- Department of Infectious Diseases, Clinic of Medicine, St. Olavs Hospital HF, Trondheim University Hospital, NO-7006 Trondheim, Norway
- Correspondence:
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Wang B, Liu X, Zhao J, Cao M, Yu Z, Fu Q, Tan F, Yang N, Li C. Characterization, evolution and expression analysis of Toll-like receptor 7 (TLR7) in turbot (Scophthalmus maximus L.). FISH & SHELLFISH IMMUNOLOGY 2022; 125:9-16. [PMID: 35477098 DOI: 10.1016/j.fsi.2022.04.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 03/23/2022] [Accepted: 04/21/2022] [Indexed: 06/14/2023]
Abstract
The pattern recognition receptors (PRRs) can recognize the conserved molecular structures of pathogens to active the innate immune responses, and subsequently induce the antigen-specific adaptive immune responses for the clearance of infected pathogen. Among the PRRs, Toll-like receptors (TLRs) are the first and best characterized PRRs across all the species. Among the TLR members, TLR7 showed significant conservation across the vertebrates, with the lowest rate of evolution for its LRR domains from primates to fishes. In the current study, one TLR7 (SmTLR7) gene was captured in turbot, with a 3144 bp open reading frame (ORF), that encoding 1047 amino acid residues. Following multiple sequence comparison, SmTLR7 was found to have the highest similarity and identity both to Paralichthys olivaceus with 91.9% and 85.9%, respectively. In phylogenetic analysis, SmTLR7 was firstly clustered with Japanese flounder, and then clustered with fugu, rainbow trout, and zebrafish. In addition, SmTLR7 was widely expressed in all the examined tissues with the highest expression level in spleen, followed by skin, while the lowest expression level was detected in blood. Following both Edwardsiella tarda and Vibrio anguillarum challenge, SmTLR7 was significantly down-regulated in gill and intestine, and up-regulated in skin. Moreover, SmTLR7 was significantly up-regulated in head kidney macrophages following LPS, LTA, PGN and polyI:C stimulation, as well as showed the strongest binding ability to LPS, followed by PGN, LTA, and polyI:C in a dose-dependent manner. Finally, following RNAi of SmTLR7, MyD88 and IL-1β were slightly up-regulated, while TRAF6 and IL-8 were significantly down-regulated. The characterization of TLR7 can expand our understanding of the PRRs in teleost fishes, and eventually aid the exploration of interactions between host and pathogen.
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Affiliation(s)
- Beibei Wang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Xiaoli Liu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Jing Zhao
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Min Cao
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Zhouxin Yu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Qiang Fu
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Fenghua Tan
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China
| | - Ning Yang
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China.
| | - Chao Li
- School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China.
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Zhang Z, Liu F, Chen W, Liao Z, Zhang W, Zhang B, Liang H, Chu L, Zhang Z. The importance of N6-methyladenosine modification in tumor immunity and immunotherapy. Exp Hematol Oncol 2022; 11:30. [PMID: 35590394 PMCID: PMC9118853 DOI: 10.1186/s40164-022-00281-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 04/16/2022] [Indexed: 12/31/2022] Open
Abstract
As the most common and abundant RNA modification in eukaryotic cells, N6-methyladenosine (m6A) modification plays an important role in different stages of tumor. m6A can participate in the regulation of tumor immune escape, so as to enhance the monitoring of tumor by the immune system and reduce tumorgenesis. m6A can also affect the tumor progression by regulating the immune cell responses to tumor in tumor microenvironment. In addition, immunotherapy has become the most popular method for the treatment of cancer, in which targets such as immune checkpoints are also closely associated with m6A. This review discusses the roles of N6-methyladenosine modification in tumor immune regulation, their regulatory mechanism, and the prospect of immunotherapy.
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Affiliation(s)
- Ze Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Furong Liu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Wei Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Zhibin Liao
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Wanguang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Bixiang Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Huifang Liang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China
| | - Liang Chu
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China.
| | - Zhanguo Zhang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Hubei Province for the Clinical Medicine Research Center of Hepatic Surgery, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Hubei, 430030, Wuhan, China.
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, 430030, Wuhan, Hubei, China.
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Duan T, Du Y, Xing C, Wang HY, Wang RF. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity. Front Immunol 2022. [PMID: 35309296 DOI: 10.3389/fimmu.2022] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2023] Open
Abstract
Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.
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Affiliation(s)
- Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.,Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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26
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Zhang Y, Liang X, Bao X, Xiao W, Chen G. Toll-like receptor 4 (TLR4) inhibitors: Current research and prospective. Eur J Med Chem 2022; 235:114291. [DOI: 10.1016/j.ejmech.2022.114291] [Citation(s) in RCA: 149] [Impact Index Per Article: 49.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 03/10/2022] [Accepted: 03/12/2022] [Indexed: 01/10/2023]
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Lei CX, Xie YJ, Li SJ, Jiang P, Du JX, Tian JJ. Fabp4 contributes toward regulating inflammatory gene expression and oxidative stress in Ctenopharyngodon idella. Comp Biochem Physiol B Biochem Mol Biol 2022; 259:110715. [PMID: 34999220 DOI: 10.1016/j.cbpb.2022.110715] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/20/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022]
Abstract
Fatty acid-binding protein (Fabp)-4 is a member of the FABP family. Mammalian fabp4 has been demonstrated to involve in inflammation and immunity, whereas the related data of fish fabp4 remain limited. Therefore, we further investigated the effects of fabp4 on immunity in Ctenopharyngodon idella. The fabp4 sequence spanned 405 bp was cloned first, sharing high identity to fabp4 from other fish and mammals. Fabp4 expression was the highest in the adipose tissue, followed by the heart, muscle, and liver. In vivo, lipopolysaccharide (LPS) triggered the expression of fabp4, toll-like receptor (tlr)-22, interleukin (il)-1β, and tumor necrosis factor (tnf)-α in the kidney and spleen. In vitro, exposing C. idella CIK cells to LPS decreased their viability, and the expression of fabp4 was also increased by LPS. However, BMS309403, an inhibitor of FABP4, mitigated these effects. Furthermore, treating the cells with LPS or fabp4 overexpression plasmids resulted in reactive oxygen species (ROS) generation and upregulation of inflammatory genes expression, including tlr22, type-I interferon (ifn-1), interferon regulatory factor (irf)-7, tnfα, il-1β, and interferon-β promoter stimulator 1. These effects were ameliorated by preincubation with BMS309403. Moreover, incubating the cells with glutathione reduced the production of ROS and the expression of inflammatory genes that were evoked by LPS and plasmid treatments. These results showed that fabp4 acts as a pro-inflammatory molecule via elevating ROS levels, providing a novel understanding of the molecular regulation of innate immunity in teleosts.
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Affiliation(s)
- Cai-Xia Lei
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, PR China; Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture and Rural Affairs, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, PR China
| | - Yu-Jing Xie
- Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture and Rural Affairs, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, PR China; College of Fisheries and Life Science, Shanghai Ocean University, Shanghai 201306, PR China
| | - Sheng-Jie Li
- Key Laboratory of Aquatic Animal Immune Technology of Guangdong Province, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, PR China; Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture and Rural Affairs, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, PR China.
| | - Peng Jiang
- Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture and Rural Affairs, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, PR China
| | - Jin-Xing Du
- Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture and Rural Affairs, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, PR China
| | - Jing-Jing Tian
- Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture and Rural Affairs, Pearl River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Guangzhou 510380, PR China
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28
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Duan T, Du Y, Xing C, Wang HY, Wang RF. Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity. Front Immunol 2022; 13:812774. [PMID: 35309296 PMCID: PMC8927970 DOI: 10.3389/fimmu.2022.812774] [Citation(s) in RCA: 425] [Impact Index Per Article: 141.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 02/08/2022] [Indexed: 12/13/2022] Open
Abstract
Innate immunity is the first defense system against invading pathogens. Toll-like receptors (TLRs) are well-defined pattern recognition receptors responsible for pathogen recognition and induction of innate immune responses. Since their discovery, TLRs have revolutionized the field of immunology by filling the gap between the initial recognition of pathogens by innate immune cells and the activation of the adaptive immune response. TLRs critically link innate immunity to adaptive immunity by regulating the activation of antigen-presenting cells and key cytokines. Furthermore, recent studies also have shown that TLR signaling can directly regulate the T cell activation, growth, differentiation, development, and function under diverse physiological conditions. This review provides an overview of TLR signaling pathways and their regulators and discusses how TLR signaling, directly and indirectly, regulates cell-mediated immunity. In addition, we also discuss how TLR signaling is critically important in the host's defense against infectious diseases, autoimmune diseases, and cancer.
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Affiliation(s)
- Tianhao Duan
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Yang Du
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Changsheng Xing
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Helen Y. Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Rong-Fu Wang
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Department of Pediatrics, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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29
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Network Pharmacology- and Molecular Docking-Based Identification of Potential Phytocompounds from Argyreia capitiformis in the Treatment of Inflammation. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:8037488. [PMID: 35140801 PMCID: PMC8820870 DOI: 10.1155/2022/8037488] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Revised: 01/03/2022] [Accepted: 01/15/2022] [Indexed: 12/16/2022]
Abstract
The methanolic extract of Argyreia capitiformis stem was examined for anti-inflammatory activities following network pharmacology analysis and molecular docking study. Based on gas chromatography-mass spectrometry (GC-MS) analysis, 49 compounds were identified from the methanolic extract of A. capitiformis stem. A network pharmacology analysis was conducted against the identified compounds, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology analysis of biological processes and molecular functions were performed. Six proteins (IL1R1, IRAK4, MYD88, TIRAP, TLR4, and TRAF6) were identified from the KEGG pathway analysis and subjected to molecular docking study. Additionally, six best ligand efficiency compounds and positive control (aspirin) from each protein were evaluated for their stability using the molecular dynamics simulation study. Our study suggested that IL1R1, IRAK4, MYD88, TIRAP, TLR4, and TRAF6 proteins may be targeted by compounds in the methanolic extract of A. capitiformis stem to provide anti-inflammatory effects.
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Gu J, Zhao L, Chen YZ, Guo YX, Sun Y, Guo Q, Duan GX, Li C, Tang ZB, Zhang ZX, Qin LQ, Xu JY. Preventive effect of sanguinarine on intestinal injury in mice exposed to whole abdominal irradiation. Biomed Pharmacother 2021; 146:112496. [PMID: 34959117 DOI: 10.1016/j.biopha.2021.112496] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/22/2021] [Accepted: 12/01/2021] [Indexed: 12/18/2022] Open
Abstract
Intestinal injury is one of the major side effects that are induced by medical radiation exposure, and has limited effective therapies. In this study, we investigated the beneficial effects of sanguinarine (SAN) on intestinal injury induced by ionizing radiation (IR) both in vitro and in vivo. Mice were exposed to whole abdominal irradiation (WAI) to mimic clinical scenarios. SAN was injected intraperitoneally to mitigate IR-induced injury. Histological examination was performed to assess the tissue injuries of the spleen and small intestine. A small intestinal epithelial cell line-6 (IEC-6) was analyzed for its viability and apoptosis in vitro under different treatments. Inflammation-related pathways and serum inflammatory cytokines were detected via Western blot analysis and ELISA, respectively. High-throughput sequencing was used to characterize the gut microbiota profile. High-performance liquid chromatography was performed to assess short-chain fatty acid contents in the colon. In vitro, SAN pretreatment protected cell viability and reduced apoptosis in IEC-6 cells. In vivo, SAN pretreatment protected immune organs, alleviated intestinal injury, and promoted intestinal recovery. SAN also reduced the levels of inflammatory cytokines, suppressed high mobility group box 1 (HMGB1)/ Toll-like receptor 4 (TLR4) pathway activation, and modulated gut microbiota composition. Our findings demonstrate that the beneficial properties of SAN alleviated intestinal radiation injury. Thus, SAN represents a therapeutic option for protecting against IR-induced intestinal injury in preclinical settings.
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Affiliation(s)
- Jia Gu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu, China
| | - Lin Zhao
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu, China
| | - Yu-Zhong Chen
- Yancheng Municipal Center for Disease Control and Prevention, Yancheng, Jiangsu, China
| | - Ya-Xin Guo
- Department of Nutrition and Food Hygiene School of Public Health, Soochow University, Suzhou, Jiangsu, China
| | - Yue Sun
- Department of Nutrition and Food Hygiene School of Public Health, Soochow University, Suzhou, Jiangsu, China
| | - Qing Guo
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu, China
| | - Guang-Xin Duan
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu, China
| | - Chao Li
- Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
| | - Zhi-Bing Tang
- Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
| | - Zi-Xiang Zhang
- State Key Laboratory of Radiation Medicine and Protection, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Li-Qiang Qin
- Department of Nutrition and Food Hygiene School of Public Health, Soochow University, Suzhou, Jiangsu, China.
| | - Jia-Ying Xu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, Jiangsu, China.
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Gao F, Liu J, Lu M, Liu Z, Wang M, Ke X, Yi M, Cao J. Nile tilapia Toll-like receptor 7 subfamily: Intracellular TLRs that recruit MyD88 as an adaptor and activate the NF-κB pathway in the immune response. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2021; 125:104173. [PMID: 34144119 DOI: 10.1016/j.dci.2021.104173] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 06/10/2021] [Accepted: 06/12/2021] [Indexed: 06/12/2023]
Abstract
Toll-like receptor 7 (TLR7) subfamily members are important pattern recognition receptors that participate in the recognition of pathogen-associated molecular patterns. In the present study, three TLR family members, OnTLR7, OnTLR8 and OnTLR9, were identified in the Nile tilapia Oreochromis niloticus. TLR7-, TLR8-and TLR9-deduced proteins have typical structural characteristics of TLRs, including Toll/interleukin-1 receptor (TIR), leucine-rich repeat (LRR) and transmembrane region (TM). OnTLR7, OnTLR8 and OnTLR9 were broadly expressed in all of the tissues tested, with the highest expression levels in the brain (TLR7) and spleen (TLR8 and TLR9). Moreover, the expression levels of OnTLR7, OnTLR8 and OnTLR9 were significantly increased in most tested tissues after Streptococcus agalactiae infection in vivo. After LPS stimulation, OnTLR7 and OnTLR9 mRNA expression levels were downregulated in the intestine and upregulated in the liver, spleen and kidney; however, OnTLR8 mRNA expression levels were upregulated in the kidney only after LPS stimulation for 5 d. After Poly I:C stimulation, OnTLR7 and OnTLR9 mRNA expression levels were upregulated in the intestine, liver, spleen and kidney, and the highest expression was found in the liver, while OnTLR8 mRNA expression levels were upregulated in the intestine, liver and kidney and downregulated in the spleen. Subcellular localization of OnTLR7, OnTLR8, and OnTLR9 in 293T cells showed that OnTLR9 was distributed in both the cytoplasm and nucleus while OnTLR8 and OnTLR7 were distributed mainly in the cytoplasm. Overexpression of OnTLR7, OnTLR8 and OnTLR9 in 293T cells had no significant effect on the activity of NF-κB, but they could significantly enhance MyD88-mediated NF-κB activity after cotransfection with MyD88. Pulldown assays showed that OnTLR7, OnTLR8, and OnTLR9 could interact with OnMyD88. Taken together, these results indicate that TLR7 subfamily genes play a role in the immune response to pathogen invasion of Nile tilapia.
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Affiliation(s)
- Fengying Gao
- Pearl River Fisheries Research Institute, Chinese Academy of Fishery Science, Guangzhou, 510380, PR China; Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, PR China
| | - Jie Liu
- Pearl River Fisheries Research Institute, Chinese Academy of Fishery Science, Guangzhou, 510380, PR China; Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, PR China; College of Fisheries, Guangdong Ocean University, Zhanjiang 524025, China
| | - Maixin Lu
- Pearl River Fisheries Research Institute, Chinese Academy of Fishery Science, Guangzhou, 510380, PR China; Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, PR China.
| | - Zhigang Liu
- Pearl River Fisheries Research Institute, Chinese Academy of Fishery Science, Guangzhou, 510380, PR China; Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, PR China
| | - Miao Wang
- Pearl River Fisheries Research Institute, Chinese Academy of Fishery Science, Guangzhou, 510380, PR China; Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, PR China
| | - Xiaoli Ke
- Pearl River Fisheries Research Institute, Chinese Academy of Fishery Science, Guangzhou, 510380, PR China; Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, PR China
| | - Mengmeng Yi
- Pearl River Fisheries Research Institute, Chinese Academy of Fishery Science, Guangzhou, 510380, PR China; Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, PR China
| | - Jianmeng Cao
- Pearl River Fisheries Research Institute, Chinese Academy of Fishery Science, Guangzhou, 510380, PR China; Key Laboratory of Tropical & Subtropical Fishery Resource Application & Cultivation, Ministry of Agriculture, PR China
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Maguire PT, Loughran ST, Harvey R, Johnson PA. A TLR5 mono-agonist restores inhibited immune responses to Streptococcus pneumoniae during influenza virus infection in human monocytes. PLoS One 2021; 16:e0258261. [PMID: 34644311 PMCID: PMC8513880 DOI: 10.1371/journal.pone.0258261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 09/22/2021] [Indexed: 11/20/2022] Open
Abstract
Influenza A virus (IAV) predisposes individuals to often more severe secondary bacterial infections with Streptococcus pneumonia (S. pneumoniae). The outcomes of these infections may be made worse with the increase in antimicrobial resistance and a lack of new treatments to combat this. Th17 responses are crucial in clearing S. pneumoniae from the lung. We previously demonstrated that early IAV infection of human monocytes significantly reduced levels of S. pneumoniae-driven cytokines involved in the Th17 response. Here, we have further identified that IAV targets specific TLRs (TLR2, TLR4, TLR9) involved in sensing S. pneumoniae infection resulting, in a reduction in TLR agonist-induced IL-23 and TGF-β. The effect of IAV is more profound on the TLR2 and TLR9 pathways. We have established that IAV-mediated inhibition of TLR9-induction is related to a downregulation of RORC, a Th17 specific transcription factor. Other studies using mouse models demonstrated that TLR5 agonism improved the efficacy of antibiotics in the treatment of IAV/S. pneumoniae co-infections. Therefore, we investigated if TLR5 agonism could restore inhibited Th17 responses in human monocytes. Levels of pneumococcus-driven cytokines, which had previously been inhibited by IAV were not reduced in the presence of the TLR5 mono-agonist, suggesting that such treatment may overcome IAV inhibition of Th17 responses. The importance of our research is in demonstrating the IAV directly targets S. pneumoniae-associated TLR pathways. Additionally, the IAV-inhibition of Th17 responses can be restored by TLR5 agonism, which indicates that there may be a different Th17 signalling pathway which is not affected by IAV infection.
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Affiliation(s)
- Paula T Maguire
- Viral Immunology Laboratory, School of Nursing, Psychotherapy and Community Health, Dublin City University, Dublin, Ireland
| | - Sinéad T Loughran
- Department of Applied Science, Dundalk Institute of Technology, County Louth, Ireland
| | - Ruth Harvey
- National Institute for Biological Standards and Controls, Potters Bar, Herts, United Kingdom
| | - Patricia A Johnson
- Viral Immunology Laboratory, School of Nursing, Psychotherapy and Community Health, Dublin City University, Dublin, Ireland
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Saadat M, Gandomkar M, Bahreinipour A, Bandehpour M, Kazemi B, Mosaffa N. Evaluation of the designed multi-epitope protein of Brucella melitensis in guinea pigs. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:833-841. [PMID: 34630961 PMCID: PMC8487608 DOI: 10.22038/ijbms.2021.54667.12267] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 05/01/2021] [Indexed: 11/06/2022]
Abstract
Objectives One of the causes of human and animal zoonotic infections is Brucella melitensis, which is transmitted to humans through dairy products. It seems for prevention of human infection we might protect the livestock by an efficient protein as a vaccine candidate. For this purpose, the use of immunogenic proteins of bacteria is able to create immunity the same as the traditional vaccines. Materials and Methods In this study, by finding the immunogenic antigens of this bacterium by 2-dimensional gel electrophoresis and MALDI-TOF methods and also the proteins reported in other studies, we found the epitopes of the bacterial antigenic determinants in silico. Nineteen peptides of T and B epitopes were selected. They were ligated with linkers and after gene synthesis, the designed polypeptide was expressed in Escherichia coli BL21. The purified recombinant MEL protein mixed with chitin was injected subcutaneously into three 300 g male guinea pigs three times. Also, PBS control and Rev.1 commercial vaccine groups were considered. Results The results show that MEL polypeptide is equal to the Rev.1 vaccine in stimulating secretion of IFNγ and IL2 and specific IgG. High levels of IL-2 emphasize the activation of the cellular immunity, and in particular comparison of PI in guinea pig's spleen cells treated with recombinant MEL protein on days 0 and 5 show that it has significant proliferation compared with PBS unstimulated cells. Conclusion This recombinant protein could be a subunit protein with sufficient efficiency in stimulating the humoral and cellular-mediated immune system against B. melitansis.
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Affiliation(s)
- Mina Saadat
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masoud Gandomkar
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Mojgan Bandehpour
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bahram Kazemi
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nariman Mosaffa
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Targeting Toll-like Receptor (TLR) Pathways in Inflammatory Arthritis: Two Better Than One? Biomolecules 2021; 11:biom11091291. [PMID: 34572504 PMCID: PMC8464963 DOI: 10.3390/biom11091291] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 12/17/2022] Open
Abstract
Inflammatory arthritis is a cluster of diseases caused by unregulated activity of the immune system. The lost homeostasis is followed by the immune attack of one’s self, what damages healthy cells and tissues and leads to chronic inflammation of various tissues and organs (e.g., joints, lungs, heart, eyes). Different medications to control the excessive immune response are in use, however, drug resistances, flare-reactions and adverse effects to the current therapies are common in the affected patients. Thus, it is essential to broaden the spectrum of alternative treatments and to develop disease-modifying drugs. In the last 20 years, the involvement of the innate immune receptors TLRs in inflammatory arthritis has been widely investigated and targeting either the receptor itself or the proteins in the downstream signalling cascades has emerged as a promising therapeutic strategy. Yet, concerns about the use of pharmacological agents that inhibit TLR activity and may leave the host unprotected against invading pathogens and toxicity issues amid inhibition of downstream kinases crucial in various cellular functions have arisen. This review summarizes the existing knowledge on the role of TLRs in inflammatory arthritis; in addition, the likely druggable related targets and the developed inhibitors, and discusses the pros and cons of their potential clinical use.
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Basheer AS, Abas F, Othman I, Naidu R. Role of Inflammatory Mediators, Macrophages, and Neutrophils in Glioma Maintenance and Progression: Mechanistic Understanding and Potential Therapeutic Applications. Cancers (Basel) 2021; 13:4226. [PMID: 34439380 PMCID: PMC8393628 DOI: 10.3390/cancers13164226] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/16/2021] [Accepted: 08/17/2021] [Indexed: 02/07/2023] Open
Abstract
Gliomas are the most common, highly malignant, and deadliest forms of brain tumors. These intra-cranial solid tumors are comprised of both cancerous and non-cancerous cells, which contribute to tumor development, progression, and resistance to the therapeutic regimen. A variety of soluble inflammatory mediators (e.g., cytokines, chemokines, and chemotactic factors) are secreted by these cells, which help in creating an inflammatory microenvironment and contribute to the various stages of cancer development, maintenance, and progression. The major tumor infiltrating immune cells of the tumor microenvironment include TAMs and TANs, which are either recruited peripherally or present as brain-resident macrophages (microglia) and support stroma for cancer cell expansion and invasion. These cells are highly plastic in nature and can be polarized into different phenotypes depending upon different types of stimuli. During neuroinflammation, glioma cells interact with TAMs and TANs, facilitating tumor cell proliferation, survival, and migration. Targeting inflammatory mediators along with the reprogramming of TAMs and TANs could be of great importance in glioma treatment and may delay disease progression. In addition, an inhibition of the key signaling pathways such as NF-κB, JAK/STAT, MAPK, PI3K/Akt/mTOR, and TLRs, which are activated during neuroinflammation and have an oncogenic role in glioblastoma (GBM), can exert more pronounced anti-glioma effects.
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Affiliation(s)
- Abdul Samad Basheer
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Malaysia; (A.S.B.); (I.O.)
| | - Faridah Abas
- Laboratory of Natural Products, Faculty of Science, University Putra Malaysia (UPM), Serdang 43400, Malaysia;
- Department of Food Science, Faculty of Food Science and Technology, University Putra Malaysia (UPM), Serdang 434000, Malaysia
| | - Iekhsan Othman
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Malaysia; (A.S.B.); (I.O.)
| | - Rakesh Naidu
- Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway 47500, Malaysia; (A.S.B.); (I.O.)
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Chen K, Cagliani J, Aziz M, Tan C, Brenner M, Wang P. Extracellular CIRP activates STING to exacerbate hemorrhagic shock. JCI Insight 2021; 6:e143715. [PMID: 34291735 PMCID: PMC8410031 DOI: 10.1172/jci.insight.143715] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 06/09/2021] [Indexed: 01/07/2023] Open
Abstract
Stimulator of IFN genes (STING) activates TANK-binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3) to produce type I IFNs. Extracellular cold-inducible RNA-binding protein (eCIRP) is released from cells during hemorrhagic shock (HS). We hypothesized that eCIRP activates STING to induce inflammation and acute lung injury (ALI) after HS. WT and STING–/– mice underwent controlled hemorrhage by bleeding, followed by fluid resuscitation. Blood and lungs were collected at 4 hours after resuscitation. Serum ALT, AST, LDH, IL-6, and IFN-β were significantly decreased in STING–/– mice compared with WT mice after HS. In STING–/– mice, the levels of pTBK1 and pIRF3, and expression of TNF-α, IL-6, and IL-1β mRNAs and proteins in the lungs, were significantly decreased compared with WT HS mice. The 10-day mortality rate in STING–/– mice was significantly reduced. I.v. injection of recombinant mouse CIRP (rmCIRP) in STING–/– mice showed a significant decrease in pTBK1 and pIRF3 and in IFN-α and IFN-β mRNAs and proteins in the lungs compared with rmCIRP-treated WT mice. Treatment of TLR4–/–, MyD88–/–, and TRIF–/– macrophages with rmCIRP significantly decreased pTBK1 and pIRF3 levels and IFN-α and IFN-β mRNAs and proteins compared with WT macrophages. HS increases eCIRP levels, which activate STING through TLR4/MyD88/TRIF pathways to exacerbate inflammation.
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Affiliation(s)
- Kehong Chen
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Joaquin Cagliani
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Monowar Aziz
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Chuyi Tan
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Max Brenner
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA
| | - Ping Wang
- Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, New York, USA.,Department of Surgery and Molecular Medicine, Zucker School of Medicine at Hofstra/Northwell, Manhasset, New York, USA
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Smyth R, Sun J. Protein Kinase R in Bacterial Infections: Friend or Foe? Front Immunol 2021; 12:702142. [PMID: 34305942 PMCID: PMC8297547 DOI: 10.3389/fimmu.2021.702142] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 06/28/2021] [Indexed: 12/28/2022] Open
Abstract
The global antimicrobial resistance crisis poses a significant threat to humankind in the coming decades. Challenges associated with the development of novel antibiotics underscore the urgent need to develop alternative treatment strategies to combat bacterial infections. Host-directed therapy is a promising new therapeutic strategy that aims to boost the host immune response to bacteria rather than target the pathogen itself, thereby circumventing the development of antibiotic resistance. However, host-directed therapy depends on the identification of druggable host targets or proteins with key functions in antibacterial defense. Protein Kinase R (PKR) is a well-characterized human kinase with established roles in cancer, metabolic disorders, neurodegeneration, and antiviral defense. However, its role in antibacterial defense has been surprisingly underappreciated. Although the canonical role of PKR is to inhibit protein translation during viral infection, this kinase senses and responds to multiple types of cellular stress by regulating cell-signaling pathways involved in inflammation, cell death, and autophagy - mechanisms that are all critical for a protective host response against bacterial pathogens. Indeed, there is accumulating evidence to demonstrate that PKR contributes significantly to the immune response to a variety of bacterial pathogens. Importantly, there are existing pharmacological modulators of PKR that are well-tolerated in animals, indicating that PKR is a feasible target for host-directed therapy. In this review, we provide an overview of immune cell functions regulated by PKR and summarize the current knowledge on the role and functions of PKR in bacterial infections. We also review the non-canonical activators of PKR and speculate on the potential mechanisms that trigger activation of PKR during bacterial infection. Finally, we provide an overview of existing pharmacological modulators of PKR that could be explored as novel treatment strategies for bacterial infections.
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Affiliation(s)
- Robin Smyth
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Jim Sun
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
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TLR4 biased small molecule modulators. Pharmacol Ther 2021; 228:107918. [PMID: 34171331 DOI: 10.1016/j.pharmthera.2021.107918] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/31/2021] [Accepted: 06/01/2021] [Indexed: 12/12/2022]
Abstract
Biased pharmacological modulators provide potential therapeutic benefits, including greater pharmacodynamic specificity, increased efficiency and reduced adverse effects. Therefore, the identification of such modulators as drug candidates is highly desirable. Currently, attention was mainly paid to biased signaling modulators targeting G protein-coupled receptors (GPCRs). The biased signaling modulation of non-GPCR receptors has yet to be exploited. Toll-like receptor 4 (TLR4) is one such non-GPCR receptor, which involves MyD88-dependent and TRIF-dependent signaling pathways. Moreover, the dysregulation of TLR4 contributes to numerous diseases, which highlights the importance of biased modulator development targeting TLR4. In this review, we aim to provide an overview of the recent progress in the discovery of biased modulators of TLR4. The challenges and methods for the discovery of TLR4 biased modulators are also outlined. Small molecules biasedly modulating the TLR4 signaling axis not only provide probes to fine-tune receptor conformation and signaling but also provide an opportunity to identify promising drug candidates. The discovery of biased modulators of TLR4 would provide insight for the future development of biased modulators for other non-GPCR receptors.
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Membrive Jiménez C, Pérez Ramírez C, Sánchez Martín A, Vieira Maroun S, Arias Santiago SA, Ramírez Tortosa MDC, Jiménez Morales A. Influence of Genetic Polymorphisms on Response to Biologics in Moderate-to-Severe Psoriasis. J Pers Med 2021; 11:293. [PMID: 33921427 PMCID: PMC8069496 DOI: 10.3390/jpm11040293] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/29/2021] [Accepted: 04/02/2021] [Indexed: 12/12/2022] Open
Abstract
Psoriasis is a chronic inflammatory skin pathology of autoimmune origin and unknown etiology. There are various therapies for treating it, including a wide range of biopharmaceuticals indicated in moderate-to-severe psoriasis. Depending on their therapeutic target, they are classified as tumor necrosis factor inhibitors (anti-TNF) or cytokine inhibitors (interleukin-12, 23, and 17 antagonists). Although they have proved effective and safe, in clinical practice, many patients show a short- and long-term suboptimal response and even varying degrees of toxicity. This variability in response may be influenced by genetic factors, such as polymorphisms in the genes involved in the pathological environment, metabolism or mechanism of action of the drug that could affect the effectiveness and toxicity of biological therapies. This review assesses pharmacogenetic studies of the impact of genetic factors on response to biopharmaceuticals and toxicity in patients diagnosed with moderate-to-severe psoriasis. The results suggest that polymorphisms detected in the HLA genes, in genes that encode cytokines (TNF, IL genes, TNFAIP3), transporters (PDE3A-SLCO1C1, SLC12A8), receptors (TNFRSF1B, CD84, FCGR2A and FCGR3A, IL17RA, IL23R, TLR genes, PGLYRP4) and associated proteins (TNFAIP3, LY96, TIRAP, FBXL19), as well as other genes implicated in the pathogenesis of psoriasis (CDKAL1, CARD14, PTTG1, MAP3K1, ZNF816A, GBP6, CTNNA2, HTR2A, CTLA4, TAP1) can be used in the future as predictive markers of treatment response and/or toxicity with biological therapies in patients diagnosed with moderate-to-severe psoriasis, tailoring treatment to the individual patient.
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Affiliation(s)
- Cristina Membrive Jiménez
- Pharmacogenetics Unit, Pharmacy Service, University Hospital Virgen de las Nieves, 18014 Granada, Spain; (C.M.J.); (A.S.M.); (S.V.M.); (A.J.M.)
| | - Cristina Pérez Ramírez
- Pharmacogenetics Unit, Pharmacy Service, University Hospital Virgen de las Nieves, 18014 Granada, Spain; (C.M.J.); (A.S.M.); (S.V.M.); (A.J.M.)
- Department of Biochemistry, Faculty of Pharmacy, Campus Universitario de Cartuja, University of Granada, 18071 Granada, Spain;
| | - Almudena Sánchez Martín
- Pharmacogenetics Unit, Pharmacy Service, University Hospital Virgen de las Nieves, 18014 Granada, Spain; (C.M.J.); (A.S.M.); (S.V.M.); (A.J.M.)
| | - Sayleth Vieira Maroun
- Pharmacogenetics Unit, Pharmacy Service, University Hospital Virgen de las Nieves, 18014 Granada, Spain; (C.M.J.); (A.S.M.); (S.V.M.); (A.J.M.)
| | | | | | - Alberto Jiménez Morales
- Pharmacogenetics Unit, Pharmacy Service, University Hospital Virgen de las Nieves, 18014 Granada, Spain; (C.M.J.); (A.S.M.); (S.V.M.); (A.J.M.)
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Freen-van Heeren JJ. Toll-like receptor-2/7-mediated T cell activation: An innate potential to augment CD8 + T cell cytokine production. Scand J Immunol 2021; 93:e13019. [PMID: 33377182 DOI: 10.1111/sji.13019] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 12/11/2022]
Abstract
CD8+ T cells are critical to combat pathogens and eradicate malignantly transformed cells. To exert their effector function and kill target cells, T cells produce copious amounts of effector molecules, including the pro-inflammatory cytokines interferon γ, tumour necrosis factor α and interleukin 2. TCR triggering alone is sufficient to induce cytokine secretion by effector and memory CD8+ T cells. However, T cells can also be directly activated by pathogen-derived molecules, such as through the triggering of Toll-like receptors (TLRs). TLR-mediated pathogen sensing by T cells results in the production of only interferon γ. However, in particular when the antigen load on target cells is low, or when TCR affinity to the antigen is limited, antigen-experienced T cells can benefit from costimulatory signals. TLR stimulation can also function in a costimulatory fashion to enhance TCR triggering. Combined TCR and TLR triggering enhances the proliferation, memory formation and effector function of T cells, resulting in enhanced production of interferon γ, tumour necrosis factor α and interleukin 2. Therefore, TLR ligands or the exploitation of TLR signalling could provide novel opportunities for immunotherapy approaches. In fact, CD19 CAR T cells bearing an intracellular TLR2 costimulatory domain were recently employed to treat cancer patients in a clinical trial. Here, the current knowledge regarding TLR2/7 stimulation-induced cytokine production by T cells is reviewed. Specifically, the transcriptional and post-transcriptional pathways engaged upon TLR2/7 sensing and TLR2/7 signalling are discussed. Finally, the potential uses of TLRs to enhance the anti-tumor effector function of T cells are explored.
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Shi M, Zhu Y, Yan J, Rouby J, Summah H, Monsel A, Qu J. Role of miR-466 in mesenchymal stromal cell derived extracellular vesicles treating inoculation pneumonia caused by multidrug-resistant Pseudomonas aeruginosa. Clin Transl Med 2021; 11:e287. [PMID: 33463070 PMCID: PMC7805403 DOI: 10.1002/ctm2.287] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 12/27/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022] Open
Abstract
RATIONALE The effects of mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC EVs) on multidrug-resistant pseudomonas aeruginosa (MDR-PA)-induced pneumonia remain unclear. MATERIALS AND METHODS MicroRNA array and RT-PCR were used to select the major microRNA in MSC EVs. Human peripheral blood monocytes were obtained and isolated from qualified patients. The crosstalk between MSCs/MSC EVs and macrophages in vitro was studied. MDR-PA pneumonia models were further established in C57BL/6 mice and MSC EVs or miR-466 overexpressing MSC EVs were intratracheally instilled. RESULTS MiR-466 was highly expressed in MSC EVs. MSCs and miR-466 promoted macrophage polarization toward Type 2 phenotype through TIRAP-MyD88-NFκB axis. Moreover, cocultured macrophages with miR-466 overexpressing MSCs significantly increased the phagocytosis of macrophages. MSC EVs significantly reduced mortality and decreased influx of BALF neutrophils, proinflammatory factor levels, protein, and bacterial load in murine MDR-PA pneumonia. Administration of miR-466 overexpressing MSC EVs further alleviated the inflammatory severity. CONCLUSIONS MSC-derived EVs containing high levels of miR-466 may partly participate in host immune responses to MDR-PA. Both MSCs and MSC EVs have therapeutic effects in treating MDR-PA-induced pneumonia.
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Affiliation(s)
- Meng‐meng Shi
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Ying‐gang Zhu
- Department of Pulmonary and Critical Care Medicine, Hua‐dong HospitalFudan UniversityShanghaiChina
| | - Jia‐yang Yan
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Jean‐Jacques Rouby
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié‐Salpêtrière Hospital, Assistance Publique‐Hôpitaux de Paris (APHP)Sorbonne UniversityParisFrance
| | - Hanssa Summah
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Antoine Monsel
- Multidisciplinary Intensive Care Unit, Department of Anesthesiology and Critical Care, La Pitié‐Salpêtrière Hospital, Assistance Publique‐Hôpitaux de Paris (APHP)Sorbonne UniversityParisFrance
- INSERM, UMR S 959, Immunology‐Immunopathology‐ Immunotherapy (I3)Sorbonne UniversitéParisF‐75005France
- Biotherapy (CIC‐BTi) and Inflammation‐Immunopathology‐Biotherapy Department (DHU i2B)Hôpital Pitié‐SalpêtrièreAP‐HPParisF‐75651France
| | - Jie‐ming Qu
- Department of Respiratory and Critical Care Medicine, Ruijin Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
- Institute of Respiratory Diseases, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
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Association of TIRAP (rs8177374) and MyD88 (rs6853) genetic polymorphisms with susceptibility to pulmonary tuberculosis and treatment response. GENE REPORTS 2020. [DOI: 10.1016/j.genrep.2020.100825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Zamyatina A, Heine H. Lipopolysaccharide Recognition in the Crossroads of TLR4 and Caspase-4/11 Mediated Inflammatory Pathways. Front Immunol 2020; 11:585146. [PMID: 33329561 PMCID: PMC7732686 DOI: 10.3389/fimmu.2020.585146] [Citation(s) in RCA: 120] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 10/23/2020] [Indexed: 12/12/2022] Open
Abstract
The innate immune response to lipopolysaccharide is essential for host defense against Gram-negative bacteria. In response to bacterial infection, the TLR4/MD-2 complex that is expressed on the surface of macrophages, monocytes, dendritic, and epithelial cells senses picomolar concentrations of endotoxic LPS and triggers the production of various pro-inflammatory mediators. In addition, LPS from extracellular bacteria which is either endocytosed or transfected into the cytosol of host cells or cytosolic LPS produced by intracellular bacteria is recognized by cytosolic proteases caspase-4/11 and hosts guanylate binding proteins that are involved in the assembly and activation of the NLRP3 inflammasome. All these events result in the initiation of pro-inflammatory signaling cascades directed at bacterial eradication. However, TLR4-mediated signaling and caspase-4/11-induced pyroptosis are largely involved in the pathogenesis of chronic and acute inflammation. Both extra- and intracellular LPS receptors-TLR4/MD-2 complex and caspase-4/11, respectively-are able to directly bind the lipid A motif of LPS. Whereas the structural basis of lipid A recognition by the TLR4 complex is profoundly studied and well understood, the atomic mechanism of LPS/lipid A interaction with caspase-4/11 is largely unknown. Here we describe the LPS-induced TLR4 and caspase-4/11 mediated signaling pathways and their cross-talk and scrutinize specific structural features of the lipid A motif of diverse LPS variants that have been reported to activate caspase-4/11 or to induce caspase-4/11 mediated activation of NLRP3 inflammasome (either upon transfection of LPS in vitro or upon infection of cell cultures with intracellular bacteria or by LPS as a component of the outer membrane vesicles). Generally, inflammatory caspases show rather similar structural requirements as the TLR4/MD-2 complex, so that a "basic" hexaacylated bisphosphorylated lipid A architecture is sufficient for activation. However, caspase-4/11 can sense and respond to much broader variety of lipid A variants compared to the very "narrow" specificity of TLR4/MD-2 complex as far as the number and the length of lipid chains attached at the diglucosamine backbone of lipid A is concerned. Besides, modification of the lipid A phosphate groups with positively charged appendages such as phosphoethanolamine or aminoarabinose could be essential for the interaction of lipid A/LPS with inflammatory caspases and related proteins.
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Affiliation(s)
- Alla Zamyatina
- Institute of Organic Chemistry, Department of Chemistry, University of Natural Resources and Life Sciences, Vienna, Austria
| | - Holger Heine
- Research Group Innate Immunity, Research Center Borstel—Leibniz Lung Center, Airway Research Center North (ARCN), German Center for Lung Disease (DZL), Borstel, Germany
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Monoclonal Antibody to CD14, TLR4, or CD11b: Impact of Epitope and Isotype Specificity on ROS Generation by Human Granulocytes and Monocytes. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:5708692. [PMID: 33294123 PMCID: PMC7700042 DOI: 10.1155/2020/5708692] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 09/24/2020] [Accepted: 11/10/2020] [Indexed: 02/01/2023]
Abstract
Lipopolysaccharides (LPSs or endotoxins) from Gram-negative bacteria represent pathogen-associated molecular patterns (PAMPs) that are recognized by CD14 and Toll-like receptor 4 (TLR4). Lipopolysaccharides prime polymorphonuclear leukocytes (PMNs) for substantial production of reactive oxygen species (ROS) during its response to secondary stimuli such as chemoattractants or pathogens. The excessive ROS production can damage surrounding host tissues, thereby amplifying the inflammatory reaction caused by pathogens. Today, specific antibodies against CD14, TLR4, and CD11b are being used as the essential tools to elucidate the role of these receptors in acute inflammation and some of these antibodies have advised as therapeutic agents for clinical use. Because each antibody has two antigen-binding arms [F(ab′)2] and one Fc arm, its effect on cellular response is much more complicated rather than simple blockage of target receptor. In fact, IgG antibody, once bound to target receptor, engages Fc receptors γ (FcγRs) and thereby is able to activate the adaptive immune system. The consequences of antibody-dependent binary heterotypic association of CD14, TLR4, or CD11b with FcγRs as well as homotypic one on ROS production are not well elucidated. Moreover, the consequences of antigenic recognition of CD14, TLR4, or CD11b by specific F(ab′)2 fragments are not always investigated. In this review, we will discuss known mechanisms underlying the therapeutic efficiency of CD14, TLR4, and CD11b/CD18 antibodies with a focus on LPS-dependent ROS or cytokine production by PMNs or monocytes. The impacts of F(ab′)2 as well as antibody IgG subclasses (isotypes) in therapeutic efficiency or agonistic potency of known antibodies against abovementioned receptors are presented. We also pay attention to how the efficiency of different IgG antibody subclasses is modulated during LPS-induced inflammation and by production of priming agents such as interferon γ (IFN-γ). Our review reinforces the molecular targets and therapeutic approaches to amelioration of harmful consequences of excessive activation of human pattern recognition receptors.
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Toshchakov VY, Javmen A. Targeting the TLR signalosome with TIR domain-derived cell-permeable decoy peptides: the current state and perspectives. Innate Immun 2020; 26:35-47. [PMID: 31955621 PMCID: PMC6974878 DOI: 10.1177/1753425919844310] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The ability to engineer pharmaceuticals that target the signal-dependent
interactions of signaling proteins should revolutionize drug development. One
approach to the rational design of protein interaction inhibitors uses decoy
peptides, i.e. segments of protein primary sequence, which are derived from
interfaces that mediate functional protein interactions. Decoy peptides often
retain the ability of the full-length prototype to bind the docking site of the
folded protein and thereby block the signal transduction. This review summarizes
advances made in the last decade in the development of cell-permeable decoy
peptide (CPDP) inhibitors to target the Toll/IL-1R resistance (TIR)
domain-mediated protein interactions in TLR signaling, in connection with the
recent progress in understanding of the TLR signalosome assembly mechanisms. We
present a large collection of currently available, TIR-targeting CPDPs and
propose their classification based on the types of TIR–TIR interactions they
target. The binding behavior of different CPDP-TIR pairs, studied in cell-based
assays and in binary in vitro systems using recombinant TIR
domains, is also reviewed. The available affinity data provide benchmarks for
rapid preliminary evaluation of future inhibitors. We review literature that
evaluates the in vivo potency of select CPDPs and attempt to
outline the areas of forthcoming progress, towards the development of CPDP-based
TLR inhibitors of pharmaceutical grade.
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Affiliation(s)
- Vladimir Y Toshchakov
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Artur Javmen
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, USA
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Kim KI, Lee UH, Cho M, Jung SH, Min EY, Park JW. Transcriptome analysis based on RNA-seq of common innate immune responses of flounder cells to IHNV, VHSV, and HIRRV. PLoS One 2020; 15:e0239925. [PMID: 32986779 PMCID: PMC7521715 DOI: 10.1371/journal.pone.0239925] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 09/15/2020] [Indexed: 12/25/2022] Open
Abstract
Viral hemorrhagic septicemia virus (VHSV) and hirame rhabdovirus (HIRRV) belong to the genus Novirhabdovirus and are the causative agents of a serious disease in cultured flounder. However, infectious hematopoietic necrosis virus (IHNV), a prototype of the genus Novirhabdovirus, does not cause disease in flounder. To determine whether IHNV growth is restricted in flounder cells, we compared the growth of IHNV with that of VHSV and HIRRV in hirame natural embryo (HINAE) cells infected with novirhabdoviruses at 1 multiplicity of infection. Unexpectedly, we found that IHNV grew as well as VHSV and HIRRV. For successful growth in host cells, viruses modulate innate immune responses exerted by virus-infected cells. Our results suggest that IHNV, like VHSV and HIRRV, has evolved the ability to overcome the innate immune response of flounder cells. To determine the innate immune response genes of virus-infected HINAE cells which are commonly modulated by the three novirhabdoviruses, we infected HINAE cells with novirhabdoviruses at multiplicity of infection (MOI) 1 and performed an RNA sequencing-based transcriptome analysis at 24 h post-infection. We discovered ~12,500 unigenes altered by novirhabdovirus infection and found that many of these were involved in multiple cellular pathways. After novirhabdovirus infection, 170 genes involved in the innate immune response were differentially expressed compared to uninfected cells. Among them, 9 genes changed expression by more than 2-fold and were commonly modulated by all three novirhabdoviruses. Interferon regulatory factor 8 (IRF8), C-X-C motif chemokine receptor 1 (CXCR1), Toll/interleukin-1 receptor domain-containing adapter protein (TIRAP), cholesterol 25-hydroxylase (CH25H), C-X-C motif chemokine ligand 11, duplicate 5 (CXCL11.5), and Toll-like receptor 2 (TLR2) were up-regulated, whereas C-C motif chemokine receptor 6a (CCR6a), interleukin-12a (IL12a), and Toll-like receptor 1 (TLR1) were down-regulated. These genes have been reported to be involved in antiviral responses and, thus, their modulation may be critical for the growth of novirhabdovirus in flounder cells. This is the first report to identify innate immune response genes in flounder that are commonly modulated by IHNV, VHSV, and HIRRV. These data will provide new insights into how novirhabdoviruses survive the innate immune response of flounder cells.
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Affiliation(s)
- Kwang Il Kim
- Pathology Research Division, National Institute of Fisheries Science, Busan, Korea
| | - Unn Hwa Lee
- Department of Biological Sciences, University of Ulsan, Ulsan, Korea
| | - Miyoung Cho
- Pathology Research Division, National Institute of Fisheries Science, Busan, Korea
| | - Sung-Hee Jung
- Pathology Research Division, National Institute of Fisheries Science, Busan, Korea
| | - Eun Young Min
- Pathology Research Division, National Institute of Fisheries Science, Busan, Korea
| | - Jeong Woo Park
- Department of Biological Sciences, University of Ulsan, Ulsan, Korea
- * E-mail:
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Fang L, Wang KK, Huang Q, Cheng F, Huang F, Liu WW. Nucleolin Mediates LPS-induced Expression of Inflammatory Mediators and Activation of Signaling Pathways. Curr Med Sci 2020; 40:646-653. [PMID: 32862374 DOI: 10.1007/s11596-020-2229-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 05/05/2020] [Indexed: 12/19/2022]
Abstract
In this study, we investigated the effects of nucleolin on lipopolysaccharide (LPS)-induced activation of MAPK and NF-KappaB (NF-κB) signaling pathways and secretion of TNF-α, IL-1β and HMGB1 in THP-1 monocytes. Immunofluorescence assay and Western blotting were used to identify the nucleolin expression in cell membrane, cytoplasm and nucleus of THP-1 monocytes. Inactivation of nucleolin was induced by neutralizing antibody against nucleolin. THP-1 monocytes were pretreated with anti-nucleolin antibody for 1 h prior to LPS challenge. The irrelevant IgG group was used as control. Secretion of inflammatory mediators (TNF-α, IL-1β and HMGB1) and activation of MAPK and NF-κB/I-κB signaling pathways were examined to assess the effects of nucleolin on LPS-mediated inflammatory response. Nucleolin existed in cell membrane, cytoplasm and nucleus of THP-1 monocytes. Pretreatment of anti-nucleolin antibody significantly inhibited the LPS-induced secretion of TNF-α, IL-1β and HMGB1. P38, JNK, ERK and NF-κB subunit p65 inhibitors could significantly inhibit the secretion of IL-1β, TNF-α and HMGB1 induced by LPS. Moreover, the phosphorylation of p38, JNK, ERK and p65 (or nuclear translocation of p65) was significantly increased after LPS challenge. In contrast, pretreatment of anti-nucleolin antibody could significantly inhibit the LPS-induced phosphorylation of p38, JNK, ERK and p65 (or nuclear translocation of p65). However, the irrelevant IgG, as a negative control, had no effect on LPS-induced secretion of TNF-α and IL-1β and phosphorylation of p38, JNK, ERK and p65 (or nuclear translocation of p65). We demonstrated that nucleolin mediated the LPS-induced activation of MAPK and NF-κB signaling pathways, and regulated the secretion of inflammatory mediators (TNF-α, IL-1β and HMGB1).
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Affiliation(s)
- Li Fang
- Department of Cardiology, the First Hospital of Changsha, Changsha, 410008, China.
| | - Kang-Kai Wang
- Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, 410008, China
| | - Qing Huang
- Department of Cardiology, the First Hospital of Changsha, Changsha, 410008, China
| | - Feng Cheng
- Department of Cardiology, the First Hospital of Changsha, Changsha, 410008, China
| | - Fang Huang
- Department of Cardiology, the First Hospital of Changsha, Changsha, 410008, China
| | - Wei-Wei Liu
- Department of Cardiology, the First Hospital of Changsha, Changsha, 410008, China
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Herpes Simplex Virus Type 1 Interactions with the Interferon System. Int J Mol Sci 2020; 21:ijms21145150. [PMID: 32708188 PMCID: PMC7404291 DOI: 10.3390/ijms21145150] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/16/2020] [Accepted: 07/17/2020] [Indexed: 12/12/2022] Open
Abstract
The interferon (IFN) system is one of the first lines of defense activated against invading viral pathogens. Upon secretion, IFNs activate a signaling cascade resulting in the production of several interferon stimulated genes (ISGs), which work to limit viral replication and establish an overall anti-viral state. Herpes simplex virus type 1 is a ubiquitous human pathogen that has evolved to downregulate the IFN response and establish lifelong latent infection in sensory neurons of the host. This review will focus on the mechanisms by which the host innate immune system detects invading HSV-1 virions, the subsequent IFN response generated to limit viral infection, and the evasion strategies developed by HSV-1 to evade the immune system and establish latency in the host.
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Erlich JR, To EE, Liong S, Brooks R, Vlahos R, O'Leary JJ, Brooks DA, Selemidis S. Targeting Evolutionary Conserved Oxidative Stress and Immunometabolic Pathways for the Treatment of Respiratory Infectious Diseases. Antioxid Redox Signal 2020; 32:993-1013. [PMID: 32008371 PMCID: PMC7426980 DOI: 10.1089/ars.2020.8028] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Significance: Up until recently, metabolism has scarcely been referenced in terms of immunology. However, emerging evidence has shown that immune cells undergo an adaptation of metabolic processes, known as the metabolic switch. This switch is key to the activation, and sustained inflammatory phenotype in immune cells, which includes the production of cytokines and reactive oxygen species (ROS) that underpin infectious diseases, respiratory and cardiovascular disease, neurodegenerative disease, as well as cancer. Recent Advances: There is a burgeoning body of evidence that immunometabolism and redox biology drive infectious diseases. For example, influenza A virus (IAV) utilizes endogenous ROS production via NADPH oxidase (NOX)2-containing NOXs and mitochondria to circumvent antiviral responses. These evolutionary conserved processes are promoted by glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle that drive inflammation. Such metabolic products involve succinate, which stimulates inflammation through ROS-dependent stabilization of hypoxia-inducible factor-1α, promoting interleukin-1β production by the inflammasome. In addition, itaconate has recently gained significant attention for its role as an anti-inflammatory and antioxidant metabolite of the TCA cycle. Critical Issues: The molecular mechanisms by which immunometabolism and ROS promote viral and bacterial pathology are largely unknown. This review will provide an overview of the current paradigms with an emphasis on the roles of immunometabolism and ROS in the context of IAV infection and secondary complications due to bacterial infection such as Streptococcus pneumoniae. Future Directions: Molecular targets based on metabolic cell processes and ROS generation may provide novel and effective therapeutic strategies for IAV and associated bacterial superinfections.
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Affiliation(s)
- Jonathan R. Erlich
- Program in Chronic Infectious and Inflammatory Diseases, Oxidant and Inflammation Biology Group, School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University, Bundoora, Australia
| | - Eunice E. To
- Program in Chronic Infectious and Inflammatory Diseases, Oxidant and Inflammation Biology Group, School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University, Bundoora, Australia
| | - Stella Liong
- Program in Chronic Infectious and Inflammatory Diseases, Oxidant and Inflammation Biology Group, School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University, Bundoora, Australia
| | - Robert Brooks
- School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, Australia
| | - Ross Vlahos
- Program in Chronic Infectious and Inflammatory Diseases, Oxidant and Inflammation Biology Group, School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University, Bundoora, Australia
| | - John J. O'Leary
- School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, Australia
- Department of Histopathology, Trinity College Dublin, Dublin, Ireland
- Sir Patrick Dun's Laboratory, Central Pathology Laboratory, St James's Hospital, Dublin, Ireland
| | - Doug A. Brooks
- School of Pharmacy and Medical Sciences, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, Australia
- Molecular Pathology Laboratory, Coombe Women and Infants' University Hospital, Dublin, Ireland
| | - Stavros Selemidis
- Program in Chronic Infectious and Inflammatory Diseases, Oxidant and Inflammation Biology Group, School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University, Bundoora, Australia
- Address correspondence to: Prof. Stavros Selemidis, Program in Chronic Infectious and Inflammatory Diseases, Oxidant and Inflammation Biology Group, School of Health and Biomedical Sciences, College of Science, Engineering & Health, RMIT University, Bundoora, VIC 3083, Australia
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Data-Driven Modeling Identifies TIRAP-Independent MyD88 Activation Complex and Myddosome Assembly Strategy in LPS/TLR4 Signaling. Int J Mol Sci 2020; 21:ijms21093061. [PMID: 32357531 PMCID: PMC7246728 DOI: 10.3390/ijms21093061] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/24/2020] [Accepted: 04/25/2020] [Indexed: 02/06/2023] Open
Abstract
TLR4 complexes are essential for the initiation of the LPS-induced innate immune response. The Myddosome, which mainly contains TLR4, TIRAP, MyD88, IRAK1/4 and TRAF6 proteins, is regarded as a major complex of TLR4. Although the Myddosome has been well studied, a quantitative description of the Myddosome assembly dynamics is still lacking. Furthermore, whether some unknown TLR4 complexes exist remains unclear. In this study, we constructed a SWATH-MS data-based mathematical model that describes the component assembly dynamics of TLR4 complexes. In addition to Myddosome, we suggest that a TIRAP-independent MyD88 activation complex is formed upon LPS stimulation, in which TRAF6 is not included. Furthermore, quantitative analysis reveals that the distribution of components in TIRAP-dependent and -independent MyD88 activation complexes are LPS stimulation-dependent. The two complexes compete for recruiting IRAK1/4 proteins. MyD88 forms higher-order assembly in the Myddosome and we show that the strategy to form higher-order assembly is also LPS stimulation-dependent. MyD88 forms a long chain upon weak stimulation, but forms a short chain upon strong stimulation. Higher-order assembly of MyD88 is directly determined by the level of TIRAP in the Myddosome, providing a formation mechanism for efficient signaling transduction. Taken together, our study provides an enhanced understanding of component assembly dynamics and strategies in TLR4 complexes.
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