|
1
|
Timm MR, Russell SK, Hultgren SJ. Urinary tract infections: pathogenesis, host susceptibility and emerging therapeutics. Nat Rev Microbiol 2025; 23:72-86. [PMID: 39251839 DOI: 10.1038/s41579-024-01092-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/25/2024] [Indexed: 09/11/2024]
Abstract
Urinary tract infections (UTIs), which include any infection of the urethra, bladder or kidneys, account for an estimated 400 million infections and billions of dollars in health-care spending per year. The most common bacterium implicated in UTI is uropathogenic Escherichia coli, but diverse pathogens including Klebsiella, Enterococcus, Pseudomonas, Staphylococcus and even yeast such as Candida species can also cause UTIs. UTIs occur in both women and men and in both healthy and immunocompromised patients. However, certain patient factors predispose to disease: for example, female sex, history of prior UTI, or the presence of a urinary catheter or other urinary tract abnormality. The current clinical paradigm for the treatment of UTIs involves the use of antibiotics. Unfortunately, the efficacy of this approach is dwindling as the prevalence of antimicrobial resistance rises among UTI isolates, and the immense quantity of antibiotics prescribed annually for these infections contributes to the emergence of resistant pathogens. Therefore, there is an urgent need for new antibiotics and non-antibiotic treatment and prevention strategies. In this Review, we discuss how recent studies of bacterial pathogenesis, recurrence, persistence, host-pathogen interactions and host susceptibility factors have elucidated new and promising targets for the treatment and prevention of UTIs.
Collapse
Affiliation(s)
- Morgan R Timm
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO, USA
| | - Seongmi K Russell
- Department of Paediatrics, Washington University School of Medicine, St. Louis, MO, USA
| | - Scott J Hultgren
- Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA.
- Center for Women's Infectious Disease Research, Washington University School of Medicine, St. Louis, MO, USA.
| |
Collapse
|
|
2
|
Doğan G, Sandıkçı M, Karagenç L. Stage-specific expression of Toll-like receptors in the seminiferous epithelium of mouse testis. Histochem Cell Biol 2024; 162:323-335. [PMID: 39085445 PMCID: PMC11364606 DOI: 10.1007/s00418-024-02310-z] [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] [Accepted: 07/15/2024] [Indexed: 08/02/2024]
Abstract
Genes encoding Toll-like receptors (TLRs) are expressed by germ cells in the mouse testis. Nevertheless, the expression of TLRs by germ cells has only been demonstrated for TLR-3, TLR-9, and TLR-11. Furthermore, the expression of each TLR in relation to the stage of spermatogenesis remains uncertain. We aimed in the present study to examine the expression pattern of all TLRs in germ cells throughout the cycle of seminiferous epithelium in the adult mouse testis. Immunohistochemistry was used to evaluate the expression of TLRs. Results of the present study reveal the expression of TLRs by specific populations of germ cells. Expression of TLRs, except for TLR-7, at endosomal compartments, acrosomes, and/or residual bodies was another interesting and novel finding of the present study. We further demonstrate that the expression of TLR-1, -2, -3, -4, -5, -7, -11, -12, and -13 follows a distinct spatiotemporal pattern throughout the cycle of seminiferous epithelium. While TLR-1, -3, -5, -11, and -12 are expressed in all stages, TLR-4 is expressed only in early and middle stages of spermatogenic cycle. On the other hand, TLR-2, -7, and -13 are expressed only in early stage of spermatogenic cycle. Evidence demonstrating the expression of TLRs in a stage specific manner throughout spermatogenesis strengthen the hypothesis that the expression of various TLRs by germ cells is a developmentally regulated process. However, if TLRs play a role in the regulation of proliferation, growth, maturation, and differentiation of germ cells throughout the cycle of the seminiferous epithelium warrants further investigations.
Collapse
Affiliation(s)
- Göksel Doğan
- Faculty of Veterinary Medicine, Department of Histology-Embryology, Aydın Adnan Menderes University, 09000, Aydın, Turkey
| | - Mustafa Sandıkçı
- Faculty of Veterinary Medicine, Department of Histology-Embryology, Aydın Adnan Menderes University, 09000, Aydın, Turkey
| | - Levent Karagenç
- Faculty of Veterinary Medicine, Department of Histology-Embryology, Aydın Adnan Menderes University, 09000, Aydın, Turkey.
| |
Collapse
|
|
3
|
Nissanka MC, Dilhari A, Wijesinghe GK, Weerasekera MM. Advances in experimental bladder models: bridging the gap between in vitro and in vivo approaches for investigating urinary tract infections. BMC Urol 2024; 24:206. [PMID: 39313789 PMCID: PMC11418205 DOI: 10.1186/s12894-024-01590-w] [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: 06/24/2024] [Accepted: 09/06/2024] [Indexed: 09/25/2024] Open
Abstract
Urinary tract infections (UTIs) pose a substantial burden on global healthcare systems. When unraveling the complex pathophysiology of UTIs, bladder models are used to understand complex and multifaceted interactions between different components within the system. This review aimed to bridge the gap between in vitro and in vivo experimental bladder models towards UTI research. We reviewed clinical, animal, and analytical studies and patents from 1959 to the end of 2023. Both in vivo and in vitro models offer unique benefits and drawbacks in understanding UTIs. In vitro models provide controlled environments for studying specific aspects of UTI biology and testing potential treatments, while in vivo models offer insights into how UTIs manifest and progress within living organisms. Thus, both types of models are leading to the development of more effective diagnostic tools and therapeutic interventions against UTIs. Moreover, advanced methodologies involving three-dimensional bladder organoids have also been used to study bladder biology, model bladder-related disorders, and explore new treatments for bladder cancers, UTIs, and urinary incontinence. Narrowing the distance between fundamental scientific research and practical medical applications, these pioneering models hold the key to unlocking new avenues for the development of personalized diagnostics, precision medicine, and ultimately, the alleviation of UTI-related morbidity worldwide.
Collapse
Affiliation(s)
| | - Ayomi Dilhari
- Department of Basic Sciences, Faculty of Allied Health Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka.
| | | | - Manjula Manoji Weerasekera
- Department of Microbiology, Faculty of Medical Sciences, University of Sri Jayewardenepura, Nugegoda, Sri Lanka
| |
Collapse
|
|
4
|
Naskar M, Choi HW. A Dynamic Interplay of Innate Immune Responses During Urinary Tract Infection. Immune Netw 2024; 24:e31. [PMID: 39246616 PMCID: PMC11377947 DOI: 10.4110/in.2024.24.e31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 07/12/2024] [Accepted: 07/17/2024] [Indexed: 09/10/2024] Open
Abstract
Urinary tract infections (UTIs) represent one of the most prevalent bacterial infections globally, manifesting in diverse clinical phenotypes with varying degrees of severity and complications. The mechanisms underlying UTIs are gradually being elucidated, leading to an enhanced understanding of the immune responses involved. Innate immune cells play a crucial defensive role against uropathogenic bacteria through various mechanisms. Despite their significant contributions to host defense, these cells often fail to achieve complete clearance of uropathogens, necessitating the frequent prescription of antibiotics for UTI patients. However, the persistence of infections and related pathological symptoms in the absence of innate immune cells in animal models underscore the importance of innate immunity in UTIs. Therefore, the host protective functions of innate immune cells, including neutrophils, macrophages, mast cells, NK cells, innate lymphoid cells, and γδ T cells, are delicately coordinated and timely regulated by a variety of cytokines to ensure successful pathogen clearance.
Collapse
Affiliation(s)
- Manisha Naskar
- Division of Life Sciences, Korea University, Seoul 02841, Korea
| | - Hae Woong Choi
- Division of Life Sciences, Korea University, Seoul 02841, Korea
| |
Collapse
|
|
5
|
Xu S, Lan H, Huang C, Ge X, Zhu J. Mechanisms and emerging strategies for irinotecan-induced diarrhea. Eur J Pharmacol 2024; 974:176614. [PMID: 38677535 DOI: 10.1016/j.ejphar.2024.176614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 04/24/2024] [Accepted: 04/24/2024] [Indexed: 04/29/2024]
Abstract
Irinotecan (also known as CPT-11) is a topoisomerase I inhibitor first approved for clinical use as an anticancer agent in 1996. Over the past more than two decades, it has been widely used for combination regimens to treat various malignancies, especially in gastrointestinal and lung cancers. However, severe dose-limiting toxicities, especially gastrointestinal toxicity such as late-onset diarrhea, were frequently observed in irinotecan-based therapy, thus largely limiting the clinical application of this agent. Current knowledge regarding the pathogenesis of irinotecan-induced diarrhea is characterized by the complicated metabolism of irinotecan to its active metabolite SN-38 and inactive metabolite SN-38G. A series of enzymes and transporters were involved in these metabolic processes, including UGT1A1 and CYP3A4. Genetic polymorphisms of these metabolizing enzymes were significantly associated with the occurrence of irinotecan-induced diarrhea. Recent discoveries and progress made on the detailed mechanisms enable the identification of potential biomarkers for predicting diarrhea and as such guiding the proper patient selection with a better range of tolerant dosages. In this review, we introduce the metabolic process of irinotecan and describe the pathogenic mechanisms underlying irinotecan-induced diarrhea. Based on the mechanisms, we further outline the potential biomarkers for predicting the severity of diarrhea. Finally, based on the current experimental evidence in preclinical and clinical studies, we discuss and prospect the current and emerging strategies for the prevention of irinotecan-induced diarrhea.
Collapse
Affiliation(s)
- Shengkun Xu
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
| | - Huiyin Lan
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
| | - Chengyi Huang
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
| | - Xingnan Ge
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China
| | - Ji Zhu
- Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China; Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, Zhejiang 310022, China.
| |
Collapse
|
|
6
|
Zhou J, Zhang L, Liu S, DeRubeis D, Zhang D. Toll-like receptors in breast cancer immunity and immunotherapy. Front Immunol 2024; 15:1418025. [PMID: 38903515 PMCID: PMC11187004 DOI: 10.3389/fimmu.2024.1418025] [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: 04/15/2024] [Accepted: 05/23/2024] [Indexed: 06/22/2024] Open
Abstract
Toll-like receptors (TLRs) are a key family of pattern recognition receptors (PRRs) in the innate immune system. The activation of TLRs will not only prevent pathogen infection but also respond to damage-induced danger signaling. Increasing evidence suggests that TLRs play a critical role in breast cancer development and treatment. However, the activation of TLRs is a double-edged sword that can induce either pro-tumor activity or anti-tumor effect. The underlying mechanisms of these opposite effects of TLR signaling in cancer are not fully understood. Targeting TLRs is a promising strategy for improving breast cancer treatment, either as monotherapies or by improving other current therapies. Here we provide an update on the role of TLRs in breast cancer immunity and immunotherapy.
Collapse
Affiliation(s)
- Joseph Zhou
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, United States
| | - Lin Zhang
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, United States
| | - Siyao Liu
- Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, United States
| | - David DeRubeis
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, United States
| | - Dekai Zhang
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, United States
| |
Collapse
|
|
7
|
Khan KN, Guo SW, Ogawa K, Fujishita A, Mori T. The role of innate and adaptive immunity in endometriosis. J Reprod Immunol 2024; 163:104242. [PMID: 38503076 DOI: 10.1016/j.jri.2024.104242] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 02/13/2024] [Accepted: 03/11/2024] [Indexed: 03/21/2024]
Abstract
The innate and adaptive immune systems are the two key branches that determine host protection at all mucosal surfaces in human body, including the female reproductive tract. The pattern recognition receptors within the host that recognize pathogen-associated molecular patterns are expressed on the cells of the innate immune system. Rapidly reactive, theinnate immune system, responds immediately to the presence of infectious or other non-self agents, thereby launching an inflammatory response to protect the host until the activation of slower adaptive immune system. Macrophages, dendritic cells, and toll-like receptors are integral components of the innate immune system. In contrast, T-helper (Th1/Th2/Th17) cells and regulatory T (Treg) cells are the primary components of adaptive immune system. Studies showed that the growth and progression of endometriosis continue even in unilateral ovariectomized animal suggesting that besides ovarian steroid hormones, the growth of endometriosis could be regulated by innate/adaptive immune systems in pelvic environment. Recent reports demonstrated a potential role of Th1/Th2/Th17/Treg cells either individually or collectively in the initiation, maintenance, and progression of endometriosis. Herewe review the fundamental knowledge of innate and adaptive immunity and elaborate the role of innate and adaptive immunity in endometriosis based on both human and experimental data.
Collapse
Affiliation(s)
- Khaleque N Khan
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
| | - Sun-Wei Guo
- Shanghai Obstetrics and Gynecology Hospital, Shanghai 200011, China.
| | - Kanae Ogawa
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| | - Akira Fujishita
- Department of Gynecology, Saiseikai Nagasaki Hospital, Nagasaki 850-0003, Japan
| | - Taisuke Mori
- Department of Obstetrics and Gynecology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
| |
Collapse
|
|
8
|
Carpenter S, O'Neill LAJ. From periphery to center stage: 50 years of advancements in innate immunity. Cell 2024; 187:2030-2051. [PMID: 38670064 PMCID: PMC11060700 DOI: 10.1016/j.cell.2024.03.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/24/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024]
Abstract
Over the past 50 years in the field of immunology, something of a Copernican revolution has happened. For a long time, immunologists were mainly concerned with what is termed adaptive immunity, which involves the exquisitely specific activities of lymphocytes. But the other arm of immunity, so-called "innate immunity," had been neglected. To celebrate Cell's 50th anniversary, we have put together a review of the processes and components of innate immunity and trace the seminal contributions leading to the modern state of this field. Innate immunity has joined adaptive immunity in the center of interest for all those who study the body's defenses, as well as homeostasis and pathology. We are now entering the era where therapeutic targeting of innate immune receptors and downstream signals hold substantial promise for infectious and inflammatory diseases and cancer.
Collapse
Affiliation(s)
- Susan Carpenter
- University of California Santa Cruz, 1156 High St., Santa Cruz, CA 95064, USA.
| | - Luke A J O'Neill
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
| |
Collapse
|
|
9
|
Kawai T, Ikegawa M, Ori D, Akira S. Decoding Toll-like receptors: Recent insights and perspectives in innate immunity. Immunity 2024; 57:649-673. [PMID: 38599164 DOI: 10.1016/j.immuni.2024.03.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/18/2024] [Accepted: 03/05/2024] [Indexed: 04/12/2024]
Abstract
Toll-like receptors (TLRs) are an evolutionarily conserved family in the innate immune system and are the first line of host defense against microbial pathogens by recognizing pathogen-associated molecular patterns (PAMPs). TLRs, categorized into cell surface and endosomal subfamilies, recognize diverse PAMPs, and structural elucidation of TLRs and PAMP complexes has revealed their intricate mechanisms. TLRs activate common and specific signaling pathways to shape immune responses. Recent studies have shown the importance of post-transcriptional regulation in TLR-mediated inflammatory responses. Despite their protective functions, aberrant responses of TLRs contribute to inflammatory and autoimmune disorders. Understanding the delicate balance between TLR activation and regulatory mechanisms is crucial for deciphering their dual role in immune defense and disease pathogenesis. This review provides an overview of recent insights into the history of TLR discovery, elucidation of TLR ligands and signaling pathways, and their relevance to various diseases.
Collapse
Affiliation(s)
- Taro Kawai
- Laboratory of Molecular Immunobiology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), Nara 630-0192, Japan; Life Science Collaboration Center (LiSCo), Nara Institute of Science and Technology (NAIST), Nara 630-0192, Japan.
| | - Moe Ikegawa
- Laboratory of Molecular Immunobiology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), Nara 630-0192, Japan
| | - Daisuke Ori
- Laboratory of Molecular Immunobiology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), Nara 630-0192, Japan
| | - Shizuo Akira
- Center for Advanced Modalities and DSS (CAMaD), Osaka University, Osaka 565-0871, Japan; Laboratory of Host Defense, Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan; Department of Host Defense, Research Institute for Microbial Diseases (RIMD), Osaka University, Osaka 565-0871, Japan.
| |
Collapse
|
|
10
|
Dickson K, Zhou J, Lehmann C. Lower Urinary Tract Inflammation and Infection: Key Microbiological and Immunological Aspects. J Clin Med 2024; 13:315. [PMID: 38256450 PMCID: PMC10816374 DOI: 10.3390/jcm13020315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/13/2023] [Accepted: 01/03/2024] [Indexed: 01/24/2024] Open
Abstract
The urinary system, primarily responsible for the filtration of blood and waste, is affected by several infectious and inflammatory conditions. Focusing on the lower tract, this review outlines the physiological and immune landscape of the urethra and bladder, addressing key immunological and microbiological aspects of important infectious/inflammatory conditions. The conditions addressed include urethritis, interstitial cystitis/bladder pain syndrome, urinary tract infections, and urosepsis. Key aspects of each condition are addressed, including epidemiology, pathophysiology, and clinical considerations. Finally, therapeutic options are outlined, highlighting gaps in the knowledge and novel therapeutic approaches.
Collapse
Affiliation(s)
- Kayle Dickson
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Juan Zhou
- Department of Anesthesiology, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Christian Lehmann
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
- Department of Anesthesiology, Pain Management and Perioperative Medicine, Dalhousie University, Halifax, NS B3H 4R2, Canada;
- Department of Pharmacology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Department of Physiology and Biophysics, Dalhousie University, Halifax, NS B3H 4R2, Canada
| |
Collapse
|
|
11
|
Chen C, Li J, Wang J, Zhang M, Zhang L, Lin Z. Oxybutynin ameliorates LPS-induced inflammatory response in human bladder epithelial cells. J Biochem Mol Toxicol 2024; 38:e23584. [PMID: 38009396 DOI: 10.1002/jbt.23584] [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: 10/22/2022] [Revised: 10/10/2023] [Accepted: 11/10/2023] [Indexed: 11/28/2023]
Abstract
Urinary tract infection (UTI) mainly results from bacterial infections in the urinary tract and markedly impacts the normal lives of millions of patients worldwide. The infection and damage to urethral epithelial cells is the first and key step of UTI development and is a critical target for treating clinical UTI. Oxybutynin, an agent for treating urinary incontinence, is recently claimed with protective effects on bladder ultrastructure. Our study will assess the impact of Oxybutynin on inflammation in lipopolysaccharide (LPS)-stimulated bladder epithelial cells. Bladder epithelial T24 cells were treated with 1 μg/mL LPS with or without 10 and 20 μM Oxybutynin for 24 h. Increased levels of oxidative stress (OS) biomarkers, such as reactive oxygen species, 8-hydroxy-2'-deoxyguanosine, malondialdehyde, as well as upregulated inducible nitric oxide synthase and promoted release of nitric oxide, were observed in LPS-managed T24 cells, all of which were signally suppressed by Oxybutynin. Furthermore, severe inflammatory responses, including enhanced release of cytokines, upregulated matrix metallopeptidase-2 (MMP-2) and MMP-9, and raised monocyte chemoattractant protein-1 level, were found in LPS-challenged T24 cells, which were markedly reversed by Oxybutynin. Moreover, the activated toll-1ike receptor 4/nuclear factor-κB pathway observed in LPS-managed T24 cells was repressed by Oxybutynin. Collectively, Oxybutynin mitigated LPS-induced inflammatory response in human bladder epithelial cells.
Collapse
Affiliation(s)
- Cheng Chen
- Department of Pharmacy, The First People's Hospital of Yibin, Yibin, China
| | - Jiangtao Li
- Department of Rheumatology and Immunology, The First People's Hospital of Yibin, Yibin, China
| | - Juan Wang
- Department of Pharmaceutical Engineering, School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| | - Mao Zhang
- Department of Pharmacy, The First People's Hospital of Yibin, Yibin, China
| | - Lei Zhang
- Department of Pharmacy, The First People's Hospital of Yibin, Yibin, China
| | - Zhihua Lin
- Department of Pharmaceutical Engineering, School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, China
| |
Collapse
|
|
12
|
Boby N, Williams KM, Das A, Pahar B. Toll-like Receptor 2 Mediated Immune Regulation in Simian Immunodeficiency Virus-Infected Rhesus Macaques. Vaccines (Basel) 2023; 11:1861. [PMID: 38140264 PMCID: PMC10747659 DOI: 10.3390/vaccines11121861] [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: 11/11/2023] [Revised: 12/11/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
Abstract
Toll-like receptors (TLRs) are crucial to the innate immune response. They regulate inflammatory reactions by initiating the production of pro-inflammatory cytokines and chemokines. TLRs also play a role in shaping the adaptive immune responses. While this protective response is important for eliminating infectious pathogens, persistent activation of TLRs may result in chronic immune activation, leading to detrimental effects. The role of TLR2 in regulating HIV-1 infection in vivo has yet to be well described. In this study, we used an SIV-infected rhesus macaque model to simulate HIV infection in humans. We evaluated the plasma of the macaques longitudinally and found a significant increase in the soluble TLR2 (sTLR2) level after SIV infection. We also observed an increase in membrane-bound TLR2 (mb-TLR2) in cytotoxic T cells, B cells, and NK cells in PBMC and NK cells in the gut after infection. Our results suggest that sTLR2 regulates the production of various cytokines and chemokines, including IL-18, IL-1RA, IL-15, IL-13, IL-9, TPO, FLT3L, and IL-17F, as well as chemokines, including IP-10, MCP-1, MCP-2, ENA-78, GRO-α, I-TAC, Fractalkine, SDF-1α, and MIP-3α. Interestingly, these cytokines and chemokines were also upregulated after the infection. The positive correlation between SIV copy number and sTLR2 in the plasma indicated the involvement of TLR2 in the regulation of viral replication. These cytokines and chemokines could directly or indirectly regulate viral replication through the TLR2 signaling pathways. When we stimulated PBMC with the TLR2 agonist in vitro, we observed a direct induction of various cytokines and chemokines. Some of these cytokines and chemokines, such as IL-1RA, IL-9, IL-15, GRO-α, and ENA-78, were positively correlated with sTLR2 in vivo, highlighting the direct involvement of TLR2 in the regulation of the production of these factors. Our findings suggest that TLR2 expression may be a target for developing new therapeutic strategies to combat HIV infection.
Collapse
Affiliation(s)
- Nongthombam Boby
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433, USA; (N.B.); (K.M.W.)
| | - Kelsey M. Williams
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433, USA; (N.B.); (K.M.W.)
| | - Arpita Das
- Division of Microbiology, Tulane National Primate Research Center, Covington, LA 70433, USA;
| | - Bapi Pahar
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA 70433, USA; (N.B.); (K.M.W.)
- School of Medicine, Tulane University, New Orleans, LA 70118, USA
| |
Collapse
|
|
13
|
Kim HJ, Kim H, Lee JH, Hwangbo C. Toll-like receptor 4 (TLR4): new insight immune and aging. Immun Ageing 2023; 20:67. [PMID: 38001481 PMCID: PMC10668412 DOI: 10.1186/s12979-023-00383-3] [Citation(s) in RCA: 90] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 10/23/2023] [Indexed: 11/26/2023]
Abstract
TLR4, a transmembrane receptor, plays a central role in the innate immune response. TLR4 not only engages with exogenous ligands at the cellular membrane's surface but also interacts with intracellular ligands, initiating intricate intracellular signaling cascades. Through MyD88, an adaptor protein, TLR4 activates transcription factors NF-κB and AP-1, thereby facilitating the upregulation of pro-inflammatory cytokines. Another adapter protein linked to TLR4, known as TRIF, autonomously propagates signaling pathways, resulting in heightened interferon expression. Recently, TLR4 has garnered attention as a significant factor in the regulation of symptoms in aging-related disorders. The persistent inflammatory response triggered by TLR4 contributes to the onset and exacerbation of these disorders. In addition, alterations in TLR4 expression levels play a pivotal role in modifying the manifestations of age-related diseases. In this review, we aim to consolidate the impact of TLR4 on cellular senescence and aging-related ailments, highlighting the potential of TLR4 as a novel therapeutic target that extends beyond immune responses.
Collapse
Affiliation(s)
- Hyo-Jin Kim
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea
- Division of Applied Life Science (BK21 Four), Research Institute of Life Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Hyemin Kim
- Division of Applied Life Science (BK21 Four), Research Institute of Life Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea
| | - Jeong-Hyung Lee
- Department of Biochemistry (BK21 Four), College of Natural Sciences, Kangwon National University, Chuncheon, 24414, Republic of Korea
| | - Cheol Hwangbo
- Division of Life Science, College of Natural Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea.
- Division of Applied Life Science (BK21 Four), Research Institute of Life Sciences, Gyeongsang National University, Jinju, 52828, Republic of Korea.
| |
Collapse
|
|
14
|
Kim DK, Huh JW, Yu H, Lee Y, Jin Y, Ha UH. Pseudomonas aeruginosa-Derived DnaJ Induces the Expression of IL-1β by Engaging the Interplay of p38 and ERK Signaling Pathways in Macrophages. Int J Mol Sci 2023; 24:15957. [PMID: 37958940 PMCID: PMC10648868 DOI: 10.3390/ijms242115957] [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: 09/26/2023] [Revised: 11/01/2023] [Accepted: 11/02/2023] [Indexed: 11/15/2023] Open
Abstract
As members of pathogen-associated molecular patterns, bacterial heat shock proteins (HSPs) are widely recognized for their role in initiating innate immune responses. This study aimed to examine the impact of DnaJ, a homolog of HSP40 derived from Pseudomonas aeruginosa (P. aeruginosa), on the regulation of IL-1β expression in macrophages. We demonstrated that DnaJ modulates macrophages to secrete IL-1β by activating NF-κB and MAPK signaling pathways. Specifically, ERK was identified as a positive mediator for IL-1β expression, while p38 acted as a negative mediator. These results suggest that the reciprocal actions of these two crucial MAPKs play a vital role in controlling IL-1β expression. Additionally, the reciprocal actions of MAPKs were found to regulate the activation of inflammasome-related molecules, including vimentin, NLRP3, caspase-1, and GSDMD. Furthermore, our investigation explored the involvement of CD91/CD40 in ERK signaling-mediated IL-1β production from DnaJ-treated macrophages. These findings emphasize the importance of understanding the signaling mechanisms underlying IL-1β induction and suggest the potential utility of DnaJ as an adjuvant for stimulating inflammasome activation.
Collapse
Affiliation(s)
- Dae-Kyum Kim
- Department of Biotechnology and Bioinformatics, Korea University, Sejong 30019, Republic of Korea; (D.-K.K.); (J.-W.H.); (H.Y.); (Y.L.)
- Interdisciplinary Graduate Program for Artificial Intelligence Smart Convergence Technology, Korea University, Sejong 30019, Republic of Korea
| | - Jin-Won Huh
- Department of Biotechnology and Bioinformatics, Korea University, Sejong 30019, Republic of Korea; (D.-K.K.); (J.-W.H.); (H.Y.); (Y.L.)
| | - Hyeonseung Yu
- Department of Biotechnology and Bioinformatics, Korea University, Sejong 30019, Republic of Korea; (D.-K.K.); (J.-W.H.); (H.Y.); (Y.L.)
| | - Yeji Lee
- Department of Biotechnology and Bioinformatics, Korea University, Sejong 30019, Republic of Korea; (D.-K.K.); (J.-W.H.); (H.Y.); (Y.L.)
| | - Yongxin Jin
- State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, Nankai University, Tianjin 300071, China;
| | - Un-Hwan Ha
- Department of Biotechnology and Bioinformatics, Korea University, Sejong 30019, Republic of Korea; (D.-K.K.); (J.-W.H.); (H.Y.); (Y.L.)
- Interdisciplinary Graduate Program for Artificial Intelligence Smart Convergence Technology, Korea University, Sejong 30019, Republic of Korea
| |
Collapse
|
|
15
|
Park BJ, Yoon YB, Park SC, Shin GS, Kwak HJ, Lee DH, Choi MY, Kim JW, Cho SJ. Multiple toll-like receptors (TLRs) display differential bacterial and ligand specificity in the earthworm, Eisenia andrei. J Invertebr Pathol 2023; 201:108010. [PMID: 37865158 DOI: 10.1016/j.jip.2023.108010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/12/2023] [Accepted: 10/17/2023] [Indexed: 10/23/2023]
Abstract
Toll-like receptors (TLRs), an ancient and well-conserved group of pattern recognition receptors (PRRs), recognize conserved pathogen-associated molecular patterns. TLRs consist of three domains: the extracellular N-terminal domain, containing one or more leucine-rich repeats (LRRs), responsible for the recognizing and binding of antigens; the type-I transmembrane domain; and the intracellular domain known as the Toll/Interleukin-1 receptor (TIR) domain required for the downstream signaling pathway. We identified six new full-length complementary DNA (cDNA) sequences, Ean-TLR1/2/3/4/5/6. The deduced amino acid sequences indicate that Ean-TLRs consist of one signal peptide, one LRR N-terminal domain (Ean-TLR4/5), varying numbers of LRRs, one (Ean-TLR1/2/3/4/5) or two (Ean-TLR6) LRR C-terminal domains, one type-I transmembrane domain, and a TIR domain. In addition, a TIR domain alignment revealed that three conserved motifs, designated as Box 1, Box 2, and Box 3, contain essential amino acid residues for downstream signaling activity. Phylogenetic analysis of earthworm TLRs generated two separate evolutionary branches representing single (sccTLR) and multiple (mccTLR) cysteine cluster TLRs. Ean-TLR1/2/3/4 (sccTLR type) and Ean-TLR6 (mccTLR type) were clustered with corresponding types of previously reported earthworm TLRs as well as TLRs from Clitellata and Polychaete. As PRRs, earthworm TLRs should be capable of sensing a diverse range of pathogens. Except for Ean-TLR3, which was not responsive to any bacteria, earthworm TLR expression was significantly induced by Gram-positive but not Gram-negative bacteria. Moreover, it is likely that earthworms can differentiate between different species of Gram-positive bacteria via their TLR responses. The ligand specificity of earthworm TLRs suggests that their pathogenic ligand recognition is likely to be as specific and diverse as the mammalian TLR pathogen-sensing system.
Collapse
Affiliation(s)
- Beom Jun Park
- Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Yoo Bin Yoon
- Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Soon Cheol Park
- Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Geun-Seup Shin
- Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea
| | - Hee-Jin Kwak
- Department of Ecology, Evolution and Behavior, Alexander Silberman Institute of Life Sciences, Faculty of Science, Hebrew University of Jerusalem, Jerusalem, 9190401, Israel
| | - Dong Ho Lee
- College of General Education, Chung-Ang University, Seoul, 06974, Republic of Korea
| | - Min Young Choi
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Chungbuk 28644, Republic of Korea
| | - Jung-Woong Kim
- Department of Life Science, Chung-Ang University, Seoul 06974, Republic of Korea.
| | - Sung-Jin Cho
- Department of Biological Sciences and Biotechnology, Chungbuk National University, Chungbuk 28644, Republic of Korea.
| |
Collapse
|
|
16
|
Liu F, Chen H, Cao C, Liang Y, Zhou Y. The role of toll-like receptors (TLRs) and their therapeutic applications in glomerulonephritis. Int Urol Nephrol 2023; 55:2845-2856. [PMID: 37060433 DOI: 10.1007/s11255-023-03592-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 04/07/2023] [Indexed: 04/16/2023]
Abstract
One of the most important features of innate immunity is the presence of a special group of pattern recognition receptors (PRRs) called toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), resulting in a quick and effective immune response to them. Glomerulonephritis (GN) is one of the most important categories of renal disorders characterized by destructive responses of the immune system to the glomerulus. To date, the association of TLRs as important innate immune system members with GN has been one of the topics that attracted the attention of researchers in this field. However, the exact role of these receptors in the immunopathogenesis of GN has not yet been fully discussed. Therefore, this study aims to overview the role of TLRs in GN and the possibility of using them as a potential therapeutic target.
Collapse
Affiliation(s)
- Feiyan Liu
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Huimin Chen
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Caixia Cao
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Yanlin Liang
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China
| | - Ying Zhou
- Hemodialysis Room, Nanchang First Hospital, No. 128, Xiangshan North Road, Nanchang, Jiangxi, China.
| |
Collapse
|
|
17
|
Schwartz L, de Dios Ruiz-Rosado J, Stonebrook E, Becknell B, Spencer JD. Uropathogen and host responses in pyelonephritis. Nat Rev Nephrol 2023; 19:658-671. [PMID: 37479904 PMCID: PMC10913074 DOI: 10.1038/s41581-023-00737-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2023] [Indexed: 07/23/2023]
Abstract
Urinary tract infections (UTIs) are among the most common bacterial infections seen in clinical practice. The ascent of UTI-causing pathogens to the kidneys results in pyelonephritis, which can trigger kidney injury, scarring and ultimately impair kidney function. Despite sizable efforts to understand how infections develop or are cleared in the bladder, our appreciation of the mechanisms by which infections develop, progress or are eradicated in the kidney is limited. The identification of virulence factors that are produced by uropathogenic Escherichia coli to promote pyelonephritis have begun to fill this knowledge gap, as have insights into the mechanisms by which kidney tubular epithelial cells oppose uropathogenic E. coli infection to prevent or eradicate UTIs. Emerging data also illustrate how specific cellular immune responses eradicate infection whereas other immune cell populations promote kidney injury. Insights into the mechanisms by which uropathogenic E. coli circumvent host immune defences or antibiotic therapy to cause pyelonephritis is paramount to the development of new prevention and treatment strategies to mitigate pyelonephritis and its associated complications.
Collapse
Affiliation(s)
- Laura Schwartz
- The Kidney and Urinary Tract Center, Nationwide Children's Abigail Wexner Research Institute, Columbus, OH, USA.
- The Ohio State University College of Medicine, Columbus, OH, USA.
| | - Juan de Dios Ruiz-Rosado
- The Kidney and Urinary Tract Center, Nationwide Children's Abigail Wexner Research Institute, Columbus, OH, USA
- The Ohio State University College of Medicine, Columbus, OH, USA
| | - Emily Stonebrook
- The Kidney and Urinary Tract Center, Nationwide Children's Abigail Wexner Research Institute, Columbus, OH, USA
- The Ohio State University College of Medicine, Columbus, OH, USA
| | - Brian Becknell
- The Kidney and Urinary Tract Center, Nationwide Children's Abigail Wexner Research Institute, Columbus, OH, USA
- The Ohio State University College of Medicine, Columbus, OH, USA
| | - John David Spencer
- The Kidney and Urinary Tract Center, Nationwide Children's Abigail Wexner Research Institute, Columbus, OH, USA.
- The Ohio State University College of Medicine, Columbus, OH, USA.
| |
Collapse
|
|
18
|
Chelangarimiyandoab F, Mungara P, Batta M, Cordat E. Urinary Tract Infections: Renal Intercalated Cells Protect against Pathogens. J Am Soc Nephrol 2023; 34:1605-1614. [PMID: 37401780 PMCID: PMC10561816 DOI: 10.1681/asn.0000000000000187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 06/22/2023] [Indexed: 07/05/2023] Open
Abstract
Urinary tract infections affect more than 1 in 2 women during their lifetime. Among these, more than 10% of patients carry antibiotic-resistant bacterial strains, highlighting the urgent need to identify alternative treatments. While innate defense mechanisms are well-characterized in the lower urinary tract, it is becoming evident that the collecting duct (CD), the first renal segment encountered by invading uropathogenic bacteria, also contributes to bacterial clearance. However, the role of this segment is beginning to be understood. This review summarizes the current knowledge on CD intercalated cells in urinary tract bacterial clearance. Understanding the innate protective role of the uroepithelium and of the CD offers new opportunities for alternative therapeutic strategies.
Collapse
Affiliation(s)
- Forough Chelangarimiyandoab
- Department of Physiology and Membrane Protein Disease Research Group, Faculty of Medicine & Dentistry, College of Health Sciences, University of Alberta, Edmonton, Alberta, Canada
| | | | | | | |
Collapse
|
|
19
|
Frey A, Lunding LP, Wegmann M. The Dual Role of the Airway Epithelium in Asthma: Active Barrier and Regulator of Inflammation. Cells 2023; 12:2208. [PMID: 37759430 PMCID: PMC10526792 DOI: 10.3390/cells12182208] [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: 07/13/2023] [Revised: 09/01/2023] [Accepted: 09/03/2023] [Indexed: 09/29/2023] Open
Abstract
Chronic airway inflammation is the cornerstone on which bronchial asthma arises, and in turn, chronic inflammation arises from a complex interplay between environmental factors such as allergens and pathogens and immune cells as well as structural cells constituting the airway mucosa. Airway epithelial cells (AECs) are at the center of these processes. On the one hand, they represent the borderline separating the body from its environment in order to keep inner homeostasis. The airway epithelium forms a multi-tiered, self-cleaning barrier that involves an unstirred, discontinuous mucous layer, the dense and rigid mesh of the glycocalyx, and the cellular layer itself, consisting of multiple, densely interconnected cell types. On the other hand, the airway epithelium represents an immunologically highly active tissue once its barrier has been penetrated: AECs play a pivotal role in releasing protective immunoglobulin A. They express a broad spectrum of pattern recognition receptors, enabling them to react to environmental stressors that overcome the mucosal barrier. By releasing alarmins-proinflammatory and regulatory cytokines-AECs play an active role in the formation, strategic orientation, and control of the subsequent defense reaction. Consequently, the airway epithelium is of vital importance to chronic inflammatory diseases, such as asthma.
Collapse
Affiliation(s)
- Andreas Frey
- Division of Mucosal Immunology and Diagnostics, Research Center Borstel, 23845 Borstel, Germany;
- Airway Research Center North (ARCN), German Center for Lung Research (DZL), 22927 Großhansdorf, Germany;
| | - Lars P. Lunding
- Airway Research Center North (ARCN), German Center for Lung Research (DZL), 22927 Großhansdorf, Germany;
- Division of Lung Immunology, Research Center Borstel, 23845 Borstel, Germany
| | - Michael Wegmann
- Airway Research Center North (ARCN), German Center for Lung Research (DZL), 22927 Großhansdorf, Germany;
- Division of Lung Immunology, Research Center Borstel, 23845 Borstel, Germany
| |
Collapse
|
|
20
|
Liang H, Zhang L, Liu Z, Hoden B, DeRubei D, Zhang Y, Wang F, Zhang D. Upregulation of TLR5 indicates a favorable prognosis in prostate cancer. Prostate 2023; 83:1035-1045. [PMID: 37118933 PMCID: PMC10330358 DOI: 10.1002/pros.24545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/03/2023] [Accepted: 04/18/2023] [Indexed: 04/30/2023]
Abstract
BACKGROUND Toll-like receptors (TLRs) are the key sensors of innate immunity for triggering immune responses against infections. TLRs are well known to be expressed and activated in innate immune cells, such as macrophage and dendritic cells, but we and others have found that some TLRs are also functional in epithelial cells. However, the role of an epithelial TLR in prostate cancer remains elusive. METHODS TLR5 expression in messenger RNA and protein level in prostate cancer was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). The activation of TLR5 signaling in epithelial cells was detected upon nuclear factor-κB activation by luciferase assay and western blot analysis, and proinflammatory cytokine activation by RT-qPCR. Distinguishing between the TLR5 and NLRC4 pathways, both recognizing flagellin, is determined by small interfering RNA and proinflammatory cytokine activation. The role of TLR5 in prostate cancer was analyzed by IHC and bioinformatics using a general and single-cell database. RESULTS In the present study, we show that TLR5, among other TLRs, is exceedingly expressed in human prostate cancer cells. This cancer epithelial cell TLR5 functions to activate the TLR5 signaling pathway in human prostate cancer cells, as it does with innate immune cell TLR5. The bacterial protein flagellin induces a robust immune response in prostate cancer cells in a TLR5-dependent but NLRC4-independent manner. TLR5 is highly expressed in prostate cancer patient specimens, and high TLR5 expression in prostate cancer patients indicates a favorable prognosis. CONCLUSIONS TLR5, as an innate immunity receptor, is a functional TLR in human prostate cancer epithelial cells. TLR5 plays an important role in prostate cancer development and is a new potential prognosis biomarker. TLR5 may represent a novel immunotherapy target against prostate cancer.
Collapse
Affiliation(s)
- Hongbin Liang
- Center for Infectious and Inflammatory Diseases, Institute of Bioscience and Technology, Department of Translational Medical Sciences, Texas A&M University, Houston, TX, USA
| | - Lin Zhang
- Center for Infectious and Inflammatory Diseases, Institute of Bioscience and Technology, Department of Translational Medical Sciences, Texas A&M University, Houston, TX, USA
| | - Ziying Liu
- Center for Translational Cancer Research, Institute of Bioscience and Technology, Department of Translational Medical Sciences, Texas A&M University, Houston, TX, USA
| | - Bettina Hoden
- Center for Infectious and Inflammatory Diseases, Institute of Bioscience and Technology, Department of Translational Medical Sciences, Texas A&M University, Houston, TX, USA
| | - David DeRubei
- Center for Infectious and Inflammatory Diseases, Institute of Bioscience and Technology, Department of Translational Medical Sciences, Texas A&M University, Houston, TX, USA
| | - Yifan Zhang
- Center for Infectious and Inflammatory Diseases, Institute of Bioscience and Technology, Department of Translational Medical Sciences, Texas A&M University, Houston, TX, USA
| | - Fen Wang
- Center for Translational Cancer Research, Institute of Bioscience and Technology, Department of Translational Medical Sciences, Texas A&M University, Houston, TX, USA
| | - Dekai Zhang
- Center for Infectious and Inflammatory Diseases, Institute of Bioscience and Technology, Department of Translational Medical Sciences, Texas A&M University, Houston, TX, USA
| |
Collapse
|
|
21
|
Rajaramon S, Shanmugam K, Dandela R, Solomon AP. Emerging evidence-based innovative approaches to control catheter-associated urinary tract infection: a review. Front Cell Infect Microbiol 2023; 13:1134433. [PMID: 37560318 PMCID: PMC10407108 DOI: 10.3389/fcimb.2023.1134433] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 07/04/2023] [Indexed: 08/11/2023] Open
Abstract
Healthcare settings have dramatically advanced the latest medical devices, such as urinary catheters (UC) for infection, prevention, and control (IPC). The continuous or intermittent flow of a warm and conducive (urine) medium in the medical device, the urinary catheter, promotes the formation of biofilms and encrustations, thereby leading to the incidence of CAUTI. Additionally, the absence of an innate immune host response in and around the lumen of the catheter reduces microbial phagocytosis and drug action. Hence, the review comprehensively overviews the challenges posed by CAUTI and associated risks in patients' morbidity and mortality. Also, detailed, up-to-date information on the various strategies that blended/tailored the surface properties of UC to have anti-fouling, biocidal, and anti-adhesive properties to provide an outlook on how they can be better managed with futuristic solutions.
Collapse
Affiliation(s)
- Shobana Rajaramon
- Quorum Sensing Laboratory, Centre for Research in Infectious Diseases (CRID), School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, India
| | - Karthi Shanmugam
- Quorum Sensing Laboratory, Centre for Research in Infectious Diseases (CRID), School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, India
| | - Rambabu Dandela
- Department of Industrial and Engineering Chemistry, Institute of Chemical Technology, Bhubaneswar, Odisha, India
| | - Adline Princy Solomon
- Quorum Sensing Laboratory, Centre for Research in Infectious Diseases (CRID), School of Chemical and Biotechnology, SASTRA Deemed to be University, Thanjavur, India
| |
Collapse
|
|
22
|
Amemiya K, Rozak DA, Dankmeyer JL, Dorman WR, Marchand C, Fetterer DP, Worsham PL, Purcell BK. Shiga-Toxin-Producing Strains of Escherichia coli O104:H4 and a Strain of O157:H7, Which Can Cause Human Hemolytic Uremic Syndrome, Differ in Biofilm Formation in the Presence of CO 2 and in Their Ability to Grow in a Novel Cell Culture Medium. Microorganisms 2023; 11:1744. [PMID: 37512916 PMCID: PMC10384166 DOI: 10.3390/microorganisms11071744] [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: 05/16/2023] [Revised: 06/13/2023] [Accepted: 06/27/2023] [Indexed: 07/30/2023] Open
Abstract
One pathogen that commonly causes gastrointestinal illnesses from the consumption of contaminated food is Escherichia coli O157:H7. In 2011 in Germany, however, there was a prominent outbreak of bloody diarrhea with a high incidence of hemolytic uremic syndrome (HUS) caused by an atypical, more virulent E. coli O104:H4 strain. To facilitate the identification of this lesser-known, atypical E. coli O104:H4 strain, we wanted to identify phenotypic differences between it and a strain of O157:H7 in different media and culture conditions. We found that E. coli O104:H4 strains produced considerably more biofilm than the strain of O157:H7 at 37 °C (p = 0.0470-0.0182) Biofilm production was significantly enhanced by the presence of 5% CO2 (p = 0.0348-0.0320). In our study on the innate immune response to the E. coli strains, we used HEK293 cells that express Toll-like receptors (TLRs) 2 or 4. We found that E. coli O104:H4 strains had the ability to grow in a novel HEK293 cell culture medium, while the E. coli O157:H7 strain could not. Thus, we uncovered previously unknown phenotypic properties of E. coli O104:H4 to further differentiate this pathogen from E. coli O157:H7.
Collapse
Affiliation(s)
- Kei Amemiya
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA
| | - David A Rozak
- Diagnostic Systems Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA
| | - Jennifer L Dankmeyer
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA
| | - William R Dorman
- Diagnostic Systems Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA
| | - Charles Marchand
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA
| | - David P Fetterer
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA
| | - Patricia L Worsham
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA
| | - Brett K Purcell
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA
- Department of Medicine, University of Florida, Orlando, FL 32816, USA
| |
Collapse
|
|
23
|
Wessels JE, Ishida Y, Rivera NA, Stirewalt SL, Brown WM, Novakofski JE, Roca AL, Mateus-Pinilla NE. The Impact of Variation in the Toll-like Receptor 3 Gene on Epizootic Hemorrhagic Disease in Illinois Wild White-Tailed Deer ( Odocoileus virginianus). Genes (Basel) 2023; 14:426. [PMID: 36833353 PMCID: PMC9956177 DOI: 10.3390/genes14020426] [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: 12/07/2022] [Revised: 01/31/2023] [Accepted: 02/03/2023] [Indexed: 02/10/2023] Open
Abstract
Epizootic hemorrhagic disease (EHD) leads to high mortality in white-tailed deer (Odocoileus virginianus) and is caused by a double-stranded RNA (dsRNA) virus. Toll-like receptor 3 (TLR3) plays a role in host immune detection and response to dsRNA viruses. We, therefore, examined the role of genetic variation within the TLR3 gene in EHD among 84 Illinois wild white-tailed deer (26 EHD-positive deer and 58 EHD-negative controls). The entire coding region of the TLR3 gene was sequenced: 2715 base pairs encoding 904 amino acids. We identified 85 haplotypes with 77 single nucleotide polymorphisms (SNPs), of which 45 were synonymous mutations and 32 were non-synonymous. Two non-synonymous SNPs differed significantly in frequency between EHD-positive and EHD-negative deer. In the EHD-positive deer, phenylalanine was relatively less likely to be encoded at codon positions 59 and 116, whereas leucine and serine (respectively) were detected less frequently in EHD-negative deer. Both amino acid substitutions were predicted to impact protein structure or function. Understanding associations between TLR3 polymorphisms and EHD provides insights into the role of host genetics in outbreaks of EHD in deer, which may allow wildlife agencies to better understand the severity of outbreaks.
Collapse
Affiliation(s)
- Jacob E. Wessels
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Illinois Natural History Survey—Prairie Research Institute, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA
| | - Yasuko Ishida
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Nelda A. Rivera
- Illinois Natural History Survey—Prairie Research Institute, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA
| | - Spencer L. Stirewalt
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Illinois Natural History Survey—Prairie Research Institute, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA
| | - William M. Brown
- Illinois Natural History Survey—Prairie Research Institute, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA
| | - Jan E. Novakofski
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Illinois Natural History Survey—Prairie Research Institute, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA
| | - Alfred L. Roca
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Illinois Natural History Survey—Prairie Research Institute, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA
| | - Nohra E. Mateus-Pinilla
- Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Illinois Natural History Survey—Prairie Research Institute, University of Illinois at Urbana-Champaign, Champaign, IL 61820, USA
- Department of Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802, USA
| |
Collapse
|
|
24
|
Qiu J, Xie Y, Shao C, Shao T, Qin M, Zhang R, Liu X, Xu Z, Wang Y. Toxoplasma gondii microneme protein MIC3 induces macrophage TNF-α production and Ly6C expression via TLR11/MyD88 pathway. PLoS Negl Trop Dis 2023; 17:e0011105. [PMID: 36730424 PMCID: PMC9928027 DOI: 10.1371/journal.pntd.0011105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 02/14/2023] [Accepted: 01/16/2023] [Indexed: 02/04/2023] Open
Abstract
Toxoplasma gondii is the most successful parasite worldwide. It is of great interest to understand how T. gondii induce different immune responses in different hosts. In this study, we found that a peptide of T. gondii microneme protein MIC3 induced TNF-α production, NF-κB phosphorylation, iNOS transcription and Ly6C expression in mouse macrophage RAW264.7 cells. MyD88 inhibition, small interfering RNA against Tlr11 and CRISPR/Cas9-mediated knock-out of Tlr11 all reduced MIC3-induced TNF-α production, NF-κB phosphorylation, iNOS transcription and Ly6C expression. Additionally, we determined the location of MIC3 peptide in mouse macrophages using immunofluorescence. MIC3 could both adhere to the cell membrane of mouse macrophages and enter the cells. These results suggest that MIC3 triggered the immune responses in mouse macrophages via TLR11/MyD88/NF-κB pathway. It is known that human macrophages lacking TLR11. We predicted that the immune responses induced by MIC3 in human macrophages were significantly different from those in mouse macrophages. As expected, MIC3 peptide failed to induce TNF-α expression, iNOS expression and NF-κB phosphorylation in human THP-1 derived macrophages. MIC3 induced macrophage immune responses via TLR11. Intriguingly, the amino acid sequence of MIC3 is completely different from the well-known TLR11 ligand profilin, which generates a potent IL-12p40, TNF-α and IL-6 response. In marked contrast to profilin, MIC3 could not induce IL-12p40 expression in both mouse RAW264.7 cells and human THP-1 derived macrophages. Furthermore, the simulated tertiary structure of MIC3 peptide shows poor similarity with the crystal structure of profilin, suggesting that MIC3 might be a different ligand from profilin. These findings about MIC3 and TLR11 will provide us with important insights into the pathogenesis of toxoplasmosis and coevolution during host-parasite interaction.
Collapse
Affiliation(s)
- Jingfan Qiu
- Key Laboratory of Pathogen Biology of Jiangsu Province, Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yanci Xie
- Key Laboratory of Pathogen Biology of Jiangsu Province, Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Chenlu Shao
- Key Laboratory of Pathogen Biology of Jiangsu Province, Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Tianye Shao
- Key Laboratory of Pathogen Biology of Jiangsu Province, Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Min Qin
- Key Laboratory of Pathogen Biology of Jiangsu Province, Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rong Zhang
- Key Laboratory of Pathogen Biology of Jiangsu Province, Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xinjian Liu
- Key Laboratory of Pathogen Biology of Jiangsu Province, Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhipeng Xu
- Key Laboratory of Pathogen Biology of Jiangsu Province, Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yong Wang
- Key Laboratory of Pathogen Biology of Jiangsu Province, Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, China
- * E-mail:
| |
Collapse
|
|
25
|
Zhang Q, Zhou M, Huo M, Si Y, Zhang Y, Fang Y, Zhang D. Mechanisms of acupuncture-electroacupuncture on inflammatory pain. Mol Pain 2023; 19:17448069231202882. [PMID: 37678839 PMCID: PMC10515556 DOI: 10.1177/17448069231202882] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 09/06/2023] [Indexed: 09/09/2023] Open
Abstract
Acupuncture, as a traditional treatment, has been extensively used in China for thousands of years. According to the World Health Organization (WHO), acupuncture is recommended for the treatment of 77 diseases. And 16 of these diseases are related to inflammatory pain. As a combination of traditional acupuncture and modern electrotherapy, electroacupuncture (EA) has satisfactory analgesic effects on various acute and chronic pain. Because of its good analgesic effects and no side effects, acupuncture has been widely accepted all over the world. Despite the increase in the number of studies, the mechanisms via which acupuncture exerts its analgesic effects have not been conclusively established. A literature review of related research is of great significance to elaborate on its mechanisms and to inform on further research directions. We elucidated on its mechanisms of action on inflammatory pain from two levels: peripheral and central. It includes the mechanisms of acupuncture in the periphery (immune cells and neurons, purinergic pathway, nociceptive ion channel, cannabinoid receptor and endogenous opioid peptide system) and central nervous system (TPRV1, glutamate and its receptors, glial cells, GABAergic interneurons and signaling molecules). In this review, we collected relevant recent studies to systematically explain the mechanisms of acupuncture in treating inflammatory pain, with a view to providing direction for future applications of acupuncture in inflammatory pain and promoting clinical development.
Collapse
Affiliation(s)
- Qingxiang Zhang
- Research Center of Experimental Acupuncture Science, College of Acumox and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Mengmeng Zhou
- Research Center of Experimental Acupuncture Science, College of Acumox and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Mingzhu Huo
- Research Center of Experimental Acupuncture Science, College of Acumox and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuxin Si
- Research Center of Experimental Acupuncture Science, College of Acumox and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Youlin Zhang
- Research Center of Experimental Acupuncture Science, College of Acumox and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuxin Fang
- Research Center of Experimental Acupuncture Science, College of Acumox and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Di Zhang
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Haihe Laboratory of Modern Chinese Medicine, Tianjin, China
| |
Collapse
|
|
26
|
Liang H, Zhang L, Hoden B, Qu B, Derubeis D, Song X, Zhang D. Delineating the Role of Toll-Like Receptors in Inflammatory Bowel Disease. Methods Mol Biol 2023; 2700:221-228. [PMID: 37603184 DOI: 10.1007/978-1-0716-3366-3_13] [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] [Indexed: 08/22/2023]
Abstract
Toll-like receptors (TLRs) recognize altered gut microbiota triggering an immune response. These responses play a critical role in the pathogenesis and treatment of inflammatory bowel disease (IBD). IBD is characterized by inflammation of the intestinal tracts as in Crohn's disease and ulcerative colitis. However, one challenge in determining the role of a specific TLR in IBD and its underlying mechanism is disparity. Variance in age, gender, race, and ethnicity shows a dramatic difference in the disease incidence, severity, and response to treatment. Delineating the role of TLRs in IBD relies on both a knockout mouse and a disease model. Here, we describe a detailed protocol on how to use nearly identical genetic backgrounds of TLR wild-type and knockout littermate mice in a dextran sodium sulfate (DSS)-induced colitis model.
Collapse
Affiliation(s)
- Hongbin Liang
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA
| | - Lin Zhang
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA
| | - Bettina Hoden
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA
| | - Bo Qu
- Department of Gastroenterology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China
| | - David Derubeis
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA
| | - Xiaotong Song
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.
| | - Dekai Zhang
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.
- Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, TX, USA.
| |
Collapse
|
|
27
|
The Role of Mononuclear Phagocytes in the Testes and Epididymis. Int J Mol Sci 2022; 24:ijms24010053. [PMID: 36613494 PMCID: PMC9820352 DOI: 10.3390/ijms24010053] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 12/08/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
The mononuclear phagocytic system (MPS) is the primary innate immune cell group in male reproductive tissues, maintaining the balance of pro-inflammatory and immune tolerance. This article aims to outline the role of mononuclear macrophages in the immune balance of the testes and epididymis, and to understand the inner immune regulation mechanism. A review of pertinent publications was performed using the PubMed and Google Scholar databases on all articles published prior to January 2021. Search terms were based on the following keywords: 'MPS', 'mononuclear phagocytes', 'testes', 'epididymis', 'macrophage', 'Mφ', 'dendritic cell', 'DC', 'TLR', 'immune', 'inflammation', and 'polarization'. Additionally, reference lists of primary and review articles were reviewed for other publications of relevance. This review concluded that MPS exhibits a precise balance in the male reproductive system. In the testes, MPS cells are mainly suppressed subtypes (M2 and cDC2) under physiological conditions, which maintain the local immune tolerance. Under pathological conditions, MPS cells will transform into M1 and cDC1, producing various cytokines, and will activate T cell specific immunity as defense to foreign pathogens or self-antigens. In the epididymis, MPS cells vary in the different segments, which express immune tolerance in the caput and pro-inflammatory condition in the cauda. Collectively, MPS is the control point for maintaining the immune tolerance of the testes and epididymis as well as for eliminating pathogens.
Collapse
|
|
28
|
Zhu C, Liu G, Gu X, Zhang T, Xia A, Zheng Y, Yin J, Han M, Jiang Q. Effects of Quercetin on the Intestinal Microflora of Freshwater Dark Sleeper Odontobutis potamophila. Antioxidants (Basel) 2022; 11:antiox11102015. [PMID: 36290739 PMCID: PMC9598073 DOI: 10.3390/antiox11102015] [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: 09/14/2022] [Revised: 09/29/2022] [Accepted: 10/08/2022] [Indexed: 11/16/2022] Open
Abstract
Flavonoids have antimicrobial and anti-oxidation properties. The effects of the flavonoid quercetin on the intestinal microflora of freshwater dark sleeper Odontobutis potamophila were tested for the first time. Odontobutis potamophila juveniles were treated with quercetin for 21 days at one of three concentrations (2.5, 5.0, or 10.0 mg/L) and compared with a control group that was not treated with quercetin. Quercetin improved the stability of the intestinal flora in O. potamophila and the probiotic bacteria Bacillus spp. and Lactobacillus spp. increased in species abundance after the low concentration quercetin treatments. Furthermore, the abundance of pathogenic bacteria Plesiomonas spp., Aeromonas spp., and Shewanella spp. decreased after the fish had been exposed to quercetin. Activity of hepatic antioxidant enzymes (superoxide dismutase, SOD), (glutathione S-transferase, GST), (glutathione peroxidase, GSH-Px), and (total antioxidant capacity, T-AOC) increased in the livers of O. potamophila treated with quercetin, thereby increasing their hepatic antioxidant capacity and their ability to scavenge free radicals.
Collapse
Affiliation(s)
- Chenxi Zhu
- Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing 210017, China
- Geography Section, School of Humanities, Universiti Sains Malaysia, Minden 11800, Malaysia
| | - Guoxing Liu
- Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing 210017, China
- College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Xiankun Gu
- Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing 210017, China
| | - Tongqing Zhang
- Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing 210017, China
| | - Aijun Xia
- Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing 210017, China
| | - You Zheng
- Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing 210017, China
| | - Jiawen Yin
- Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing 210017, China
| | - Mingming Han
- Biology Program, School of Distance Education, Universiti Sains Malaysia, Minden 11800, Malaysia
| | - Qichen Jiang
- Freshwater Fisheries Research Institute of Jiangsu Province, Nanjing 210017, China
- Correspondence:
| |
Collapse
|
|
29
|
Reyes EY, Shinohara ML. Host immune responses in the central nervous system during fungal infections. Immunol Rev 2022; 311:50-74. [PMID: 35672656 PMCID: PMC9489659 DOI: 10.1111/imr.13101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 04/24/2022] [Accepted: 05/18/2022] [Indexed: 12/19/2023]
Abstract
Fungal infections in the central nervous system (CNS) cause high morbidity and mortality. The frequency of CNS mycosis has increased over the last two decades as more individuals go through immunocompromised conditions for various reasons. Nevertheless, options for clinical interventions for CNS mycoses are still limited. Thus, there is an urgent need to understand the host-pathogen interaction mechanisms in CNS mycoses for developing novel treatments. Although the CNS has been regarded as an immune-privileged site, recent studies demonstrate the critical involvement of immune responses elicited by CNS-resident and CNS-infiltrated cells during fungal infections. In this review, we discuss mechanisms of fungal invasion in the CNS, fungal pathogen detection by CNS-resident cells (microglia, astrocytes, oligodendrocytes, neurons), roles of CNS-infiltrated leukocytes, and host immune responses. We consider that understanding host immune responses in the CNS is crucial for endeavors to develop treatments for CNS mycosis.
Collapse
Affiliation(s)
- Estefany Y. Reyes
- Department of Immunology, Duke University School of Medicine, Durham, NC 27705, USA
| | - Mari L. Shinohara
- Department of Immunology, Duke University School of Medicine, Durham, NC 27705, USA
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27705, USA
| |
Collapse
|
|
30
|
The distinct roles of exosomes in innate immune responses and therapeutic applications in cancer. Eur J Pharmacol 2022; 933:175292. [PMID: 36150532 DOI: 10.1016/j.ejphar.2022.175292] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 11/21/2022]
Abstract
The innate immune system is one of the major constituents of the host's defense against invading pathogens and extracellular vesicles (EVs) are involved in regulating its responses. Exosomes, a subclass of EVs, released from eukaryotic cells, contribute to intracellular communication and drive various biological processes by transferring nuclei acids, proteins, lipids, and carbohydrates between cells, protecting cargo from enzymatic degradation and immune recognition and consequent elimination by the immune system. A growing body of evidence has revealed that exosomes produced from host cells, infected cells, tumor cells, and immune cells regulate innate immune signaling and responses and thus play a significant role in the propagation of pathogens. Immune cells can recognize exosomes-bearing components including DNA strands, viral RNAs, and even proteins by various mechanisms such as through Toll-like receptor/NF-κB signaling, inducing cytokine production and reprogramming the innate immune responses, immunosuppression or immunesupportive. There is persuasive preclinical and clinical evidence that exosomes are therapeutic strategies for immunotherapy, cancer vaccine, drug-delivery system, and diagnostic biomarker. However, further scrutiny is essential to validate these findings. In this review, we describe the current facts on the regulation of innate immune responses by exosomes. We also describe the translational application of exosomes as cancer-therapy agents and immunotherapy.
Collapse
|
|
31
|
Wang AS, Steers NJ, Parab AR, Gachon F, Sweet MJ, Mysorekar IU. Timing is everything: impact of development, ageing and circadian rhythm on macrophage functions in urinary tract infections. Mucosal Immunol 2022; 15:1114-1126. [PMID: 36038769 DOI: 10.1038/s41385-022-00558-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 07/31/2022] [Accepted: 08/08/2022] [Indexed: 02/04/2023]
Abstract
The bladder supports a diversity of macrophage populations with functional roles related to homeostasis and host defense, including clearance of cell debris from tissue, immune surveillance, and inflammatory responses. This review examines these roles with particular attention given to macrophage origins, differentiation, recruitment, and engagement in host defense against urinary tract infections (UTIs), where these cells recognize uropathogens through a combination of receptor-mediated responses. Time is an important variable that is often overlooked in many clinical and biological studies, including in relation to macrophages and UTIs. Given that ageing is a significant factor in urinary tract infection pathogenesis and macrophages have been shown to harbor their own circadian system, this review also explores the influence of age on macrophage functions and the role of diurnal variations in macrophage functions in host defense and inflammation during UTIs. We provide a conceptual framework for future studies that address these key knowledge gaps.
Collapse
Affiliation(s)
- Alison S Wang
- Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, QLD, Australia.,Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia, QLD, Australia
| | - Nicholas J Steers
- Division of Nephrology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
| | - Adwaita R Parab
- Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA
| | - Frédéric Gachon
- Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, QLD, Australia
| | - Matthew J Sweet
- Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, QLD, Australia. .,Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia, QLD, Australia.
| | - Indira U Mysorekar
- Department of Medicine, Section of Infectious Diseases, Baylor College of Medicine, Houston, TX, USA. .,Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
| |
Collapse
|
|
32
|
Saad AA. Targeting cancer-associated glycans as a therapeutic strategy in leukemia. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2049901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Ashraf Abdullah Saad
- Unit of Pediatric Hematologic Oncology and BMT, Sultan Qaboos University Hospital, Muscat, Oman
| |
Collapse
|
|
33
|
Yang T, Sim KY, Ko GH, Ahn JS, Kim HJ, Park SG. FAM167A is a key molecule to induce BCR-ABL-independent TKI resistance in CML via noncanonical NF-κB signaling activation. J Exp Clin Cancer Res 2022; 41:82. [PMID: 35241148 PMCID: PMC8892744 DOI: 10.1186/s13046-022-02298-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/21/2022] [Indexed: 04/18/2023] Open
Abstract
BACKGROUND BCR-ABL-independent drug resistance is a barrier to curative treatment of chronic myeloid leukemia (CML). However, the molecular pathways underlying BCR-ABL-independent tyrosine kinase inhibitor (TKI) resistance remain unclear. METHODS In silico bioinformatic analysis was performed to identify the most active transcription factor and its inducer that contribute to BCR-ABL-independent TKI resistance. Tandem mass spectrometry analysis was performed to identify the receptor for the noncanonical NF-κB activator FAM167A. In vitro and in vivo mouse experiments revealed detailed molecular insights into the functional role of the FAM167A-desmoglein-1 (DSG1) axis in BCL-ABL-independent TKI resistance. CML cells derived from CML patients were analyzed using quantitative reverse transcription PCR and flow cytometry. RESULTS We found that NF-κB had the greatest effect on differential gene expression of BCR-ABL-independent TKI-resistant CML cells. Moreover, we found that the previously uncharacterized protein FAM167A activates the noncanonical NF-κB pathway and induces BCR-ABL-independent TKI resistance. Molecular analyses revealed that FAM167A activates the noncanonical NF-κB pathway by binding to the cell adhesion protein DSG1 to upregulate NF-κB-inducing kinase (NIK) by blocking its ubiquitination. Neutralization of FAM167A in a mouse tumor model reduced noncanonical NF-κB activity and restored sensitivity of cells to TKIs. Furthermore, FAM167A and surface DSG1 levels were highly upregulated in CD34+ CML cells from patients with BCR-ABL-independent TKI-resistant disease. CONCLUSIONS These results reveal that FAM167A acts as an essential factor for BCR-ABL-independent TKI resistance in CML by activating the noncanonical NF-κB pathway. In addition, FAM167A may serve as an important target and biomarker for BCR-ABL-independent TKI resistance.
Collapse
MESH Headings
- Animals
- Apoptosis
- Drug Resistance, Neoplasm/genetics
- Fusion Proteins, bcr-abl
- Humans
- Imatinib Mesylate/pharmacology
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology
- Mice
- NF-kappa B/metabolism
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Proteins/metabolism
Collapse
Affiliation(s)
- Taewoo Yang
- Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 08826 Seoul, Republic of Korea
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005 Republic of Korea
| | - Kyu-Young Sim
- Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 08826 Seoul, Republic of Korea
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005 Republic of Korea
| | - Gwang-Hoon Ko
- Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 08826 Seoul, Republic of Korea
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, 61005 Republic of Korea
| | - Jae-Sook Ahn
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 58128 Hwasun, Republic of Korea
| | - Hyeoung-Joon Kim
- Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 58128 Hwasun, Republic of Korea
| | - Sung-Gyoo Park
- Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, 08826 Seoul, Republic of Korea
| |
Collapse
|
|
34
|
Focus on the Mechanisms and Functions of Pyroptosis, Inflammasomes, and Inflammatory Caspases in Infectious Diseases. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:2501279. [PMID: 35132346 PMCID: PMC8817853 DOI: 10.1155/2022/2501279] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 12/28/2021] [Indexed: 12/17/2022]
Abstract
Eukaryotic cells can initiate several distinct self-destruction mechanisms to display essential roles for the homeostasis maintenance, development, and survival of an organism. Pyroptosis, a key response mode in innate immunity, also referred to as caspase-1-dependent proinflammatory programmed necrotic cell death activated by human caspase-1/4/5, or mouse caspase-1/11, plays indispensable roles in response to cytoplasmic insults and immune defense against infectious diseases. These inflammatory caspases are employed by the host to eliminate pathogen infections such as bacteria, viruses, protozoans, and fungi. Gasdermin D requires to be cleaved and activated by these inflammatory caspases to trigger the pyroptosis process. Physiological rupture of cells results in the release of proinflammatory cytokines, the alarmins IL-1β and IL-18, symbolizing the inflammatory potential of pyroptosis. Moreover, long noncoding RNAs play direct or indirect roles in the upstream of the pyroptosis trigger pathway. Here, we review in detail recently acquired insights into the central roles of inflammatory caspases, inflammasomes, and pyroptosis, as well as the crosstalk between pyroptosis and long noncoding RNAs in mediating infection immunity and pathogen clearance.
Collapse
|
|
35
|
Amemiya K, Dankmeyer JL, Bernhards RC, Fetterer DP, Waag DM, Worsham PL, DeShazer D. Activation of Toll-Like Receptors by Live Gram-Negative Bacterial Pathogens Reveals Mitigation of TLR4 Responses and Activation of TLR5 by Flagella. Front Cell Infect Microbiol 2021; 11:745325. [PMID: 34888257 PMCID: PMC8650638 DOI: 10.3389/fcimb.2021.745325] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 10/18/2021] [Indexed: 12/27/2022] Open
Abstract
Successful bacterial pathogens have evolved to avoid activating an innate immune system in the host that responds to the pathogen through distinct Toll-like receptors (TLRs). The general class of biochemical components that activate TLRs has been studied extensively, but less is known about how TLRs interact with the class of compounds that are still associated with the live pathogen. Accordingly, we examined the activation of surface assembled TLR 2, 4, and 5 with live Tier 1 Gram-negative pathogens that included Yersinia pestis (plague), Burkholderia mallei (glanders), Burkholderia pseudomallei (melioidosis), and Francisella tularensis (tularemia). We found that Y. pestis CO92 grown at 28°C activated TLR2 and TLR4, but at 37°C the pathogen activated primarily TLR2. Although B. mallei and B. pseudomallei are genetically related, the former microorganism activated predominately TLR4, while the latter activated predominately TLR2. The capsule of wild-type B. pseudomallei 1026b was found to mitigate the activation of TLR2 and TLR4 when compared to a capsule mutant. Live F. tularensis (Ft) Schu S4 did not activate TLR2 or 4, although the less virulent Ft LVS and F. novicida activated only TLR2. B. pseudomallei purified flagellin or flagella attached to the microorganism activated TLR5. Activation of TLR5 was abolished by an antibody to TLR5, or a mutation of fliC, or elimination of the pathogen by filtration. In conclusion, we have uncovered new properties of the Gram-negative pathogens, and their interaction with TLRs of the host. Further studies are needed to include other microorganism to extend our observations with their interaction with TLRs, and to the possibility of leading to new efforts in therapeutics against these pathogens.
Collapse
Affiliation(s)
- Kei Amemiya
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, United States
| | - Jennifer L Dankmeyer
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, United States
| | - Robert C Bernhards
- Edgewood Chemical Biological Centre, Aberdeen Proving Ground, Edgewood, MD, United States
| | - David P Fetterer
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, United States
| | - David M Waag
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, United States
| | - Patricia L Worsham
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, United States
| | - David DeShazer
- Bacteriology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Frederick, MD, United States
| |
Collapse
|
|
36
|
Lin YJ, Flaczyk A, Wolfheimer S, Goretzki A, Jamin A, Wangorsch A, Vieths S, Scheurer S, Schülke S. The Fusion Protein rFlaA:Betv1 Modulates DC Responses by a p38-MAPK and COX2-Dependent Secretion of PGE 2 from Epithelial Cells. Cells 2021; 10:3415. [PMID: 34943923 PMCID: PMC8700022 DOI: 10.3390/cells10123415] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 11/26/2021] [Accepted: 12/02/2021] [Indexed: 11/16/2022] Open
Abstract
Developing new adjuvants/vaccines and better understanding their mode-of-action is an important task. To specifically improve birch pollen allergy treatment, we designed a fusion protein consisting of major birch pollen allergen Betv1 conjugated to the TLR5-ligand flagellin (rFlaA:Betv1). This study investigates the immune-modulatory effects of rFlaA:Betv1 on airway epithelial cells. LA-4 mouse lung epithelial cells were stimulated with rFlaA:Betv1 in the presence/absence of various inhibitors with cytokine- and chemokine secretion quantified by ELISA and activation of intracellular signaling cascades demonstrated by Western blot (WB). Either LA-4 cells or LA-4-derived supernatants were co-cultured with BALB/c bone marrow-derived myeloid dendritic cells (mDCs). Compared to equimolar amounts of flagellin and Betv1 provided as a mixture, rFlaA:Betv1 induced higher secretion of IL-6 and the chemokines CCL2 and CCL20 from LA-4 cells and a pronounced MAPK- and NFκB-activation. Mechanistically, rFlaA:Betv1 was taken up more strongly and the induced cytokine production was inhibited by NFκB-inhibitors, while ERK- and p38-MAPK-inhibitors only suppressed IL-6 and CCL2 secretion. In co-cultures of LA-4 cells with mDCs, rFlaA:Betv1-stimulated LA-4 cells p38-MAPK- and COX2-dependently secreted PGE2, which modulated DC responses by suppressing pro-inflammatory IL-12 and TNF-α secretion. Taken together, these results contribute to our understanding of the mechanisms underlying the strong immune-modulatory effects of flagellin-containing fusion proteins.
Collapse
Affiliation(s)
- Yen-Ju Lin
- Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany; (Y.-J.L.); (A.F.); (S.W.); (A.G.); (A.J.); (A.W.); (S.V.); (S.S.)
| | - Adam Flaczyk
- Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany; (Y.-J.L.); (A.F.); (S.W.); (A.G.); (A.J.); (A.W.); (S.V.); (S.S.)
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Sonja Wolfheimer
- Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany; (Y.-J.L.); (A.F.); (S.W.); (A.G.); (A.J.); (A.W.); (S.V.); (S.S.)
| | - Alexandra Goretzki
- Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany; (Y.-J.L.); (A.F.); (S.W.); (A.G.); (A.J.); (A.W.); (S.V.); (S.S.)
| | - Annette Jamin
- Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany; (Y.-J.L.); (A.F.); (S.W.); (A.G.); (A.J.); (A.W.); (S.V.); (S.S.)
| | - Andrea Wangorsch
- Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany; (Y.-J.L.); (A.F.); (S.W.); (A.G.); (A.J.); (A.W.); (S.V.); (S.S.)
| | - Stefan Vieths
- Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany; (Y.-J.L.); (A.F.); (S.W.); (A.G.); (A.J.); (A.W.); (S.V.); (S.S.)
| | - Stephan Scheurer
- Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany; (Y.-J.L.); (A.F.); (S.W.); (A.G.); (A.J.); (A.W.); (S.V.); (S.S.)
| | - Stefan Schülke
- Molecular Allergology, Paul-Ehrlich-Institut, 63225 Langen, Germany; (Y.-J.L.); (A.F.); (S.W.); (A.G.); (A.J.); (A.W.); (S.V.); (S.S.)
| |
Collapse
|
|
37
|
Chen F, Zou L, Williams B, Chao W. Targeting Toll-Like Receptors in Sepsis: From Bench to Clinical Trials. Antioxid Redox Signal 2021; 35:1324-1339. [PMID: 33588628 PMCID: PMC8817700 DOI: 10.1089/ars.2021.0005] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Significance: Sepsis is a critical clinical syndrome with life-threatening organ dysfunction induced by a dysregulated host response to infection. Despite decades of intensive research, sepsis remains a leading cause of in-hospital mortality with few specific treatments. Recent Advances: Toll-like receptors (TLRs) are a part of the innate immune system and play an important role in host defense against invading pathogens such as bacteria, virus, and fungi. Using a combination of genetically modified animal models and pharmacological agents, numerous preclinical studies during the past two decades have demonstrated that dysregulated TLR signaling may contribute to sepsis pathogenesis. However, many clinical trials targeting inflammation and innate immunity such as TLR4 have yielded mixed results. Critical Issues: Here we review various TLRs and the specific molecules these TLRs sense-both the pathogen-associated and host-derived stress molecules, and their converging signaling pathways. We critically analyze preclinical investigations into the role of TLRs in animal sepsis, the complexity of targeting TLRs for sepsis intervention, and the disappointing clinical trials of the TLR4 antagonist eritoran. Future Directions: Future sepsis treatments will depend on better understanding the complex biological mechanisms of sepsis pathogenesis, the high heterogeneity of septic humans as defined by clinical presentations and unique immunological biomarkers, and improved stratifications for targeted interventions.
Collapse
Affiliation(s)
- Fengqian Chen
- Translational Research Program, Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Lin Zou
- Translational Research Program, Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Brittney Williams
- Translational Research Program, Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Wei Chao
- Translational Research Program, Department of Anesthesiology and Center for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, Maryland, USA
| |
Collapse
|
|
38
|
Sartorius R, Trovato M, Manco R, D'Apice L, De Berardinis P. Exploiting viral sensing mediated by Toll-like receptors to design innovative vaccines. NPJ Vaccines 2021; 6:127. [PMID: 34711839 PMCID: PMC8553822 DOI: 10.1038/s41541-021-00391-8] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Accepted: 10/01/2021] [Indexed: 12/12/2022] Open
Abstract
Toll-like receptors (TLRs) are transmembrane proteins belonging to the family of pattern-recognition receptors. They function as sensors of invading pathogens through recognition of pathogen-associated molecular patterns. After their engagement by microbial ligands, TLRs trigger downstream signaling pathways that culminate into transcriptional upregulation of genes involved in immune defense. Here we provide an updated overview on members of the TLR family and we focus on their role in antiviral response. Understanding of innate sensing and signaling of viruses triggered by these receptors would provide useful knowledge to prompt the development of vaccines able to elicit effective and long-lasting immune responses. We describe the mechanisms developed by viral pathogens to escape from immune surveillance mediated by TLRs and finally discuss how TLR/virus interplay might be exploited to guide the design of innovative vaccine platforms.
Collapse
Affiliation(s)
- Rossella Sartorius
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy.
| | - Maria Trovato
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy
| | - Roberta Manco
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy
| | - Luciana D'Apice
- Institute of Biochemistry and Cell Biology, C.N.R., Via Pietro Castellino 111, 80131, Naples, Italy.
| | | |
Collapse
|
|
39
|
Gern OL, Mulenge F, Pavlou A, Ghita L, Steffen I, Stangel M, Kalinke U. Toll-like Receptors in Viral Encephalitis. Viruses 2021; 13:v13102065. [PMID: 34696494 PMCID: PMC8540543 DOI: 10.3390/v13102065] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/06/2021] [Accepted: 10/08/2021] [Indexed: 12/23/2022] Open
Abstract
Viral encephalitis is a rare but serious syndrome. In addition to DNA-encoded herpes viruses, such as herpes simplex virus and varicella zoster virus, RNA-encoded viruses from the families of Flaviviridae, Rhabdoviridae and Paramyxoviridae are important neurotropic viruses. Whereas in the periphery, the role of Toll-like receptors (TLR) during immune stimulation is well understood, TLR functions within the CNS are less clear. On one hand, TLRs can affect the physiology of neurons during neuronal progenitor cell differentiation and neurite outgrowth, whereas under conditions of infection, the complex interplay between TLR stimulated neurons, astrocytes and microglia is just on the verge of being understood. In this review, we summarize the current knowledge about which TLRs are expressed by cell subsets of the CNS. Furthermore, we specifically highlight functional implications of TLR stimulation in neurons, astrocytes and microglia. After briefly illuminating some examples of viral evasion strategies from TLR signaling, we report on the current knowledge of primary immunodeficiencies in TLR signaling and their consequences for viral encephalitis. Finally, we provide an outlook with examples of TLR agonist mediated intervention strategies and potentiation of vaccine responses against neurotropic virus infections.
Collapse
Affiliation(s)
- Olivia Luise Gern
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany; (F.M.); (A.P.); (L.G.); (U.K.)
- Department of Pathology, University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany
- Correspondence:
| | - Felix Mulenge
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany; (F.M.); (A.P.); (L.G.); (U.K.)
| | - Andreas Pavlou
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany; (F.M.); (A.P.); (L.G.); (U.K.)
- Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, 30625 Hannover, Germany
- Center for Systems Neuroscience, University of Veterinary Medicine Hannover, 30559 Hannover, Germany
| | - Luca Ghita
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany; (F.M.); (A.P.); (L.G.); (U.K.)
- Division of Infectious Diseases and Geographic Medicine, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Imke Steffen
- Department of Biochemistry and Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine Hannover, Foundation, 30559 Hannover, Germany;
| | - Martin Stangel
- Translational Medicine, Novartis Institute for Biomedical Research (NIBR), 4056 Basel, Switzerland;
| | - Ulrich Kalinke
- Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, 30625 Hannover, Germany; (F.M.); (A.P.); (L.G.); (U.K.)
- Cluster of Excellence—Resolving Infection Susceptibility (RESIST, EXC 2155), Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany
| |
Collapse
|
|
40
|
Recent advances in immunotherapy, immunoadjuvant, and nanomaterial-based combination immunotherapy. Coord Chem Rev 2021. [DOI: 10.1016/j.ccr.2021.214009] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
41
|
Jones-Freeman B, Chonwerawong M, Marcelino VR, Deshpande AV, Forster SC, Starkey MR. The microbiome and host mucosal interactions in urinary tract diseases. Mucosal Immunol 2021; 14:779-792. [PMID: 33542492 DOI: 10.1038/s41385-020-00372-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 12/03/2020] [Indexed: 02/06/2023]
Abstract
The urinary tract consists of the bladder, ureters, and kidneys, and is an essential organ system for filtration and excretion of waste products and maintaining systemic homeostasis. In this capacity, the urinary tract is impacted by its interactions with other mucosal sites, including the genitourinary and gastrointestinal systems. Each of these sites harbors diverse ecosystems of microbes termed the microbiota, that regulates complex interactions with the local and systemic immune system. It remains unclear whether changes in the microbiota and associated metabolites may be a consequence or a driver of urinary tract diseases. Here, we review the current literature, investigating the impact of the microbiota on the urinary tract in homeostasis and disease including urinary stones, acute kidney injury, chronic kidney disease, and urinary tract infection. We propose new avenues for exploration of the urinary microbiome using emerging technology and discuss the potential of microbiome-based medicine for urinary tract conditions.
Collapse
Affiliation(s)
- Bernadette Jones-Freeman
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Michelle Chonwerawong
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia
| | - Vanessa R Marcelino
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia
| | - Aniruddh V Deshpande
- Priority Research Centre GrowUpWell, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia.,Department of Pediatric Urology and Surgery, John Hunter Children's Hospital, New Lambton Heights, NSW, Australia.,Urology Unit, Department of Pediatric Surgery, Children's Hospital at Westmead, Sydney Children's Hospital Network, Westmead, NSW, Australia
| | - Samuel C Forster
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia
| | - Malcolm R Starkey
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia. .,Priority Research Centre GrowUpWell, Faculty of Health and Medicine, The University of Newcastle, Callaghan, NSW, Australia.
| |
Collapse
|
|
42
|
Diversity of Rainbow Trout Blood B Cells Revealed by Single Cell RNA Sequencing. BIOLOGY 2021; 10:biology10060511. [PMID: 34207643 PMCID: PMC8227096 DOI: 10.3390/biology10060511] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/03/2021] [Accepted: 06/06/2021] [Indexed: 01/13/2023]
Abstract
Simple Summary Although evolutionarily jawed fish constitute the first group of animals in which a complete adaptive immune system based on immunoglobulins (Igs) is present, many structural immune differences between fish and mammals predict important functional and phenotypical differences between B cells in these two animal groups. However, to date, very few tools are available to study B cell heterogeneity and functionality in fish. Hence, thus far, antibodies targeting the different Igs have been almost exclusively applied as tools to investigate B cell functionality in fish. In the current study, we used the newly developed 10× Genomics single cell RNA sequencing technology and used it to analyze the transcriptional pattern of single B cells from peripheral blood. The results obtained provide us with a transcriptional profile at single cell level of what seem to correspond to different B cell subsets or B cells in different stages of maturation or differentiation. The information provided will not only help us understand the biology of teleost B cells, but also provides us with a repertoire of potential markers that could be used in the future to differentiate trout B cell subsets. Abstract Single-cell sequencing technologies capable of providing us with immune information from dozens to thousands of individual cells simultaneously have revolutionized the field of immunology these past years. However, to date, most of these novel technologies have not been broadly applied to non-model organisms such as teleost fish. In this study, we used the 10× Genomics single cell RNA sequencing technology and used it to analyze for the first time in teleost fish the transcriptional pattern of single B cells from peripheral blood. The analysis of the data obtained in rainbow trout revealed ten distinct cell clusters that seem to be associated with different subsets and/or maturation/differentiation stages of circulating B cells. The potential characteristics and functions of these different B cell subpopulations are discussed on the basis of their transcriptomic profile. The results obtained provide us with valuable information to understand the biology of teleost B cells and offer us a repertoire of potential markers that could be used in the future to differentiate trout B cell subsets.
Collapse
|
|
43
|
McSweeney KR, Gadanec LK, Qaradakhi T, Ali BA, Zulli A, Apostolopoulos V. Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations. Cancers (Basel) 2021; 13:1572. [PMID: 33805488 PMCID: PMC8036620 DOI: 10.3390/cancers13071572] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/19/2021] [Accepted: 03/25/2021] [Indexed: 02/06/2023] Open
Abstract
Administration of the chemotherapeutic agent cisplatin leads to acute kidney injury (AKI). Cisplatin-induced AKI (CIAKI) has a complex pathophysiological map, which has been linked to cellular uptake and efflux, apoptosis, vascular injury, oxidative and endoplasmic reticulum stress, and inflammation. Despite research efforts, pharmaceutical interventions, and clinical trials spanning over several decades, a consistent and stable pharmacological treatment option to reduce AKI in patients receiving cisplatin remains unavailable. This has been predominately linked to the incomplete understanding of CIAKI pathophysiology and molecular mechanisms involved. Herein, we detail the extensively known pathophysiology of cisplatin-induced nephrotoxicity that manifests and the variety of pharmacological and genetic alteration studies that target them.
Collapse
|
|
44
|
Wang M, Li L, Xiao S, Chen W, Hu F, Li F, Guo P, Chen X, Cai W, Tang X. The Association of TLR2, TLR3, and TLR9 Gene Polymorphisms With Susceptibility to Talaromycosis Among Han Chinese AIDS Patients in Guangdong. Front Cell Infect Microbiol 2021; 11:625461. [PMID: 33777838 PMCID: PMC7991721 DOI: 10.3389/fcimb.2021.625461] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 02/15/2021] [Indexed: 11/13/2022] Open
Abstract
Background Talaromycosis (TM) caused by Talaromyces marneffei (T. marneffei) is a growing public health concern. Although Toll-like receptor (TLR) genes play a critical role in the host defense against fungal infection, the influence of polymorphisms in these genes on the susceptibility of acquired immune deficiency syndrome (AIDS) patients to TM remains unknown. This study aims to uncover the associations of single nucleotide polymorphisms (SNPs) in TLR genes with TM susceptibility among patients with AIDS. Methods Altogether 200 AIDS patients complicated with TM, 200 matched AIDS patients without TM, and 76 healthy controls (HCs) were enrolled in this case-control study. In total, 23 SNPs in the TLR2, TLR4, and TLR9 genes, which may influence the susceptibility of AIDS patients to TM, were checked by the time of flight mass spectrometry (TOF/MS) method among these Han Chinese subjects. Results No significant differences in genotype or allele frequencies of selected SNPs were found among the TM group, Non-TM group, and HC group. Haplotype analysis also demonstrated no correlation of these SNPs with TM. However, subgroup analysis showed that the genotype TT and the T allele in TLR2 SNP rs1339 were more frequent in typical TM cases than controls (50.0 vs. 35.8%, 70.5 vs. 59.7%); the frequency of the GT genotype in TLR2 SNP rs7656411 was markedly higher in severe TM cases compared to controls (57.8 vs. 34.4%). Conclusion Our results demonstrate a genetic connection of TLR2 SNPs rs1339 and rs7656411 with an increased susceptibility and severity of TM among Han Chinese populations.
Collapse
Affiliation(s)
- Min Wang
- The First Affiliated Hospital, Jinan University, Guangzhou, China.,Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Linghua Li
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Saiyin Xiao
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China.,Jiangmen Central Hospital, Affiliated Jiangmen Hospital of Sun Yat-sen University, Jiangmen, China
| | - Wanshan Chen
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Fengyu Hu
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Feng Li
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Pengle Guo
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xiejie Chen
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Weiping Cai
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xiaoping Tang
- Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China
| |
Collapse
|
|
45
|
Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, Zitvogel L, Kroemer G. Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology 2021; 1:699-716. [PMID: 22934262 PMCID: PMC3429574 DOI: 10.4161/onci.20696] [Citation(s) in RCA: 165] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are prototypic pattern recognition receptors (PRRs) best known for their ability to activate the innate immune system in response to conserved microbial components such as lipopolysaccharide and double-stranded RNA. Accumulating evidence indicates that the function of TLRs is not restricted to the elicitation of innate immune responses against invading pathogens. TLRs have indeed been shown to participate in tissue repair and injury-induced regeneration as well as in adaptive immune responses against cancer. In particular, TLR4 signaling appears to be required for the efficient processing and cross-presentation of cell-associated tumor antigens by dendritic cells, which de facto underlie optimal therapeutic responses to some anticancer drugs. Thus, TLRs constitute prominent therapeutic targets for the activation/intensification of anticancer immune responses. In line with this notion, long-used preparations such as the Coley toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and the bacillus Calmette-Guérin (BCG, an attenuated strain of Mycobacterium bovis originally developed as a vaccine against tuberculosis), both of which have been associated with consistent anticancer responses, potently activate TLR2 and TLR4 signaling. Today, besides BCG, only one TLR agonist is FDA-approved for therapeutic use in cancer patients: imiquimod. In this Trial Watch, we will briefly present the role of TLRs in innate and cognate immunity and discuss the progress of clinical studies evaluating the safety and efficacy of experimental TLR agonists as immunostimulatory agents for oncological indications.
Collapse
Affiliation(s)
- Lorenzo Galluzzi
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France ; Institut Gustave Roussy; Villejuif, France
| | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Masum MA, Ichii O, Elewa YHA, Kon Y. Podocyte Injury Through Interaction Between Tlr8 and Its Endogenous Ligand miR-21 in Obstructed and Its Collateral Kidney. Front Immunol 2021; 11:606488. [PMID: 33552064 PMCID: PMC7862702 DOI: 10.3389/fimmu.2020.606488] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 12/07/2020] [Indexed: 11/13/2022] Open
Abstract
While chronic kidney disease is prevalent in adults, obstructive nephropathy (ON) has been reported in both young and old patients. In ON, tubulointerstitial lesions (TILs) have been widely investigated, but glomerular lesions (GLs) have been largely neglected. Here, we show a novel mechanism underlying GL development in ON in young and old mice. TILs develop earlier than GLs owing to infiltration of inflammatory cells in the tubulointerstitium, but GLs develop following the activation of Toll-like receptor 8 (Tlr8) even though the absence of inflammatory cells infiltrating the glomerulus. TLR8 and interleukin 1 beta (IL1β) proteins colocalize with reducing podocyte function markers (PFMs), indicating the activation of TLR8 signaling in injured podocytes. Furthermore, glomerular and serum levels of miR-21, an endogenous ligand for Tlr8, were higher in the ON mouse model than in the sham control. The glomerular expression of Tlr8 positively correlates with miR-21 and the downstream cytokines Il1b and Il6 and negatively correlated with PFMs (Nphs1 and Synpo). We also show the colocalization of TLR8 and IL1β proteins with reducing PFMs in both obstructed and collateral kidney of young and old mice. Furthermore, in vitro study results revealed higher expression of Tlr8 and its downstream cytokines in glomeruli from obstructed kidneys following treatment with miR-21 mimic than in the control. In conclusion, the overexpression of Tlr8 may serve as a plausible mechanism underlying GL development in ON through podocyte injury.
Collapse
Affiliation(s)
- Md. Abdul Masum
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- Department of Anatomy, Histology and Physiology, Faculty of Animal Science and Veterinary Medicine, Sher-e-Bangla Agricultural University, Dhaka, Bangladesh
| | - Osamu Ichii
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- Laboratory of Agrobiomedical Science, Faculty of Agriculture, Hokkaido University, Sapporo, Japan
| | - Yaser Hosny Ali Elewa
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
- Department of Histology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt
| | - Yasuhiro Kon
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan
| |
Collapse
|
|
47
|
Ambite I, Butler D, Wan MLY, Rosenblad T, Tran TH, Chao SM, Svanborg C. Molecular determinants of disease severity in urinary tract infection. Nat Rev Urol 2021; 18:468-486. [PMID: 34131331 PMCID: PMC8204302 DOI: 10.1038/s41585-021-00477-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/07/2021] [Indexed: 02/06/2023]
Abstract
The most common and lethal bacterial pathogens have co-evolved with the host. Pathogens are the aggressors, and the host immune system is responsible for the defence. However, immune responses can also become destructive, and excessive innate immune activation is a major cause of infection-associated morbidity, exemplified by symptomatic urinary tract infections (UTIs), which are caused, in part, by excessive innate immune activation. Severe kidney infections (acute pyelonephritis) are a major cause of morbidity and mortality, and painful infections of the urinary bladder (acute cystitis) can become debilitating in susceptible patients. Disease severity is controlled at specific innate immune checkpoints, and a detailed understanding of their functions is crucial for strategies to counter microbial aggression with novel treatment and prevention measures. One approach is the use of bacterial molecules that reprogramme the innate immune system, accelerating or inhibiting disease processes. A very different outcome is asymptomatic bacteriuria, defined by low host immune responsiveness to bacteria with attenuated virulence. This observation provides the rationale for immunomodulation as a new therapeutic tool to deliberately modify host susceptibility, control the host response and avoid severe disease. The power of innate immunity as an arbitrator of health and disease is also highly relevant for emerging pathogens, including the current COVID-19 pandemic.
Collapse
Affiliation(s)
- Ines Ambite
- grid.4514.40000 0001 0930 2361Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden
| | - Daniel Butler
- grid.4514.40000 0001 0930 2361Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden
| | - Murphy Lam Yim Wan
- grid.4514.40000 0001 0930 2361Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden
| | - Therese Rosenblad
- grid.4514.40000 0001 0930 2361Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden
| | - Thi Hien Tran
- grid.4514.40000 0001 0930 2361Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden
| | - Sing Ming Chao
- Nephrology Service, Department of Paediatrics, KK Hospital, Singapore, Singapore
| | - Catharina Svanborg
- grid.4514.40000 0001 0930 2361Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, Lund, Sweden
| |
Collapse
|
|
48
|
Ren Q, Cheng L, Yi J, Ma L, Pan J, Gou SJ, Fu P. Toll-like Receptors as Potential Therapeutic Targets in Kidney Diseases. Curr Med Chem 2020; 27:5829-5854. [PMID: 31161985 DOI: 10.2174/0929867325666190603110907] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/15/2019] [Accepted: 05/13/2019] [Indexed: 02/08/2023]
Abstract
Toll-like Receptors (TLRs) are members of pattern recognition receptors and serve a pivotal role in host immunity. TLRs response to pathogen-associated molecular patterns encoded by pathogens or damage-associated molecular patterns released by dying cells, initiating an inflammatory cascade, where both beneficial and detrimental effects can be exerted. Accumulated evidence has revealed that TLRs are closely associated with various kidney diseases but their roles are still not well understood. This review updated evidence on the roles of TLRs in the pathogenesis of kidney diseases including urinary tract infection, glomerulonephritis, acute kidney injury, transplant allograft dysfunction and chronic kidney diseases.
Collapse
Affiliation(s)
- Qian Ren
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lu Cheng
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jing Yi
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Liang Ma
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Jing Pan
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Shen-Ju Gou
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ping Fu
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
49
|
Sivak KV, Stosman KI, Rassokha TA, Aleksandrov AG, Kuzmich NN, Orshanskaya YR, Savateeva-Lubimova TN, Lesiovskaya EE. The Effect of TLR4 Blockade on Some Indicators of Systemic Inflammatory Response to Proteus mirabilis LPS in Rats. Bull Exp Biol Med 2020; 169:795-797. [PMID: 33098506 DOI: 10.1007/s10517-020-04981-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Indexed: 10/23/2022]
Abstract
The effects of TLR4 blocker on blood cell morphology, concentrations proinflammatory cytokines, and functional state of the liver and kidneys were studied in outbred male rats (n=60) after intravenous injection of 20 mg/kg LPS isolated from opportunistic Proteus mirabilis strain ATCC 51393. TLR4 blocker TLR4-IN-C34 was injected intravenously in a dose of 1 mg/kg/day over 3 days. Systemic inflammatory reaction induced by LPS was characterized by elevation of serum TNFα, IL-1β, IL-6, erythrocyte sedimentation rate, leukocytosis, and thrombocytosis. Increased activity of hepatocyte enzymes (ALT, alkaline phosphatase, and lactate dehydrogenase), retention of nitrogen metabolites (urea and creatinine), elevated content of protein oxidation products, and enhanced protein catabolism were also observed. Administration of TLR4 blocker reduced parameters of inflammatory reaction and prevented the development of hypercatabolic syndrome; endotoxicosis and kidney function indicators approached the normal levels.
Collapse
Affiliation(s)
- K V Sivak
- A. A. Smorodintsev Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, Russia
| | - K I Stosman
- A. A. Smorodintsev Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, Russia.
| | - T A Rassokha
- A. A. Smorodintsev Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, Russia
| | - A G Aleksandrov
- A. A. Smorodintsev Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, Russia
| | - N N Kuzmich
- A. A. Smorodintsev Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, Russia
| | - Ya R Orshanskaya
- A. A. Smorodintsev Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, Russia
| | - T N Savateeva-Lubimova
- A. A. Smorodintsev Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, Russia
| | - E E Lesiovskaya
- A. A. Smorodintsev Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, Russia
| |
Collapse
|
|
50
|
Kumar V. Toll-like receptors in sepsis-associated cytokine storm and their endogenous negative regulators as future immunomodulatory targets. Int Immunopharmacol 2020; 89:107087. [PMID: 33075714 PMCID: PMC7550173 DOI: 10.1016/j.intimp.2020.107087] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 10/04/2020] [Accepted: 10/08/2020] [Indexed: 12/15/2022]
Abstract
Sepsis infects more than 48.9 million people world-wide, with 19.7 million deaths. Cytokine storm plays a significant role in sepsis, along with severe COVID-19. TLR signaling pathways plays a crucial role in generating the cytokine storm. Endogenous negative regulators of TLR signaling are crucial to regulate cytokine storm. Cytokine storm generates during various systemic acute infections, including sepsis and current pandemic called COVID-19 (severe) causing devastating inflammatory conditions, which include multi-organ failure or multi-organ dysfunction syndrome (MODS) and death of the patient. Toll-like receptors (TLRs) are one of the major pattern recognition receptors (PRRs) expressed by immune cells as well as non-immune cells, including neurons, which play a crucial role in generating cytokine storm. They recognize microbial-associated molecular patterns (MAMPs, expressed by pathogens) and damage or death-associate molecular patterns (DAMPs; released and/expressed by damaged/killed host cells). Upon recognition of MAMPs and DAMPs, TLRs activate downstream signaling pathways releasing several pro-inflammatory mediators [cytokines, chemokines, interferons, and reactive oxygen and nitrogen species (ROS or RNS)], which cause acute inflammation meant to control the pathogen and repair the damage. Induction of an exaggerated response due to genetic makeup of the host and/or persistence of the pathogen due to its evasion mechanisms may lead to severe systemic inflammatory condition called sepsis in response to the generation of cytokine storm and organ dysfunction. The activation of TLR-induced inflammatory response is hardwired to the induction of several negative feedback mechanisms that come into play to conclude the response and maintain immune homeostasis. This state-of-the-art review describes the importance of TLR signaling in the onset of the sepsis-associated cytokine storm and discusses various host-derived endogenous negative regulators of TLR signaling pathways. The subject is very important as there is a vast array of genes and processes implicated in these negative feedback mechanisms. These molecules and mechanisms can be targeted for developing novel therapeutic drugs for cytokine storm-associated diseases, including sepsis, severe COVID-19, and other inflammatory diseases, where TLR-signaling plays a significant role.
Collapse
Affiliation(s)
- V Kumar
- Children Health Clinical Unit, Faculty of Medicine, Mater Research, University of Queensland, ST Lucia, Brisbane, Queensland 4078, Australia; School of Biomedical Sciences, Faculty of Medicine, University of Queensland, ST Lucia, Brisbane, Queensland 4078, Australia.
| |
Collapse
|