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Han Y, Wang S, Xiong Y, Sha T, Xiong Z, Li S, She W, Zhang Y, He X, Zou S, Cheng J, Meng J, Yuan Q, Huang L, Xie Y, Tao L, Peng Z. Peroxiredoxin-1 aggravates hypoxia-induced renal injury by promoting inflammation through the TLR4/MAPK/NF-κB signaling pathway. Free Radic Biol Med 2025:S0891-5849(25)00682-3. [PMID: 40398686 DOI: 10.1016/j.freeradbiomed.2025.05.399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Revised: 04/28/2025] [Accepted: 05/19/2025] [Indexed: 05/23/2025]
Abstract
Hypoxia can induce pathological alterations to the kidneys, such as activation of inflammatory signaling pathways. This form of inflammation is pathogen-free and is referred to as aseptic inflammation. Currently, the mechanisms leading to aseptic inflammation under hypoxia are not well understood. Emerging evidence has indicated that Prdx1, a member of the peroxidase family, contributes to the development of various diseases by stimulating aseptic inflammation. This study was conducted to reveal the potential role of Prdx1 in the pathogenesis of hypoxia-induced renal injury. A mouse model of systemic hypoxia was developed, which revealed that Prdx1 levels were elevated in injured kidneys and peripheral circulation. A comparable increase was also observed in hypoxia-treated immortalized bone marrow-derived macrophages (iBMDMs). Knock-down of Prdx1 in mice caused a significant reduction in renal tissue injury and inflammation induced by hypoxic injury. In addition, we demonstrated that Prdx1 modulates inflammatory responses by activating the TLR4/MAPK/NF-κB signaling pathways. Recombinant Prdx1 promoted the activation of these pathways in macrophages, whereas genetic knockout of Prdx1 or pharmacological inhibition suppressed their activity. Altogether, we found a previously unrecognized role for Prdx1 in the regulation of inflammation in hypoxia-induced renal injury. These findings suggest that Prdx1 can be a potential target for treating this severe disease.
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Affiliation(s)
- Yuanyuan Han
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China
| | - Songkai Wang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China
| | - Yiwei Xiong
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China
| | - Tu Sha
- Department of Gastroenterology, Guangdong Provincial People's Hospital,Guangzhou Guangdong,China
| | - Zujian Xiong
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Shenglan Li
- Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China; Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha Hunan, China
| | - Wenzhe She
- Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China; Department of Cell biology, School of Life Sciences, Central South University, Changsha Hunan, China
| | - Yan Zhang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China
| | - Xin He
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China
| | - Sijue Zou
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China
| | - Jiawei Cheng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China
| | - Jie Meng
- Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China; Department of Respiratory Medicine, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiongjing Yuan
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China
| | - Ling Huang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China
| | - Yanyun Xie
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China
| | - Lijian Tao
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China
| | - Zhangzhe Peng
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha Hunan, China; Key Laboratory of Organ Fibrosis of Hunan Province, Central South University, Changsha Hunan, China.
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Hu Q, Leung WK, Acharya A, Li X, Pelekos G. Akkermansia muciniphila Alleviates Porphyromonas gingivalis-induced Periodontal Disease by Enhancing Bacterial Clearance. Probiotics Antimicrob Proteins 2025:10.1007/s12602-025-10541-2. [PMID: 40299200 DOI: 10.1007/s12602-025-10541-2] [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] [Accepted: 04/16/2025] [Indexed: 04/30/2025]
Abstract
This study is to investigate the role of Akkermansia muciniphila (Am) in enhancing immune defense against Porphyromonas gingivalis (Pg)-induced periodontal disease. Twenty C57BL/6 J mice received 50 µL of Pg suspension (1.5 × 109 CFU/mL) with or without 50 µL of Am suspension (1.5 × 109 CFU/mL) orally every 2 days for a total of 18 administrations to assess bone resorption and inflammation. Gingival cervical fluid and periodontal plaques were collected for microbiota analysis using 16S sequencing. THP-1 (a human leukemia monocytic cell line) differentiated macrophages were used to explore the underlying beneficial mechanisms of Am by evaluating gene expression, cytokine production, and phagocytosis activity. Am administration attenuated alveolar bone loss and reduced inflammation in Pg-induced periodontitis in mice. Microbiota analysis revealed that Am reduced bacterial load and modified the composition of periodontal microbiota. In THP-1 macrophages, Am enhanced the phagocytosis of Pg by restoring MyD88 protein levels. RNA sequencing and western blotting results showed that Am upregulated TLR2 and MyD88 expression while downregulating C5aR, indicating interference with the TLR2-C5aR-MyD88 interplay. Am enhances immune defense against Pg-induced periodontal disease by modulating the TLR2-C5aR-MyD88 signaling pathway. These findings suggest that Am could be a promising therapeutic option for managing periodontal disease.
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Affiliation(s)
- Qin Hu
- Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Sai Ying Pun, Hong Kong SAR, China
| | - Wai Keung Leung
- Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Sai Ying Pun, Hong Kong SAR, China
| | - Aneesha Acharya
- Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Sai Ying Pun, Hong Kong SAR, China
- Dr D Y Patil Dental College and Hospital, Pune, India
| | - Xuan Li
- Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Sai Ying Pun, Hong Kong SAR, China.
| | - George Pelekos
- Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Sai Ying Pun, Hong Kong SAR, China.
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Hou S, Yu J, Li Y, Zhao D, Zhang Z. Advances in Fecal Microbiota Transplantation for Gut Dysbiosis-Related Diseases. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2413197. [PMID: 40013938 PMCID: PMC11967859 DOI: 10.1002/advs.202413197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 01/22/2025] [Indexed: 02/28/2025]
Abstract
This article provides an overview of the advancements in the application of fecal microbiota transplantation (FMT) in treating diseases related to intestinal dysbiosis. FMT involves the transfer of healthy donor fecal microbiota into the patient's body, aiming to restore the balance of intestinal microbiota and thereby treat a variety of intestinal diseases such as recurrent Clostridioides difficile infection (rCDI), inflammatory bowel disease (IBD), constipation, short bowel syndrome (SBS), and irritable bowel syndrome (IBS). While FMT has shown high efficacy in the treatment of rCDI, further research is needed for its application in other chronic conditions. This article elaborates on the application of FMT in intestinal diseases and the mechanisms of intestinal dysbiosis, as well as discusses key factors influencing the effectiveness of FMT, including donor selection, recipient characteristics, treatment protocols, and methods for assessing microbiota. Additionally, it emphasizes the key to successful FMT. Future research should focus on optimizing the FMT process to ensure long-term safety and explore the potential application of FMT in a broader range of medical conditions.
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Affiliation(s)
- Shuna Hou
- Department of OrthopedicsThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
- Department of general surgeryThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
| | - Jiachen Yu
- Department of OrthopedicsThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
| | - Yongshuang Li
- Department of general surgeryThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
| | - Duoyi Zhao
- Department of OrthopedicsThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
| | - Zhiyu Zhang
- Department of OrthopedicsThe Fourth Affiliated Hospital of China Medical UniversityChina Medical UniversityLiao NingShen Yang110032P. R. China
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Hiti L, Markovič T, Lainscak M, Farkaš Lainščak J, Pal E, Mlinarič-Raščan I. The immunopathogenesis of a cytokine storm: The key mechanisms underlying severe COVID-19. Cytokine Growth Factor Rev 2025; 82:1-17. [PMID: 39884914 DOI: 10.1016/j.cytogfr.2024.12.003] [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: 10/22/2024] [Revised: 12/18/2024] [Accepted: 12/26/2024] [Indexed: 02/01/2025]
Abstract
A cytokine storm is marked by excessive pro-inflammatory cytokine release, and has emerged as a key factor in severe COVID-19 cases - making it a critical therapeutic target. However, its pathophysiology was poorly understood, which hindered effective treatment. SARS-CoV-2 initially disrupts angiotensin signalling, promoting inflammation through ACE-2 downregulation. Some patients' immune systems then fail to shift from innate to adaptive immunity, suppressing interferon responses and leading to excessive pyroptosis and neutrophil activation. This amplifies tissue damage and inflammation, creating a pro-inflammatory loop. The result is the disruption of Th1/Th2 and Th17/Treg balances, lymphocyte exhaustion, and extensive blood clotting. Cytokine storm treatments include glucocorticoids to suppress the immune system, monoclonal antibodies to neutralize specific cytokines, and JAK inhibitors to block cytokine receptor signalling. However, the most effective treatment options for mitigating SARS-CoV-2 infection remain vaccines as a preventive measure and antiviral drugs for the early stages of infection. This article synthesizes insights into immune dysregulation in COVID-19, offering a framework to better understand cytokine storms and to improve monitoring, biomarker discovery, and treatment strategies for COVID-19 and other conditions involving cytokine storms.
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Affiliation(s)
- Luka Hiti
- Faculty of Pharmacy, University of Ljubljana, Slovenia
| | | | - Mitja Lainscak
- General Hospital Murska Sobota, Slovenia; Faculty of Medicine, University of Ljubljana, Slovenia
| | | | - Emil Pal
- General Hospital Murska Sobota, Slovenia
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Tan C, Li C, Ge R, Zhang W, Wu Z, Wang S, Cui H, Wang X, Zhang L. Mcl-1 downregulation enhances BCG treatment efficacy in bladder cancer by promoting macrophage polarization. Cancer Cell Int 2025; 25:48. [PMID: 39955585 PMCID: PMC11830210 DOI: 10.1186/s12935-025-03676-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Accepted: 02/04/2025] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND Bacillus Calmette-Guérin (BCG) is the primary method of postoperative perfusion treatment for bladder cancer. The myeloid cell leukemia gene-1 (Mcl-1) is closely associated with the development of malignant tumors. Previous research by our group has demonstrated that downregulating Mcl-1 using shRNA can enhance the efficacy of BCG treatment in bladder cancer. This study aims to investigate the impact of Mcl-1 downregulation in combination with BCG treatment on bladder cancer, macrophage polarization, and the underlying mechanism of action, with the goal of reducing recurrence and metastasis in bladder cancer. METHODS The GSE190529 dataset was analyzed to identify differential genes for enrichment analysis. The WGCNA algorithm was then employed to pinpoint gene modules closely associated with the Mcl-1 gene. The overlapping genes between these modules and the differentially expressed genes were subjected to enrichment analysis in GO and KEGG pathways to unveil crucial signaling pathways. In vitro experiments involved the co-culture of Raw264.7 macrophages and MB49 to establish a tumor microenvironment model, while in vivo experiments utilized an MNU-induced rat bladder cancer model. Various methods including Enzyme-Linked Immunosorbent Assay (ELISA), Western blot, immunofluorescence, HE staining, etc. were utilized to assess macrophage polarization and the expression of proteins linked to the ASK1/MKK7/JNK/cJUN signaling pathway. RESULTS Bioinformatics analysis indicates that the therapeutic mechanism of Mcl-1 in BCG treatment for bladder cancer may be linked to the Mitogen-Activated Protein Kinase (MAPK) signaling pathway. Both in vivo and in vitro experiments have demonstrated that the combination of BCG treatment and Mcl-1shRNA intervention results in elevated expression of M1 markers (TNF-α, CD86, INOS) and reduced expression of M2 markers (IL-10, CD206, Arg-1). Moreover, there was a notable increase in protein levels of P-ASK1, P-MKK7, P-JNK, P-cJUN, and CX43, leading to a significant rise in the apoptosis rate of bladder cancer cells and diminished proliferation, migration, and invasion capabilities. The expression of these markers can be reversed by employing the JNK signaling pathway inhibitor SP600125. CONCLUSION Down-regulation of Mcl-1 promotes the polarization of macrophages towards the M1 type through activation of the ASK1/MKK7/JNK signaling pathway. This enhances intercellular communication and improves the efficacy of BCG in bladder cancer treatment.
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Affiliation(s)
- Caixia Tan
- Department of Pathophysiology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Xinjiang Key Laboratory of Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi, Xinjiang, China
| | - Chen Li
- Department of Pathophysiology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Xinjiang Key Laboratory of Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi, Xinjiang, China
- The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, China
| | - Ruihan Ge
- Department of Pathophysiology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Xinjiang Key Laboratory of Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi, Xinjiang, China
| | - Wei Zhang
- Department of Pathophysiology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Xinjiang Key Laboratory of Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi, Xinjiang, China
| | - Ziyi Wu
- Xinjiang Key Laboratory of Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi, Xinjiang, China
- The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, China
| | - Shengpeng Wang
- Xinjiang Key Laboratory of Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi, Xinjiang, China
- The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, China
| | - Haotian Cui
- Department of Pathophysiology, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Xinjiang Key Laboratory of Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi, Xinjiang, China
| | - Xinmin Wang
- Xinjiang Key Laboratory of Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi, Xinjiang, China.
- The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, China.
| | - Le Zhang
- Department of Pathophysiology, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
- Xinjiang Key Laboratory of Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang, China.
- NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, Shihezi, Xinjiang, China.
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Tu W, Guo M, Zhang Z, Li C. Pathogen-induced apoptosis in echinoderms: A review. FISH & SHELLFISH IMMUNOLOGY 2024; 155:109990. [PMID: 39481501 DOI: 10.1016/j.fsi.2024.109990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 10/16/2024] [Accepted: 10/26/2024] [Indexed: 11/02/2024]
Abstract
Echinoderms possess unique biological traits that make them valuable models in immunology, regeneration, and developmental biology studies. As a class rich in active substances with significant nutritional and medicinal value, echinoderms face threats from marine pathogens, including bacteria, viruses, fungi, protozoa, and parasites, which have caused substantial economic losses in echinoderm aquaculture. Echinoderms counteract pathogen invasion through innate immunity and programmed cell death, in particular, with apoptosis being essential for eliminating infected or damaged cells and maintaining homeostasis in many echinoderm cell types. Despite the importance of this process, there is a lack of comprehensive and updated reviews on this topic. This review underscores that echinoderm apoptotic pathways exhibit a complexity comparable to that of vertebrates, featuring proteins with unique domains that may indicate the presence of novel signaling mechanisms. We synthesize current knowledge on how echinoderms utilize diverse transcriptional and post-transcriptional mechanisms to regulate apoptosis in response to pathogen infections and explore how pathogens have evolved strategies to manipulate echinoderm apoptosis, either by inhibiting it to create survival niches or by inducing excessive apoptosis to weaken the host. By elucidating the primary apoptotic pathways in echinoderms and the host-pathogen interactions that modulate these pathways, this review aims to reveal new mechanisms of apoptosis in animal immune defense and provide insights into the evolutionary arms race between hosts and pathogens.
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Affiliation(s)
- Weitao Tu
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Ming Guo
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China.
| | - Zhen Zhang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China
| | - Chenghua Li
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, School of Marine Sciences, Ningbo University, Ningbo, 315211, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266071, China.
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Biennier S, Fontaine M, Duquenoy A, Schwintner C, Doré J, Corvaia N. Narrative Review: Advancing Dysbiosis Treatment in Onco-Hematology with Microbiome-Based Therapeutic Approach. Microorganisms 2024; 12:2256. [PMID: 39597645 PMCID: PMC11596191 DOI: 10.3390/microorganisms12112256] [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: 09/30/2024] [Revised: 10/29/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024] Open
Abstract
This review explores the complex relationship between gut dysbiosis and hematological malignancies, focusing on graft-versus-host disease (GvHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. We discuss how alterations in microbial diversity and composition can influence disease development, progression, and treatment outcomes in blood cancers. The mechanisms by which the gut microbiota impacts these conditions are examined, including modulation of immune responses, production of metabolites, and effects on intestinal barrier function. Recent advances in microbiome-based therapies for treating and preventing GvHD are highlighted, with emphasis on full ecosystem standardized donor-derived products. Overall, this review underscores the growing importance of microbiome research in hematology-oncology and its potential to complement existing treatments and improve outcomes for thousands of patients worldwide.
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Affiliation(s)
- Salomé Biennier
- MaaT Pharma, 69007 Lyon, France; (S.B.); (A.D.); (C.S.); (N.C.)
| | | | - Aurore Duquenoy
- MaaT Pharma, 69007 Lyon, France; (S.B.); (A.D.); (C.S.); (N.C.)
| | | | - Joël Doré
- Université Paris-Saclay, INRAE, MetaGenoPolis, AgroParisTech, MICALIS, 78350 Jouy-en-Josas, France;
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Pushpamithran G, Blomgran R. Macrophage-derived extracellular vesicles from Ascaris lumbricoides antigen exposure enhance Mycobacterium tuberculosis growth control, reduce IL-1β, and contain miR-342-5p, miR-516b-5p, and miR-570-3p that regulate PI3K/AKT and MAPK signaling pathways. Front Immunol 2024; 15:1454881. [PMID: 39569198 PMCID: PMC11576181 DOI: 10.3389/fimmu.2024.1454881] [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: 06/25/2024] [Accepted: 10/07/2024] [Indexed: 11/22/2024] Open
Abstract
Background Helminth coinfection with tuberculosis (TB) can alter the phenotype and function of macrophages, which are the major host cells responsible for controlling Mycobacterium tuberculosis (Mtb). However, it is not known whether helminth infection stimulates the release of host-derived extracellular vesicles (EVs) to induce or maintain their regulatory network that suppresses TB immunity. We previously showed that pre-exposure of human monocyte-derived macrophages (hMDMs) with Ascaris lumbricoides protein antigens (ASC) results in reduced Mtb infection-driven proinflammation and gained bacterial control. This effect was entirely dependent on the presence of soluble components in the conditioned medium from helminth antigen-pre-exposed macrophages. Methods Our objective was to investigate the role of EVs released from helminth antigen-exposed hMDMs on Mtb-induced proinflammation and its effect on Mtb growth in hMDMs. Conditioned medium from 48-h pre-exposure with ASC or Schistosoma mansoni antigen (SM) was used to isolate EVs by ultracentrifugation. EVs were characterized by immunoblotting, flow cytometry, nanoparticle tracking assay, transmission electron microscopy, and a total of 377 microRNA (miRNA) from EVs screened by TaqMan array. Luciferase-expressing Mtb H37Rv was used to evaluate the impact of isolated EVs on Mtb growth control in hMDMs. Results EV characterization confirmed double-membraned EVs, with a mean size of 140 nm, expressing the classical exosome markers CD63, CD81, CD9, and flotillin-1. Specifically, EVs from the ASC conditioned medium increased the bacterial control in treatment-naïve hMDMs and attenuated Mtb-induced IL-1β at 5 days post-infection. Four miRNAs showed unique upregulation in response to ASC exposure in five donors. Pathway enrichment analysis showed that the MAPK and PI3K-AKT signaling pathways were regulated. Among the mRNA targets, relevant for regulating inflammatory responses and cellular stress pathways, CREB1 and MAPK13 were identified. In contrast, SM exposure showed significant regulation of the TGF-β signaling pathway with SMAD4 as a common target. Conclusion Overall, our findings suggest that miRNAs in EVs released from helminth-exposed macrophages regulate important signaling pathways that influence macrophage control of Mtb and reduce inflammation. Understanding these interactions between helminth-induced EVs, miRNAs, and macrophage responses may inform novel therapeutic strategies for TB management.
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Affiliation(s)
- Giggil Pushpamithran
- Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
| | - Robert Blomgran
- Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
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Zhao X, Wang M, Zhang Y, Zhang Y, Tang H, Yue H, Zhang L, Song D. Macrophages in the inflammatory response to endotoxic shock. Immun Inflamm Dis 2024; 12:e70027. [PMID: 39387442 PMCID: PMC11465138 DOI: 10.1002/iid3.70027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 08/24/2024] [Accepted: 09/13/2024] [Indexed: 10/15/2024] Open
Abstract
BACKGROUND Endotoxic shock, particularly prevalent in intensive care units, represents a significant medical challenge. Endotoxin, upon invading the host, triggers intricate interactions with the innate immune system, particularly macrophages. This activation leads to the production of inflammatory mediators such as tumor necrosis factor-alpha, interleukin-6, and interleukin-1-beta, as well as aberrant activation of the nuclear factor-kappa-B and mitogen-activated protein kinase signaling pathways. OBJECTIVE This review delves into the intricate inflammatory cascades underpinning endotoxic shock, with a particular focus on the pivotal role of macrophages. It aims to elucidate the clinical implications of these processes and offer insights into potential therapeutic strategies. RESULTS Macrophages, central to immune regulation, manifest in two distinct subsets: M1 (classically activated subtype) macrophages and M2 (alternatively activated subtype) macrophages. The former exhibit an inflammatory phenotype, while the latter adopt an anti-inflammatory role. By modulating the inflammatory response in patients with endotoxic shock, these macrophages play a crucial role in restoring immune balance and facilitating recovery. CONCLUSION Macrophages undergo dynamic changes within the immune system, orchestrating essential processes for maintaining tissue homeostasis. A deeper comprehension of the mechanisms governing macrophage-mediated inflammation lays the groundwork for an anti-inflammatory, targeted approach to treating endotoxic shock. This understanding can significantly contribute to the development of more effective therapeutic interventions.
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Affiliation(s)
- Xinjie Zhao
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of MedicineXizang Minzu UniversityXianyangShaanxiChina
- School of MedicineXizang Minzu UniversityXianyangChina
| | - Mengjie Wang
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of MedicineXizang Minzu UniversityXianyangShaanxiChina
| | - Yanru Zhang
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of MedicineXizang Minzu UniversityXianyangShaanxiChina
| | - Yiyi Zhang
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of MedicineXizang Minzu UniversityXianyangShaanxiChina
| | - Haojie Tang
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of MedicineXizang Minzu UniversityXianyangShaanxiChina
| | - Hongyi Yue
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of MedicineXizang Minzu UniversityXianyangShaanxiChina
| | - Li Zhang
- Affiliated Hospital of Xizang Minzu UniversityXianyangShaanxiChina
| | - Dan Song
- Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region, School of MedicineXizang Minzu UniversityXianyangShaanxiChina
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Archambaud C, Nunez N, da Silva RAG, Kline KA, Serror P. Enterococcus faecalis: an overlooked cell invader. Microbiol Mol Biol Rev 2024; 88:e0006924. [PMID: 39239986 PMCID: PMC11426025 DOI: 10.1128/mmbr.00069-24] [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] [Indexed: 09/07/2024] Open
Abstract
SUMMARYEnterococcus faecalis and Enterococcus faecium are human pathobionts that exhibit a dual lifestyle as commensal and pathogenic bacteria. The pathogenic lifestyle is associated with specific conditions involving host susceptibility and intestinal overgrowth or the use of a medical device. Although the virulence of E. faecium appears to benefit from its antimicrobial resistance, E. faecalis is recognized for its higher pathogenic potential. E. faecalis has long been considered a predominantly extracellular pathogen; it adheres to and is taken up by a wide range of mammalian cells, albeit with less efficiency than classical intracellular enteropathogens. Carbohydrate structures, rather than proteinaceous moieties, are likely to be primarily involved in the adhesion of E. faecalis to epithelial cells. Consistently, few adhesins have been implicated in the adhesion of E. faecalis to epithelial cells. On the host side, very little is known about cognate receptors, except for the role of glycosaminoglycans during macrophage infection. Several lines of evidence indicate that E. faecalis internalization may involve a zipper-like mechanism as well as a macropinocytosis pathway. Conversely, E. faecalis can use several strategies to prevent engulfment in phagocytes. However, the bacterial and host mechanisms underlying cell infection by E. faecalis are still in their infancy. The most recent striking finding is the existence of an intracellular lifestyle where E. faecalis can replicate within a variety of host cells. In this review, we summarize and discuss the current knowledge of E. faecalis-host cell interactions and argue on the need for further mechanistic studies to prevent or reduce infections.
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Affiliation(s)
- Cristel Archambaud
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Natalia Nunez
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
| | - Ronni A G da Silva
- Singapore-MIT Alliance for Research and Technology, Antimicrobial Drug Resistance Interdisciplinary Research Group, Singapore, Singapore
- Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore
| | - Kimberly A Kline
- Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore, Singapore
- Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
| | - Pascale Serror
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, Jouy-en-Josas, France
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11
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Marrufo AM, Flores-Mireles AL. Macrophage fate: to kill or not to kill? Infect Immun 2024; 92:e0047623. [PMID: 38829045 PMCID: PMC11385966 DOI: 10.1128/iai.00476-23] [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: 06/05/2024] Open
Abstract
Macrophages are dynamic innate immune cells that either reside in tissue, serving as sentinels, or recruited as monocytes from bone marrow into inflamed and infected tissue. In response to cues in the tissue microenvironment (TME), macrophages polarize on a continuum toward M1 or M2 with diverse roles in progression and resolution of disease. M1-like macrophages exhibit proinflammatory functions with antimicrobial and anti-tumorigenic activities, while M2-like macrophages have anti-inflammatory functions that generally resolve inflammatory responses and orchestrate a tissue healing process. Given these opposite phenotypes, proper spatiotemporal coordination of macrophage polarization in response to cues within the TME is critical to effectively resolve infectious disease and regulate wound healing. However, if this spatiotemporal coordination becomes disrupted due to persistent infection or dysregulated coagulation, macrophages' inappropriate response to these cues will result in the development of diseases with clinically unfavorable outcomes. Since plasticity and heterogeneity are hallmarks of macrophages, they are attractive targets for therapies to reprogram toward specific phenotypes that could resolve disease and favor clinical prognosis. In this review, we discuss how basic science studies have elucidated macrophage polarization mechanisms in TMEs during infections and inflammation, particularly coagulation. Therefore, understanding the dynamics of macrophage polarization within TMEs in diseases is important in further development of targeted therapies.
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Affiliation(s)
- Armando M. Marrufo
- Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA
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12
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Sawoo R, Bishayi B. TLR4/TNFR1 blockade suppresses STAT1/STAT3 expression and increases SOCS3 expression in modulation of LPS-induced macrophage responses. Immunobiology 2024; 229:152840. [PMID: 39126792 DOI: 10.1016/j.imbio.2024.152840] [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: 12/15/2023] [Revised: 07/15/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024]
Abstract
Due to the urgent need to create appropriate treatment techniques, which are currently unavailable, LPS-induced sepsis has become a serious concern on a global scale. The primary active component in the pathophysiology of inflammatory diseases such as sepsis is the Gram-negative bacterial lipopolysaccharide (LPS). LPS interacts with cell surface TLR4 in macrophages, causing the formation of reactive oxygen species (ROS), TNF-α, IL-1β and oxidative stress. It also significantly activates the MAPKs and NF-κB pathway. Excessive production of pro-inflammatory cytokines is one of the primary characteristic features in the onset and progression of inflammation. Cytokines mainly signal through the JAK/STAT pathway. We hypothesize that blocking of TLR4 along with TNFR1 might be beneficial in suppressing the effects of STAT1/STAT3 due to the stimulation of SOCS3 proteins. Prior to the LPS challenge, the macrophages were treated with antibodies against TLR4 and TNFR1 either individually or in combination. On analysis of the macrophage populations by flowcytometry, it was seen that receptor blockade facilitated the phenotypic shift of the M1 macrophages towards M2 resulting in lowered oxidative stress. Blocking of TLR4/TNFR1 upregulated the SOCS3 and mTOR expressions that enabled the transition of inflammatory M1 macrophages towards the anti-inflammatory M2 phenotype, which might be crucial in curbing the inflammatory responses. Also the reduction in the production of inflammatory cytokines such as IL-6, IL-1β due to the reduction in the activation of the STAT1 and STAT3 molecules was observed in our combination treatment group. All these results indicated that neutralization of both TLR4 and TNFR1 might provide new insights in establishing an alternative therapeutic strategy for LPS-sepsis.
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Affiliation(s)
- Ritasha Sawoo
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India
| | - Biswadev Bishayi
- Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta 700009, West Bengal, India.
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13
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Shyanti RK, Greggs J, Malik S, Mishra M. Gut dysbiosis impacts the immune system and promotes prostate cancer. Immunol Lett 2024; 268:106883. [PMID: 38852888 PMCID: PMC11249078 DOI: 10.1016/j.imlet.2024.106883] [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: 05/02/2024] [Revised: 05/31/2024] [Accepted: 06/07/2024] [Indexed: 06/11/2024]
Abstract
The gut microbiota is a system of microorganisms in the human gastrointestinal (GI) system, consisting of trillions of microorganisms residing in epithelial surfaces of the body. Gut microbiota are exposed to various external and internal factors and form a unique gut-associated immunity maintained through a balancing act among diverse groups of microorganisms. The role of microbiota in dysbiosis of the gut in aiding prostate cancer development has created an urgency for extending research toward comprehension and preventative measures. The gut microbiota varies among persons based on diet, race, genetic background, and geographic location. Bacteriome, mainly, has been linked to GI complications, metabolism, weight gain, and high blood sugar. Studies have shown that manipulating the microbiome (bacteriome, virome, and mycobiome) through the dietary intake of phytochemicals positively influences physical and emotional health, preventing and delaying diseases caused by microbiota. In this review, we discuss the wealth of knowledge about the GI tract and factors associated with dysbiosis-mediated compromised gut immunity. This review also focuses on the relationship of dysbiosis to prostate cancer, the impact of microbial metabolites short-chain fatty acids (SCFAs) on host health, and the phytochemicals improving health while inhibiting prostate cancer.
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Affiliation(s)
- Ritis K Shyanti
- Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36104, USA
| | - Jazmyn Greggs
- Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36104, USA
| | - Shalie Malik
- Department of Zoology, University of Lucknow, Lucknow, Uttar Pradesh 226007, India
| | - Manoj Mishra
- Cancer Biology Research and Training Program, Department of Biological Sciences, Alabama State University, AL 36104, USA.
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14
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González A, Fullaondo A, Odriozola A. Microbiota-associated mechanisms in colorectal cancer. ADVANCES IN GENETICS 2024; 112:123-205. [PMID: 39396836 DOI: 10.1016/bs.adgen.2024.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, ranking third in terms of incidence and second as a cause of cancer-related death. There is growing scientific evidence that the gut microbiota plays a key role in the initiation and development of CRC. Specific bacterial species and complex microbial communities contribute directly to CRC pathogenesis by promoting the neoplastic transformation of intestinal epithelial cells or indirectly through their interaction with the host immune system. As a result, a protumoural and immunosuppressive environment is created conducive to CRC development. On the other hand, certain bacteria in the gut microbiota contribute to protection against CRC. In this chapter, we analysed the relationship of the gut microbiota to CRC and the associations identified with specific bacteria. Microbiota plays a key role in CRC through various mechanisms, such as increased intestinal permeability, inflammation and immune system dysregulation, biofilm formation, genotoxin production, virulence factors and oxidative stress. Exploring the interaction between gut microbiota and tumourigenesis is essential for developing innovative therapeutic approaches in the fight against CRC.
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Affiliation(s)
- Adriana González
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain.
| | - Asier Fullaondo
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Adrian Odriozola
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
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15
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Al-Ghamdi AY. Caffeic acid phenethyl ester attenuates Enterococcus faecalis infection in vivo: antioxidants and NF-κB have a protective role against stomach damage. J Med Life 2024; 17:574-581. [PMID: 39296435 PMCID: PMC11407487 DOI: 10.25122/jml-2023-0544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 04/16/2024] [Indexed: 09/21/2024] Open
Abstract
The mammalian gastrointestinal tract hosts a significant microbial symbiont community, an intriguing feature of this complex organ system. This study aimed to investigate the anti-inflammatory, antioxidant, and protective effects of caffeic acid phenethyl ester (CAPE) against Enterococcus faecalis infection in the stomach at a dose of 106 CFU in Swiss mice. A total of 30 mice were randomly assigned to three groups of ten mice each. Group I was the negative control, Group II was infected orally with E. faecalis for 18 days, and Group III was infected with E. faecalis and treated with CAPE orally at a daily dose of 4 mg/kg for 18 days. We assessed the antioxidant activities of stomach homogenate and the immunohistochemical expressions of the transcription factor nuclear factor kappa B (NF-κB) and proliferating cell nuclear antigen (PCNA). Histopathological examination was performed on the stomachs of all mice. Group II had decreased levels of antioxidant activity and positive expressions of NF-κB and PCNA. Histological observations revealed an increase in mucosal and glandular thickness compared with Group I. Group III, treated with CAPE, showed a significant increase in antioxidant activities and a significant decrease in NF-κB and PCNA immunoreactivities compared with Group II. In addition, Group III showed restoration of the normal thickness of the non-glandular and glandular parts of the stomach. Our results revealed that E. faecalis infection has damaging effects on the stomach and proved that CAPE has promising protective, anti-inflammatory, and antioxidant effects against E. faecalis. Further studies may investigate the potential therapeutic effects of CAPE against E. faecalis infection.
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16
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Daca A, Jarzembowski T. From the Friend to the Foe- Enterococcus faecalis Diverse Impact on the Human Immune System. Int J Mol Sci 2024; 25:2422. [PMID: 38397099 PMCID: PMC10888668 DOI: 10.3390/ijms25042422] [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: 01/30/2024] [Revised: 02/14/2024] [Accepted: 02/16/2024] [Indexed: 02/25/2024] Open
Abstract
Enterococcus faecalis is a bacterium which accompanies us from the first days of our life. As a commensal it produces vitamins, metabolizes nutrients, and maintains intestinal pH. All of that happens in exchange for a niche to inhabit. It is not surprising then, that the bacterium was and is used as an element of many probiotics and its positive impact on the human immune system and the body in general is hard to ignore. This bacterium has also a dark side though. The plasticity and relative ease with which one acquires virulence traits, and the ability to hide from or even deceive and use the immune system to spread throughout the body make E. faecalis a more and more dangerous opponent. The statistics clearly show its increasing role, especially in the case of nosocomial infections. Here we present the summarization of current knowledge about E. faecalis, especially in the context of its relations with the human immune system.
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Affiliation(s)
- Agnieszka Daca
- Department of Physiopathology, Medical University of Gdańsk, 80-210 Gdańsk, Poland
| | - Tomasz Jarzembowski
- Department of Microbiology, Medical University of Gdańsk, 80-210 Gdańsk, Poland
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17
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Radi MH, El-Shiekh RA, Hegab AM, Henry SR, Avula B, Katragunta K, Khan IA, El-Halawany AM, Abdel-Sattar E. LC-QToF chemical profiling of Euphorbia grantii Oliv. and its potential to inhibit LPS-induced lung inflammation in rats via the NF-κB, CY450P2E1, and P38 MAPK14 pathways. Inflammopharmacology 2024; 32:461-494. [PMID: 37572137 PMCID: PMC10907465 DOI: 10.1007/s10787-023-01298-7] [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: 05/18/2023] [Accepted: 07/12/2023] [Indexed: 08/14/2023]
Abstract
Acute lung injury (ALI) is a life-threatening syndrome that causes high morbidity and mortality worldwide. The aerial parts of Euphorbia grantii Oliv. were extracted with methanol to give a total methanolic extract (TME), which was further fractionated into dichloromethane (DCMF) and the remaining mother liquor (MLF) fractions. Biological guided anti-inflammatory assays in vitro revealed that the DCMF showed the highest activity (IC50 6.9 ± 0.2 μg/mL and 0.29 ± 0.01 μg/mL) compared to. celecoxib (IC50 of 88.0 ± 1 μg/mL and 0.30 ± 0.01 μg/mL) on COX-1 and COX-2, respectively. Additionally, anti-LOX activity was IC50 = 24.0 ± 2.5 μg/mL vs. zileuton with IC50 of 40.0 ± 0.5 μg/mL. LC-DAD-QToF analysis of TME and the active DCMF resulted in the tentative identification and characterization of 56 phytochemical compounds, where the diterpenes were the dominated metabolites. An LPS-induced inflammatory model of ALI (10 mg/kg i.p) was used to assess the anti-inflammatory potential of DCMF in vivo at dose of 200 mg/kg and 300 mg/kg compared to dexamethasone (5 mg/kg i.p). Our treatments significantly reduced the pro-inflammatory cytokines (TNF-α, IL-1, IL-6, and MPO), increased the activity of antioxidant enzymes (SOD, CAT, and GSH), decreased the activity of oxidative stress enzyme (MDA), and reduced the expression of inflammatory genes (p38.MAPK14 and CY450P2E1). The western blotting of NF-κB p65 in lung tissues was inhibited after orally administration of the DCMF. Histopathological study of the lung tissues, scoring, and immunohistochemistry of transforming growth factor-beta 1 (TGF-β1) were also assessed. In both dose regimens, DCMF of E. grantii prevented further lung damage and reduced the side effects of LPS on acute lung tissue injury.
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Affiliation(s)
- Mai Hussin Radi
- Herbal Department, Egyptian Drug Authority (EDA), Giza, Egypt
| | - Riham A El-Shiekh
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
| | - Amany Mohammed Hegab
- Developmental Pharmacology Department, Egyptian Drug Authority (EDA), Giza, Egypt
| | | | - Bharathi Avula
- School of Pharmacy, National Center for Natural Products Research, University of Mississippi, University, MS, 38677, USA
| | - Kumar Katragunta
- School of Pharmacy, National Center for Natural Products Research, University of Mississippi, University, MS, 38677, USA
| | - Ikhlas A Khan
- School of Pharmacy, National Center for Natural Products Research, University of Mississippi, University, MS, 38677, USA
- Division of Pharmacognosy, Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS, 38677, USA
| | - Ali M El-Halawany
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt
| | - Essam Abdel-Sattar
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.
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18
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Jiang M, Chen X, Li H, Peng X, Peng B. Exogenous L-Alanine promotes phagocytosis of multidrug-resistant bacterial pathogens. EMBO Rep 2023; 24:e49561. [PMID: 37943703 PMCID: PMC10702822 DOI: 10.15252/embr.201949561] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 10/22/2023] [Accepted: 10/24/2023] [Indexed: 11/12/2023] Open
Abstract
Multidrug-resistant bacteria present a major threat to public health that urgently requires new drugs or treatment approaches. Here, we conduct integrated proteomic and metabolomics analyses to screen for molecular candidates improving survival of mice infected with Vibrio parahaemolyticus, which indicate that L-Alanine metabolism and phagocytosis are strongly correlated with mouse survival. We also assess the role of L-Alanine in improving mouse survival by in vivo bacterial challenge experiments using various bacteria species, including V. parahaemolyticus, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Functional studies demonstrate that exogenous L-Alanine promotes phagocytosis of these multidrug-resistant pathogen species. We reveal that the underlying mechanism involves two events boosted by L-Alanine: TLR4 expression and L-Alanine-enhanced TLR4 signaling via increased biosynthesis and secretion of fatty acids, including palmitate. Palmitate enhances binding of lipopolysaccharide to TLR4, thereby promoting TLR4 dimer formation and endocytosis for subsequent activation of the PI3K/Akt and NF-κB pathways and bacteria phagocytosis. Our data suggest that modulation of the metabolic environment is a plausible approach for combating multidrug-resistant bacteria infection.
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Affiliation(s)
- Ming Jiang
- State Key Laboratory of Bio‐Control, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai)Sun Yat‐sen UniversityGuangzhouChina
- Laboratory for Marine Biology and Biotechnology and Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and TechnologyQingdaoChina
- Institute of Animal ScienceGuangdong Academy of Agricultural SciencesGuangzhouChina
| | - Xin‐Hai Chen
- State Key Laboratory of Bio‐Control, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai)Sun Yat‐sen UniversityGuangzhouChina
| | - Hui Li
- State Key Laboratory of Bio‐Control, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai)Sun Yat‐sen UniversityGuangzhouChina
- Laboratory for Marine Biology and Biotechnology and Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and TechnologyQingdaoChina
| | - Xuan‐Xian Peng
- State Key Laboratory of Bio‐Control, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai)Sun Yat‐sen UniversityGuangzhouChina
- Laboratory for Marine Biology and Biotechnology and Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and TechnologyQingdaoChina
| | - Bo Peng
- State Key Laboratory of Bio‐Control, Guangdong Key Laboratory of Pharmaceutical Functional Genes, School of Life Sciences, Southern Marine Science and Engineering Guangdong Laboratory (Zhuhai)Sun Yat‐sen UniversityGuangzhouChina
- Laboratory for Marine Biology and Biotechnology and Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and TechnologyQingdaoChina
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Zheng X, Zhang X, Dong L, Zhao J, Zhang C, Chen R. Neuroprotective mechanism of salvianolic acid B against cerebral ischemia-reperfusion injury in mice through downregulation of TLR4, p-p38MAPK, p-JNK, NF-κB, and IL-1β. Immun Inflamm Dis 2023; 11:e1030. [PMID: 37904689 PMCID: PMC10549825 DOI: 10.1002/iid3.1030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 08/02/2023] [Accepted: 09/13/2023] [Indexed: 11/01/2023] Open
Abstract
OBJECTIVE Tissue injury and inflammation are two potential outcomes of cerebral ischemia-reperfusion (I/R) injury. Salvianolic acid B (Sal B), isolated from the roots of Salvia miltiorrhiza, is one of the major water-soluble compounds with a wide range of pharmacological effects including antioxidant, anti-inflammatory, antiproliferative, and neuroprotective effects. In the present study, we explored the neuroprotective effects and potential mechanisms of Sal B after I/R injury. METHODS We induced cerebral ischemia in male CD-1 mice through transient (60 min) middle cerebral artery occlusion (tMCAO), and then injected Sal B (30 mg/kg) intraperitoneally. Neurological deficits, infarct volumes, and brain edema were assessed at 24 and 72 h after tMCAO. We detected the expression of Toll-like receptor 4 (TLR4), phosphorylated-p38 mitogen-activated protein kinase (P-p38 MAPK), phosphorylated c-Jun amino (N)-terminal kinases (p-JNK), nuclear factor-κB (NF-κB), and interleukin-1β (IL-1β) in the brain tissue. RESULTS Compared with the tMCAO group, Sal B significantly improved neurological deficits, reduced infarct size, attenuated cerebral edema, and downregulated the expression of pro-inflammatory mediators TLR4, p-p38MAPK, p-JNK, nuclear NF-κB, and IL-1β in brain tissue after I/R injury. CONCLUSION We found that Sal B protects brain tissues from I/R injury by activating its anti-inflammatory properties.
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Affiliation(s)
- Xiu‐fen Zheng
- Department of NeurologySecond Hospital of Hebei Medical UniversityShijiazhuangHebeiPR China
- Department of PediatricsTangshan Central HospitalTangshanHebeiPR China
| | - Xiang‐jian Zhang
- Department of NeurologySecond Hospital of Hebei Medical UniversityShijiazhuangHebeiPR China
- Hebei Collaborative Innovation Center for Cardio‐cerebrovascular DiseaseShijiazhuangHebeiPR China
- Hebei Key Laboratory of Vascular HomeostasisShijiazhuangHebeiPR China
| | - Li‐peng Dong
- Department of NeurologySecond Hospital of Hebei Medical UniversityShijiazhuangHebeiPR China
- Department of NeurologyHebei General HospitalShijiazhuangHebeiPR China
| | - Jing‐ru Zhao
- Department of NeurologySecond Hospital of Hebei Medical UniversityShijiazhuangHebeiPR China
- Department of NeurologyHebei General HospitalShijiazhuangHebeiPR China
| | - Cong Zhang
- Department of NeurologySecond Hospital of Hebei Medical UniversityShijiazhuangHebeiPR China
| | - Rong Chen
- Department of NeurologySecond Hospital of Hebei Medical UniversityShijiazhuangHebeiPR China
- Hebei Collaborative Innovation Center for Cardio‐cerebrovascular DiseaseShijiazhuangHebeiPR China
- Hebei Key Laboratory of Vascular HomeostasisShijiazhuangHebeiPR China
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20
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Wong CC, Yu J. Gut microbiota in colorectal cancer development and therapy. Nat Rev Clin Oncol 2023:10.1038/s41571-023-00766-x. [PMID: 37169888 DOI: 10.1038/s41571-023-00766-x] [Citation(s) in RCA: 252] [Impact Index Per Article: 126.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2023] [Indexed: 05/13/2023]
Abstract
Colorectal cancer (CRC) is one of the commonest cancers globally. A unique aspect of CRC is its intimate association with the gut microbiota, which forms an essential part of the tumour microenvironment. Research over the past decade has established that dysbiosis of gut bacteria, fungi, viruses and Archaea accompanies colorectal tumorigenesis, and these changes might be causative. Data from mechanistic studies demonstrate the ability of the gut microbiota to interact with the colonic epithelia and immune cells of the host via the release of a diverse range of metabolites, proteins and macromolecules that regulate CRC development. Preclinical and some clinical evidence also underscores the role of the gut microbiota in modifying the therapeutic responses of patients with CRC to chemotherapy and immunotherapy. Herein, we summarize our current understanding of the role of gut microbiota in CRC and outline the potential translational and clinical implications for CRC diagnosis, prevention and treatment. Emphasis is placed on how the gut microbiota could now be better harnessed by developing targeted microbial therapeutics as chemopreventive agents against colorectal tumorigenesis, as adjuvants for chemotherapy and immunotherapy to boost drug efficacy and safety, and as non-invasive biomarkers for CRC screening and patient stratification. Finally, we highlight the hurdles and potential solutions to translating our knowledge of the gut microbiota into clinical practice.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Patra T, Ray R. Bystander effect of SARS-CoV-2 spike protein on human monocytic THP-1 cell activation and initiation of prothrombogenic stimulus representing severe COVID-19. J Inflamm (Lond) 2022; 19:28. [PMID: 36585712 PMCID: PMC9801152 DOI: 10.1186/s12950-022-00325-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 12/16/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Hypercoagulable state and thromboembolic complications are potential life-threatening events in COVID-19 patients. Our previous studies demonstrated that SARS-CoV-2 infection as well as viral spike protein expressed epithelial cells exhibit senescence with the release of inflammatory molecules, including alarmins. FINDINGS We observed extracellular alarmins present in the culture media of SARS-CoV-2 spike expressing cells activate human THP-1 monocytes to secrete pro-inflammatory cytokines to a significant level. The release of THP-1 derived pro-inflammatory cytokine signature correlated with the serum of acute COVID-19 patient, but not in post-COVID-19 state. Our study suggested that the alarmins secreted by spike expressing cells, initiated phagocytosis property of THP-1 cells. The phagocytic monocytes secreted complement component C5a and generated an autocrine signal via C5aR1 receptor. The C5a-C5aR1 signal induced formation of monocyte mediated extracellular trap resulted in the generation of a prothrombogenic stimulus with activating platelets and increased tissue factor activity. We also observed an enhanced C5a level, platelet activating factor, and high tissue factor activity in the serum of acute COVID-19 patients, but not in recovered patients. CONCLUSION Our present study demonstrated that SARS-CoV-2 spike protein modulates monocyte responses in a paracrine manner for prothrombogenic stimulus by the generation of C5a complement component.
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Affiliation(s)
- Tapas Patra
- Departments of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Edward A. Doisy Research Center, 1100 South Grand Blvd, MO 63104 Saint Louis, USA
| | - Ranjit Ray
- Departments of Internal Medicine, Division of Infectious Diseases, Allergy & Immunology, Edward A. Doisy Research Center, 1100 South Grand Blvd, MO 63104 Saint Louis, USA ,grid.262962.b0000 0004 1936 9342Molecular Microbiology & Immunology, Saint Louis University, 63104 Saint Louis, Missouri, MO USA
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Yang W, Li M, Zhang C, Zhang X, Guo M, Wu Y. Pathogenicity, colonization, and innate immune response to Pasteurella multocida in rabbits. BMC Vet Res 2022; 18:416. [PMID: 36447208 PMCID: PMC9706998 DOI: 10.1186/s12917-022-03517-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 11/14/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Pasteurella multocida (P. multocida) infection can cause a series of diseases in different animals and cause huge economic losses to the breeding industry. P. multocida is considered to be one of the most significant pathogens in rabbits. In order to elucidate the pathogenic mechanism and innate immune response of P. multocida, an infection experiment was carried out in this study. RESULTS Our results showed that the clinical symptoms of rabbits were severe dyspnoea and serous nasal fluid. During the course of the disease, the deaths peaked at 2 days post infection (dpi) and mortality rate was 60%. The pathological changes of the lung, trachea, and thymus were observed. In particular, consolidation and abscesses appeared in lung. Histopathologic changes in rabbits showed edema, hemorrhage, and neutrophil infiltration in the lung. P. multocida can rapidly replicate in a variety of tissues, and the colonization in most of the tested tissues reached the maximum at 2 dpi and then decreased at 3 dpi. The number of P. multocida in lung and thymus remained high level at 3 dpi. Toll-like receptors 2 and 4 signaling pathways were activated after P. multocida infection. The expression of Il1β, Il6, Il8, and Tnf-α was significantly increased. The expression of most proinflammatory cytokines peaked at 2 dpi and decreased at 3 dpi, and the expression trend of cytokines was consistent with the colonization of P. multocida in rabbit tissues. CONCLUSIONS The P. multocida can rapidly replicate in various tissues of rabbit and cause bacteremia after infection. TLRs signaling pathways were activated after P. multocida infection, significantly inducing the expression of proinflammatory cytokines, which is might the main cause of respiratory inflammation and septicemia.
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Affiliation(s)
- Wenhao Yang
- grid.268415.cJiangsu Co-Innovation Center for Prevention of Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 China
| | - Mingtao Li
- grid.268415.cJiangsu Co-Innovation Center for Prevention of Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 China
| | - Chengcheng Zhang
- grid.268415.cJiangsu Co-Innovation Center for Prevention of Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 China
| | - Xiaorong Zhang
- grid.268415.cJiangsu Co-Innovation Center for Prevention of Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 China
| | - Mengjiao Guo
- grid.268415.cJiangsu Co-Innovation Center for Prevention of Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 China
| | - Yantao Wu
- grid.268415.cJiangsu Co-Innovation Center for Prevention of Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009 China ,grid.268415.cJoint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University (JIRLAAPS), Yangzhou, 225009 China
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23
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Kim YK, Hwang JH, Lee HT. Differential susceptibility to lipopolysaccharide affects the activation of toll-like-receptor 4 signaling in THP-1 cells and PMA-differentiated THP-1 cells. Innate Immun 2022; 28:122-129. [PMID: 35612375 PMCID: PMC9136465 DOI: 10.1177/17534259221100170] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/31/2022] [Accepted: 04/26/2022] [Indexed: 11/16/2022] Open
Abstract
Monocytes and macrophages that originate from common myeloid progenitors perform various crucial roles in the innate immune system. Stimulation with LPS combined with TLR4 drives the production of pro-inflammatory cytokines through MAPKs and NF-κB pathway in different cells. However, the difference in LPS susceptibility between monocytes and macrophages is poorly understood. In this study, we found that pro-inflammatory cytokines-IL-1β, IL-6 and TNFα showed greater induction in phorbol-12-myristate-13-acetate (PMA)-differentiated THP-1 cells than in THP-1 cells. To determine the difference in cytokine expression, the surface proteins such as TLR4-related proteins and intracellular adaptor proteins were more preserved in PMA-differentiated THP-1 cells than in THP-1 cells. MyD88 is a key molecule responsible for the difference in LPS susceptibility. Moreover, MAPKs and NF-κB pathway-related molecules showed higher levels of phosphorylation in PMA-differentiated THP-1 cells than in THP-1 cells. Upon MyD88 depletion, there was no difference in the phosphorylation of MAPK pathway-related molecules. Therefore, these results demonstrate that the difference in LPS susceptibility between THP-1 cells and PMA-differentiated THP-1 cells occur as a result of gap between the activated MAPKs and NF-κB pathways via changes in the expression of LPS-related receptors and MyD88.
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Affiliation(s)
- Young Kyu Kim
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul-si, Republic of Korea
- Animal Model Research Group, Korea Institute of Toxicology, Jeollabuk-do, Republic of Korea
| | - Jeong Ho Hwang
- Animal Model Research Group, Korea Institute of Toxicology, Jeollabuk-do, Republic of Korea
| | - Hoon Taek Lee
- Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul-si, Republic of Korea
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24
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Seely KD, Morgan AD, Hagenstein LD, Florey GM, Small JM. Bacterial Involvement in Progression and Metastasis of Colorectal Neoplasia. Cancers (Basel) 2022; 14:1019. [PMID: 35205767 PMCID: PMC8870662 DOI: 10.3390/cancers14041019] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/14/2022] [Accepted: 02/15/2022] [Indexed: 02/06/2023] Open
Abstract
While the gut microbiome is composed of numerous bacteria, specific bacteria within the gut may play a significant role in carcinogenesis, progression, and metastasis of colorectal carcinoma (CRC). Certain microbial species are known to be associated with specific cancers; however, the interrelationship between bacteria and metastasis is still enigmatic. Mounting evidence suggests that bacteria participate in cancer organotropism during solid tumor metastasis. A critical review of the literature was conducted to better characterize what is known about bacteria populating a distant site and whether a tumor depends upon the same microenvironment during or after metastasis. The processes of carcinogenesis, tumor growth and metastatic spread in the setting of bacterial infection were examined in detail. The literature was scrutinized to discover the role of the lymphatic and venous systems in tumor metastasis and how microbes affect these processes. Some bacteria have a potent ability to enhance epithelial-mesenchymal transition, a critical step in the metastatic cascade. Bacteria also can modify the microenvironment and the local immune profile at a metastatic site. Early targeted antibiotic therapy should be further investigated as a measure to prevent metastatic spread in the setting of bacterial infection.
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Affiliation(s)
- Kevin D. Seely
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA; (A.D.M.); (L.D.H.)
| | - Amanda D. Morgan
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA; (A.D.M.); (L.D.H.)
| | - Lauren D. Hagenstein
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA; (A.D.M.); (L.D.H.)
| | - Garrett M. Florey
- College of Osteopathic Medicine, Rocky Vista University, Parker, CO 80134, USA;
| | - James M. Small
- Department of Biomedical Sciences, Rocky Vista University, Parker, CO 80134, USA;
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25
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Yi YS, Kim HG, Kim JH, Yang WS, Kim E, Jeong D, Park JG, Aziz N, Kim S, Parameswaran N, Cho JY. Syk-MyD88 Axis Is a Critical Determinant of Inflammatory-Response in Activated Macrophages. Front Immunol 2022; 12:767366. [PMID: 35003083 PMCID: PMC8733199 DOI: 10.3389/fimmu.2021.767366] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/06/2021] [Indexed: 01/04/2023] Open
Abstract
Background Inflammation, a vital immune response to infection and injury, is mediated by macrophage activation. While spleen tyrosine kinase (Syk) and myeloid differentiation primary response 88 (MyD88) are reportedly involved in inflammatory responses in macrophages, their roles and underlying mechanisms are largely unknown. Methods Here, the role of the MyD88-Syk axis and the mechanism by which Syk and MyD88 cooperate during macrophage-mediated inflammatory responses are explored using knockout conditions of these proteins and mutation strategy as well as flowcytometric and immunoblotting analyses. Results Syk rapidly activates the nuclear factor-kappa B (NF-κB) signaling pathway in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and the activation of the NF-κB signaling pathway is abolished in Syk−/− RAW264.7 cells. MyD88 activates Syk and Syk-induced activation of NF-κB signaling pathway in LPS-stimulated RAW264.7 cells but Syk-induced inflammatory responses are significantly inhibited in MyD88−/− RAW264.7 cells. MyD88 interacts with Syk through the tyrosine 58 residue (Y58) in the hemi-immunoreceptor tyrosine-based activation motif (ITAM) of MyD88, leading to Syk activation and Syk-induced activation of the NF-κB signaling pathway. Src activates MyD88 by phosphorylation at Y58 via the Src kinase domain. In addition, Ras-related C3 botulinum toxin substrate 1 (Rac1) activation and Rac1-induced formation of filamentous actin (F actin) activate Src in LPS-stimulated RAW264.7 cells. Conclusions These results suggest that the MyD88-Syk axis is a critical player in macrophage-mediated inflammatory responses, and its function is promoted by an upstream Src kinase activated by Rac1-generated filamentous actin (F-actin).
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Affiliation(s)
- Young-Su Yi
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, South Korea.,Department of Life Sciences, Kyonggi University, Suwon, South Korea
| | - Han Gyung Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, South Korea
| | - Ji Hye Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, South Korea
| | - Woo Seok Yang
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, South Korea
| | - Eunji Kim
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, South Korea
| | - Deok Jeong
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, South Korea
| | - Jae Gwang Park
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, South Korea
| | - Nur Aziz
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, South Korea
| | - Suk Kim
- Institute of Animal Science, College of Veterinary Medicine, Gyeongsang National University, Jinju, South Korea
| | - Narayanan Parameswaran
- Department of Physiology and Division of Pathology, Michigan State University, East Lansing, MI, United States
| | - Jae Youl Cho
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, South Korea
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26
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Wuryandari MRE, Atho'illah MF, Laili RD, Fatmawati S, Widodo N, Widjajanto E, Rifa'i M. Lactobacillus plantarum FNCC 0137 fermented red Moringa oleifera exhibits protective effects in mice challenged with Salmonella typhi via TLR3/TLR4 inhibition and down-regulation of proinflammatory cytokines. J Ayurveda Integr Med 2021; 13:100531. [PMID: 34903438 PMCID: PMC8728064 DOI: 10.1016/j.jaim.2021.10.003] [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: 08/10/2021] [Revised: 10/02/2021] [Accepted: 10/22/2021] [Indexed: 02/07/2023] Open
Abstract
Background Salmonella typhi is a foodborne pathogenic bacterium that threatens health. S. typhi infection exacerbated the antibiotic resistance problem that needs alternative strategies. Moringa oleifera possesses anti-inflammatory and antimicrobial effects. However, there is a lack of information about the pharmacological value of red M. oleifera. The fermentation of red M. oleifera leaves extract (RMOL) is expected to add to its nutritional value. Objective The present study aimed to evaluate non-fermented RMOL (NRMOL) and fermented RMOL (FRMOL) effects on S. typhi infection in mice. Materials and methods Female Balb/C mice were randomly divided into eight groups. The treatment groups were orally administered with NRMOL or FRMOL at doses 14, 42, and 84 mg/kg BW during the 28 days experimental period. Then S. typhi was introduced to mice through intraperitoneal injection except in the healthy groups. The NRMOL or FRMOL administration was continued for the next seven days. Cells that expressed CD11b+ TLR3+, CD11b+TLR4+, CD11b+IL-6+, CD11b+IL-17+, CD11b+TNF-a+, and CD4+CD25+CD62L+ were assessed by flow cytometry. Results Our result suggested that NRMOL and FRMOL extracts significantly reduced (p < 0.05) the expression of CD11b+TLR3+, CD11b+TLR4+, CD11b+IL-6+, CD11b+IL-17+, and CD11b+TNF-α+ subsets. In contrast, NRMOL and FRMOL extracts significantly increased (p < 0.05) the expression of CD4+CD25+CD62L+ subsets. NRMOL at dose 14 and 42 mg/kg BW was more effective compared to FRMOL in reducing the expression of CD11b+TLR3+, CD11b+TLR4+, and CD11b+TNF-α+ subsets. Conclusion Our findings demonstrated that NRMOL and FRMOL extracts could be promising agents for protection against S. typhi infection via modulation of TLR3/TLR4, regulatory T cells, and proinflammatory cytokines.
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Affiliation(s)
- Mm Riyaniarti Estri Wuryandari
- Department of Biology, Faculty of Technology and Health Management, Institut Ilmu Kesehatan Bhakti Wiyata, 64114, Kediri, East Java, Indonesia.
| | - Mochammad Fitri Atho'illah
- Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, 65145, Malang, East Java, Indonesia
| | - Rizky Dzariyani Laili
- Department of Nutrition, Sekolah Tinggi Ilmu Kesehatan Hang Tuah Surabaya, 60244, Surabaya, East Java, Indonesia
| | - Siti Fatmawati
- Department of Food Sciences and Technology, Faculty of Agricultural Technology, Brawijaya University, 65145, Malang, East Java, Indonesia
| | - Nashi Widodo
- Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, 65145, Malang, East Java, Indonesia; Center of Biosystem Study, LPPM of Brawijaya University, 65145, Malang, East Java, Indonesia
| | - Edi Widjajanto
- Faculty of Medicine, Brawijaya University, 65145, Malang, East Java, Indonesia
| | - Muhaimin Rifa'i
- Department of Biology, Faculty of Mathematics and Natural Sciences, Brawijaya University, 65145, Malang, East Java, Indonesia; Center of Biosystem Study, LPPM of Brawijaya University, 65145, Malang, East Java, Indonesia.
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27
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Hu J, Li W, Huang B, Zhao Q, Fan X. The Profiles of Long Non-coding RNA and mRNA Transcriptome Reveals the Genes and Pathway Potentially Involved in Pasteurella multocida Infection of New Zealand Rabbits. Front Vet Sci 2021; 8:591273. [PMID: 34026883 PMCID: PMC8131872 DOI: 10.3389/fvets.2021.591273] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 03/19/2021] [Indexed: 12/22/2022] Open
Abstract
Infection with Pasteurella multocida (P. multocida) causes severe epidemic diseases in rabbits and is responsible for the pronounced economic losses in the livestock industry. Long non-coding RNAs (lncRNAs) have been proven to exert vital functions in regulating the host immune responses to bacterial attacks. However, little is known about how lncRNAs participate in the rabbit's immune response against P. multocida infection in the lungs. LncRNA and mRNA expression profiles were analyzed by transcriptomics and bioinformatics during P. multocida infection. A total of 336 lncRNAs and 7,014 mRNAs were differentially regulated at 1 day and 3 days post infection (dpi). Nearly 80% of the differentially expressed lncRNAs exhibited an increased expression at 3 dpi suggesting that the P. multocida genes are responsible for regulation. Moreover, GO and KEGG enriched analysis indicated that the immune-related pathways including pattern recognition receptors (PRRs), cytokines, and chemokines were significantly enriched at 3 dpi. These results indicate that the dysregulated immune-related genes may play crucial roles in defending against P. multocida attacks. Overall, these results advance our cognition of the role of lncRNAs and mRNAs in modulating the rabbit's innate immune response against P. multocida attacks, which will offer a valuable clue for further studies into exploring P. multocida-related diseases in human.
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Affiliation(s)
- Jiaqing Hu
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Wenqiang Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
| | - Bing Huang
- Shandong Provincial Key Laboratory of Poultry Disease Diagnose and Immune, Institute of Poultry, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Qiaoya Zhao
- Shandong Provincial Key Laboratory of Poultry Disease Diagnose and Immune, Institute of Poultry, Shandong Academy of Agricultural Sciences, Jinan, China
| | - Xinzhong Fan
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Taian, China
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28
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Mohamed Elashiry M, Tian F, Elashiry M, Zeitoun R, Elsayed R, Andrews ML, Bergeon BE, Cutler C, Tay F. Enterococcus faecalis shifts macrophage polarization toward M1-like phenotype with an altered cytokine profile. J Oral Microbiol 2021; 13:1868152. [PMID: 33488991 PMCID: PMC7801083 DOI: 10.1080/20002297.2020.1868152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Background: The macrophage is an innate immune defense cell involved in pathogen recognition and clearance. Aim: In view of the diversity of the macrophage phenotype and function, the present study investigated how Enterococcus faecalis infection affects the differentiation, phenotype and cytokine profile of macrophages. Methods: Murine bone marrow-derived stem cells were co-cultured with E. faecalis before and after differentiation. Macrophage M0 polarization towards M1 or M2 was initiated at day 6 by addition of LPS and INF-γ, or IL-4 and IL-13, respectively. Results: E. faecalis did not inhibit macrophage differentiation and were identified within macrophages. Viability of the macrophages infected with E. faecalis prior to differentiation was enhanced, evidenced by apoptosis inhibition, as was expression of CD38 and IRF5 proteins, indicators of M1-like polarization. These M1-like macrophages expressed an aberrant cytokine mRNA profile, with reduction in inflammatory cytokines IL-1β and IL-12 and increase in regulatory cytokine IL-10. No changes in TNF-α or TGF-β1 were detected, compared with the control groups. This atypical M1-like phenotype was retained even upon stimulation with growth factors that normally trigger their development into M2 macrophages. Conclusions: These findings suggested that E. faecalis infection of bone marrow-derived stem cells during differentiation into macrophages induces an atypical M1-like phenotype associated with intracellular bacterial survival.
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Affiliation(s)
- Mohamed Mohamed Elashiry
- Department of Endodontics, Faculty of Dentistry, Ain Shams University, Cairo, Egypt.,Department of Periodontics, The Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Fucong Tian
- Department of Endodontics, The Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Mahmoud Elashiry
- Department of Periodontics, The Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Rana Zeitoun
- Department of Fixed Prosthodontics, Faculty of Dentistry, Ain Shams University, Cairo, Egypt.,Department of Oral Biology and Diagnostic Science, The Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Ranya Elsayed
- Department of Periodontics, The Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Matthew L Andrews
- Department of Endodontics, The Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Brian E Bergeon
- Department of Endodontics, The Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Christopher Cutler
- Department of Periodontics, The Dental College of Georgia, Augusta University, Augusta, GA, USA
| | - Franklin Tay
- Department of Endodontics, The Dental College of Georgia, Augusta University, Augusta, GA, USA
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29
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Possible Susceptibility Genes for Intervention against Chemotherapy-Induced Cardiotoxicity. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:4894625. [PMID: 33110473 PMCID: PMC7578723 DOI: 10.1155/2020/4894625] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 07/07/2020] [Accepted: 07/30/2020] [Indexed: 12/12/2022]
Abstract
Recent therapeutic advances have significantly improved the short- and long-term survival rates in patients with heart disease and cancer. Survival in cancer patients may, however, be accompanied by disadvantages, namely, increased rates of cardiovascular events. Chemotherapy-related cardiac dysfunction is an important side effect of anticancer therapy. While advances in cancer treatment have increased patient survival, treatments are associated with cardiovascular complications, including heart failure (HF), arrhythmias, cardiac ischemia, valve disease, pericarditis, and fibrosis of the pericardium and myocardium. The molecular mechanisms of cardiotoxicity caused by cancer treatment have not yet been elucidated, and they may be both varied and complex. By identifying the functional genetic variations responsible for this toxicity, we may be able to improve our understanding of the potential mechanisms and pathways of treatment, paving the way for the development of new therapies to target these toxicities. Data from studies on genetic defects and pharmacological interventions have suggested that many molecules, primarily those regulating oxidative stress, inflammation, autophagy, apoptosis, and metabolism, contribute to the pathogenesis of cardiotoxicity induced by cancer treatment. Here, we review the progress of genetic research in illuminating the molecular mechanisms of cancer treatment-mediated cardiotoxicity and provide insights for the research and development of new therapies to treat or even prevent cardiotoxicity in patients undergoing cancer treatment. The current evidence is not clear about the role of pharmacogenomic screening of susceptible genes. Further studies need to done in chemotherapy-induced cardiotoxicity.
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30
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Wang B, Wu Y, Liu R, Xu H, Mei X, Shang Q, Liu S, Yu D, Li W. Lactobacillus rhamnosus GG promotes M1 polarization in murine bone marrow-derived macrophages by activating TLR2/MyD88/MAPK signaling pathway. Anim Sci J 2020; 91:e13439. [PMID: 32779289 DOI: 10.1111/asj.13439] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/23/2020] [Accepted: 06/15/2020] [Indexed: 12/11/2022]
Abstract
Lactobacillus rhamnosus GG (LGG) is increasingly applied in functional food products and acts as a probiotic model in nutritious and clinical studies. Increasing evidences have revealed the immune modulation of LGG on macrophages. The aim of this study is to investigate the effect of LGG on macrophage polarization of murine bone marrow-derived macrophages (BMDMs). BMDMs were treated with 108 colony-forming units (CFU)/ml LGG for 1.5, 3, and 6 hr. Results showed that LGG obviously upregulated the mRNA expression of M1-associated cytokines (p < .05), including interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNF-α), and inducible nitric oxide synthase (iNOS), whereas had no effect on the expression of M2-associated markers (p > .05), including arginase 1 (Arg1), mannose receptor, and chitinase-like protein 3 (YM1). Furthermore, LGG markedly increased the expression of pro-inflammatory cytokines (IL-12p40, cyclooxygenase-2 [COX-2], and interferon-γ [IFN-γ]) (p < .05) and anti-inflammatory cytokines (IL-10, IL-4, and transforming growth factor-β [TGF-β]) (p < .05). In addition, we also found that TLR2/MyD88/MAPK signaling pathway was required for LGG-induced M1 macrophage polarization and M1-related cytokines expression. Together, these findings demonstrate that probiotic LGG facilitates M1 polarization of BMDMs, suggesting that LGG may have an immunotherapeutic potential in regulating the host defense against pathogen invasion.
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Affiliation(s)
- Baikui Wang
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China) of the Ministry of Agriculture, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Yanping Wu
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China) of the Ministry of Agriculture, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Rongrong Liu
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China) of the Ministry of Agriculture, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Han Xu
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China) of the Ministry of Agriculture, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Xiaoqiang Mei
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China) of the Ministry of Agriculture, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Qinqin Shang
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China) of the Ministry of Agriculture, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Shijie Liu
- National Animal Husbandry Service, Beijing, China
| | - Dongyou Yu
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China) of the Ministry of Agriculture, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Weifen Li
- Key Laboratory of Molecular Animal Nutrition of the Ministry of Education, Key Laboratory of Animal Nutrition and Feed Science (Eastern of China) of the Ministry of Agriculture, Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Institute of Animal Nutrition and Feed Sciences, College of Animal Sciences, Zhejiang University, Hangzhou, China
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31
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Gutierrez-Merino J, Isla B, Combes T, Martinez-Estrada F, Maluquer De Motes C. Beneficial bacteria activate type-I interferon production via the intracellular cytosolic sensors STING and MAVS. Gut Microbes 2020; 11:771-788. [PMID: 31941397 PMCID: PMC7524384 DOI: 10.1080/19490976.2019.1707015] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 12/09/2019] [Accepted: 12/10/2019] [Indexed: 02/07/2023] Open
Abstract
Type-I interferon (IFN-I) cytokines are produced by immune cells in response to microbial infections, cancer and autoimmune diseases, and subsequently, trigger cytoprotective and antiviral responses through the activation of IFN-I stimulated genes (ISGs). The ability of intestinal microbiota to modulate innate immune responses is well known, but the mechanisms underlying such responses remain elusive. Here we report that the intracellular sensors stimulator of IFN genes (STING) and mitochondrial antiviral signaling (MAVS) are essential for the production of IFN-I in response to lactic acid bacteria (LAB), common gut commensal bacteria with beneficial properties. Using human macrophage cells we show that LAB strains that potently activate the inflammatory transcription factor NF-κB are poor inducers of IFN-I and conversely, those triggering significant amounts of IFN-I fail to activate NF-κB. This IFN-I response is also observed in human primary macrophages, which modulate CD64 and CD40 upon challenge with IFN-I-inducing LAB. Mechanistically, IFN-I inducers interact more intimately with phagocytes as compared to NF-κB-inducers, and fail to activate IFN-I in the presence of phagocytosis inhibitors. These bacteria are then sensed intracellularly by the cytoplasmic sensors STING and, to a lesser extent, MAVS. Accordingly, macrophages deficient for STING showed dramatically reduced phosphorylation of TANK-binding kinase (TBK)-1 and IFN-I activation, which resulted in lower expression of ISGs. Our findings demonstrate a major role for intracellular sensing and STING in the production of IFN-I by beneficial bacteria and the existence of bacteria-specific immune signatures, which can be exploited to promote cytoprotective responses and prevent overreactive NF-κB-dependent inflammation in the gut.
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Affiliation(s)
| | - Beatriz Isla
- School of Biosciences and Medicine, University of Surrey, GU2 7XH Guildford, UK
| | - Theo Combes
- School of Biosciences and Medicine, University of Surrey, GU2 7XH Guildford, UK
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Lim SG, Suk K, Lee WH. LETMD1 Regulates Phagocytosis and Inflammatory Responses to Lipopolysaccharide via Reactive Oxygen Species Generation and NF-κB Activation in Macrophages. THE JOURNAL OF IMMUNOLOGY 2020; 204:1299-1309. [PMID: 31980577 DOI: 10.4049/jimmunol.1900551] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 12/23/2019] [Indexed: 01/10/2023]
Abstract
LETM1 domain-containing protein 1 (LETMD1), also known as HCCR-1, is a mitochondrial protein and is known to regulate p53 and STAT3 activities in cancer cells. In this study, we present, for the first time (to our knowledge), data indicating that LETMD1 suppresses multiple immune responses in monocyte/macrophage lineage cells and mouse primary macrophages. Attenuation of LETMD1 expression with specific small interfering RNA and short hairpin RNA constructs enhanced LPS-induced expressions of inflammatory mediators in macrophages. In addition, LETMD1 attenuation caused potentiation of phagocytosis as well as migration in a macrophage-like cell line, U937. These enhancing effects were associated with altered activation of signaling adaptors (such as NF-κB, MAPKs, p53, and JAK-STAT) involved in TLR4 signaling. Especially, LETMD1 selectively regulated TLR4-induced NF-κB activation via MyD88 but not via TIR-domain-containing adapter-inducing IFN-β (TRIF). Attenuation of LETMD1 expression caused mitochondrial hyperpolarization and subsequent decrease in ATP production and increase in mitochondrial/cellular reactive oxygen species (ROS) and intracellular calcium levels. LETMD1 attenuation also enhanced LPS-induced expression of NADPH oxidase (NOX) 2, the main producer of cellular ROS in phagocytes, through augmenting IFN regulatory factor 1. Accordingly, treatment with ROS scavenger, NOX2 suppressing agents, or calcium chelators resulted in suppression of LPS-induced cytokine production as well as NF-κB activation in cells with LETMD1 attenuation. These findings reveal a previously unknown function of LETMD1 and provide evidences showing LETMD1 negatively regulates macrophage functions by modulating mitochondrial function, subsequent ROS generation, and NF-κB activation.
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Affiliation(s)
- Su-Geun Lim
- School of Life Sciences, Brain Korea 21 Plus/Kyungpook National University Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; and
| | - Kyoungho Suk
- Department of Pharmacology, Brain Science and Engineering Institute, Brain Korea 21 Plus/Kyungpook National University Biomedical Convergence Program, Kyungpook National University School of Medicine, Daegu 41944, Republic of Korea
| | - Won-Ha Lee
- School of Life Sciences, Brain Korea 21 Plus/Kyungpook National University Creative BioResearch Group, Kyungpook National University, Daegu 41566, Republic of Korea; and
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circAtp9b knockdown alleviates LPS-caused inflammation provided that microRNA-27a is upregulated. Int Immunopharmacol 2020; 78:105925. [PMID: 31735661 DOI: 10.1016/j.intimp.2019.105925] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 08/30/2019] [Accepted: 09/19/2019] [Indexed: 12/13/2022]
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Sabit H, Cevik E, Tombuloglu H. Colorectal cancer: The epigenetic role of microbiome. World J Clin Cases 2019; 7:3683-3697. [PMID: 31799293 PMCID: PMC6887622 DOI: 10.12998/wjcc.v7.i22.3683] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 10/23/2019] [Accepted: 10/30/2019] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in men (746000 cases per year) and the second most common cancer in women globally (614000 cases per year). The incidence rate of CRC in developed countries (737000 cases per year) is higher than that in less developed countries (624000 cases per year). CRC can arise from genetic causes such as chromosomal instability and microsatellite instability. Several etiologic factors underlie CRC including age, diet, and lifestyle. Gut microbiota represent a proven cause of the disease, where they play pivotal roles in modulating and reshaping the host epigenome. Several active microbial metabolites have been found to drive carcinogenesis, invasion, and metastasis via modifying both the methylation landscape along with histone structure in intestinal cells. Gut microbiota, in response to diet, can exert both beneficial and harmful functions in humans, according to the intestinal balance of number and types of these bacteria. Although the intestinal microbial community is diverse among individuals, these microbes cumulatively produce 100-fold more proteins than the human genome itself, which calls for further studies to elaborate on the complicated interaction between these microorganisms and intestinal cells. Therefore, understanding the exact role that gut microbiota play in inducing CRC will help attain reliable strategies to precisely diagnose and treat this fatal disease.
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Affiliation(s)
- Hussein Sabit
- Department of Genetics, Institute for Medical Research and Consultations, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Emre Cevik
- Department of Genetics, Institute for Medical Research and Consultations, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Huseyin Tombuloglu
- Department of Genetics, Institute for Medical Research and Consultations, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
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Development of a Gut-On-A-Chip Model for High Throughput Disease Modeling and Drug Discovery. Int J Mol Sci 2019; 20:ijms20225661. [PMID: 31726729 PMCID: PMC6888156 DOI: 10.3390/ijms20225661] [Citation(s) in RCA: 110] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 11/07/2019] [Accepted: 11/08/2019] [Indexed: 12/13/2022] Open
Abstract
A common bottleneck in any drug development process is finding sufficiently accurate models that capture key aspects of disease development and progression. Conventional drug screening models often rely on simple 2D culture systems that fail to recapitulate the complexity of the organ situation. In this study, we show the application of a robust high throughput 3D gut-on-a-chip model for investigating hallmarks of inflammatory bowel disease (IBD). Using the OrganoPlate platform, we subjected enterocyte-like cells to an immune-relevant inflammatory trigger in order to recapitulate key events of IBD and to further investigate the suitability of this model for compound discovery and target validation activities. The induction of inflammatory conditions caused a loss of barrier function of the intestinal epithelium and its activation by increased cytokine production, two events observed in IBD physiopathology. More importantly, anti-inflammatory compound exposure prevented the loss of barrier function and the increased cytokine release. Furthermore, knockdown of key inflammatory regulators RELA and MYD88 through on-chip adenoviral shRNA transduction alleviated IBD phenotype by decreasing cytokine production. In summary, we demonstrate the routine use of a gut-on-a-chip platform for disease-specific aspects modeling. The approach can be used for larger scale disease modeling, target validation and drug discovery purposes.
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Exosome Treatment Enhances Anti-Inflammatory M2 Macrophages and Reduces Inflammation-Induced Pyroptosis in Doxorubicin-Induced Cardiomyopathy. Cells 2019; 8:cells8101224. [PMID: 31600901 PMCID: PMC6830113 DOI: 10.3390/cells8101224] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/18/2019] [Accepted: 09/26/2019] [Indexed: 12/20/2022] Open
Abstract
Doxorubicin (Dox) is an effective antineoplastic agent used to treat cancers, but its use is limited as Dox induces adverse cardiotoxic effects. Dox-induced cardiotoxicity (DIC) can lead to heart failure and death. There is no study that investigates whether embryonic stem cell-derived exosomes (ES-Exos) in DIC can attenuate inflammation-induced pyroptosis, pro-inflammatory M1 macrophages, inflammatory cell signaling, and adverse cardiac remodeling. For this purpose, we transplanted ES-Exos and compared with ES-cells (ESCs) to examine pyroptosis, inflammation, cell signaling, adverse cardiac remodeling, and their influence on DIC induced cardiac dysfunction. Therefore, we used C57BL/6J mice ages 10 ± 2 weeks and divided them into four groups (n = 6–8/group): Control, Dox, Dox + ESCs, and Dox + ES-Exos. Our data shows that the Dox treatment significantly increased expression of inflammasome markers (TLR4 and NLRP3), pyroptotic markers (caspase-1, IL1-β, and IL-18), cell signaling proteins (MyD88, p-P38, and p-JNK), pro-inflammatory M1 macrophages, and TNF-α cytokine. This increased pyroptosis, inflammation, and cell signaling proteins were inhibited with ES-Exos or ESCs. Moreover, ES-Exos or ESCs increased M2 macrophages and anti-inflammatory cytokine, IL-10. Additionally, ES-Exos or ESCs treatment inhibited significantly cytoplasmic vacuolization, myofibril loss, hypertrophy, and improved heart function. In conclusion, for the first time we demonstrated that Dox-induced pyroptosis and cardiac remodeling are ameliorated by ES-Exos or ESCs.
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Lv Z, Wang L, Jia Z, Sun J, Wang W, Liu Z, Qiu L, Wang M, Song L. Hemolymph C1qDC promotes the phagocytosis of oyster Crassostrea gigas hemocytes by interacting with the membrane receptor β-integrin. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2019; 98:42-53. [PMID: 30995452 DOI: 10.1016/j.dci.2019.04.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 04/08/2019] [Accepted: 04/09/2019] [Indexed: 06/09/2023]
Abstract
Phagocytosis constitutes a conserved cellular process for multicellular animals to ingest or engulf other cells or particles, which is facilitated by the use of opsonins to bind foreign particles and interact with cell surface receptors. The invertebrate secreted C1q domain-containing proteins (C1qDCs) have been reported to exhibit opsonic activity, while the detailed mechanisms of opsonization still remain unclear. In the present study, a C1qDC (designated as CgC1qDC-5) with opsonic activity was identified from the hemolymph of oyster Crassostrea gigas. CgC1qDC-5 exhibited the ability to bind pathogen-associated molecular patterns (PAMPs) of lipopolysaccharides (LPS) and Lipid A. It could also bind and agglutinate Gram-negative bacteria Escherichia coli, Vibrio splendidus and Vibrio anguillarum, whereas the agglutinating activity could be inhibited by LPS. In addition, CgC1qDC-5 could enhance the phagocytosis of hemocytes toward E. coli, V. splendidus, and V. anguillarum. GST pull-down and surface plasmon resonance assays in vitro revealed that CgC1qDC-5 could interact with β-integrin (CgIntegrin). In vivo, CgC1qDC-5 was observed to bind hemocytes and co-localized with CgIntegrin on the cell membrane of hemocytes. Antibody-mediated blockage of CgIntegrin hindered the CgC1qDC-5-enhanced hemocytic phagocytosis. CgIntegrin also exhibited the ability to bind the Gram-negative bacteria E. coli, V. splendidus, V. anguillarum and Vibrio parahaemolyticus, and PAMP of LPS, but not Lipid A. A phagocytosis assay demonstrated that CgIntegrin could directly mediate phagocytosis toward bacteria as a phagocytic receptor. These results collectively suggested that CgC1qDC-5 could serve as an opsonin to recognize and bind bacteria, and subsequently interact with CgIntegrin on the hemocyte surface to enhance the CgIntegrin-mediated phagocytosis in oyster.
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Affiliation(s)
- Zhao Lv
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Lingling Wang
- Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China
| | - Zhihao Jia
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jiejie Sun
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China
| | - Weilin Wang
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China
| | - Zhaoqun Liu
- Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China
| | - Limei Qiu
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China
| | - Mengqiang Wang
- Key Laboratory of Experimental Marine Biology, Institute of Oceanology, Chinese Academy of Sciences, Qingdao, 266071, China
| | - Linsheng Song
- Laboratory of Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266235, China; Liaoning Key Laboratory of Marine Animal Immunology, Dalian Ocean University, Dalian, 116023, China; Liaoning Key Laboratory of Marine Animal Immunology and Disease Control, Dalian Ocean University, Dalian, 116023, China.
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Ding J, Liu Q. Toll-like receptor 4: A promising therapeutic target for pneumonia caused by Gram-negative bacteria. J Cell Mol Med 2019; 23:5868-5875. [PMID: 31350813 PMCID: PMC6714139 DOI: 10.1111/jcmm.14529] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 06/11/2019] [Accepted: 06/15/2019] [Indexed: 02/06/2023] Open
Abstract
Gram‐negative bacteria (GNB) emerge as important pathogens causing pulmonary infection, which can develop into sepsis due to bacterial resistance to antibiotics. GNB pneumonia poses a huge social and economic burden all over the world. During GNB infection in the lung, Toll‐like receptor 4 (TLR4) can form a complex with MD2 and CD14 after recognizing lipopolysaccharide of GNB, initiate the MyD88‐ and TRIF‐dependent signalling pathways and stimulate host non‐specific immune response. In this review, we summarize recent progress in our understanding of the role of TLR4 in GNB pneumonia. The latest experimental results, especially in TLR4 knockout animals, suggest a promising potential of targeting TLR4 signalling pathway for the treatment of GNB pneumonia. Furthermore, we highlight the benefits of Traditional Chinese Medicine as novel candidates for the therapy of GNB pneumonia due to the modulation of TLR4 signalling pathway. Finally, we discuss the promise and challenge in the development of TLR4‐based drugs for GNB pneumonia.
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Affiliation(s)
- Junying Ding
- Beijing Key Laboratory of Basic Research with Traditional Chinese Medicine on Infectious Diseases, Beijing, China.,Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.,Beijing Institute of Traditional Chinese Medicine, Beijing, China
| | - Qingquan Liu
- Beijing Key Laboratory of Basic Research with Traditional Chinese Medicine on Infectious Diseases, Beijing, China.,Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, China.,Beijing Institute of Traditional Chinese Medicine, Beijing, China
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Tang J, Zhen H, Wang N, Yan Q, Jing H, Jiang Z. Curdlan oligosaccharides having higher immunostimulatory activity than curdlan in mice treated with cyclophosphamide. Carbohydr Polym 2019; 207:131-142. [DOI: 10.1016/j.carbpol.2018.10.120] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 10/26/2018] [Accepted: 10/27/2018] [Indexed: 01/05/2023]
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Koonpaew S, Teeravechyan S, Frantz PN, Chailangkarn T, Jongkaewwattana A. PEDV and PDCoV Pathogenesis: The Interplay Between Host Innate Immune Responses and Porcine Enteric Coronaviruses. Front Vet Sci 2019; 6:34. [PMID: 30854373 PMCID: PMC6395401 DOI: 10.3389/fvets.2019.00034] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 01/28/2019] [Indexed: 12/24/2022] Open
Abstract
Enteropathogenic porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV), members of the coronavirus family, account for the majority of lethal watery diarrhea in neonatal pigs in the past decade. These two viruses pose significant economic and public health burdens, even as both continue to emerge and reemerge worldwide. The ability to evade, circumvent or subvert the host’s first line of defense, namely the innate immune system, is the key determinant for pathogen virulence, survival, and the establishment of successful infection. Unfortunately, we have only started to unravel the underlying viral mechanisms used to manipulate host innate immune responses. In this review, we gather current knowledge concerning the interplay between these viruses and components of host innate immunity, focusing on type I interferon induction and signaling in particular, and the mechanisms by which virus-encoded gene products antagonize and subvert host innate immune responses. Finally, we provide some perspectives on the advantages gained from a better understanding of host-pathogen interactions. This includes their implications for the future development of PEDV and PDCoV vaccines and how we can further our knowledge of the molecular mechanisms underlying virus pathogenesis, virulence, and host coevolution.
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Affiliation(s)
- Surapong Koonpaew
- Virology and Cell Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathumthani, Thailand
| | - Samaporn Teeravechyan
- Virology and Cell Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathumthani, Thailand
| | - Phanramphoei Namprachan Frantz
- Virology and Cell Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathumthani, Thailand
| | - Thanathom Chailangkarn
- Virology and Cell Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathumthani, Thailand
| | - Anan Jongkaewwattana
- Virology and Cell Technology Laboratory, National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency, Pathumthani, Thailand
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Wei S, Yang D, Yang J, Zhang X, Zhang J, Fu J, Zhou G, Liu H, Lian Z, Han H. Overexpression of Toll-like receptor 4 enhances LPS-induced inflammatory response and inhibits Salmonella Typhimurium growth in ovine macrophages. Eur J Cell Biol 2019; 98:36-50. [PMID: 30522781 DOI: 10.1016/j.ejcb.2018.11.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 11/06/2018] [Accepted: 11/28/2018] [Indexed: 12/15/2022] Open
Abstract
The Toll-like receptor 4 (TLR4) plays a crucial role in innate inflammatory responses, as it recognizes gram-negative bacteria (or their products) and contributes greatly to host defense against invading pathogens. Though TLR4 overexpressing transgenic sheep, resistant to certain diseases related with gram-negative bacteria, had been bred in our previous research, the effects of overexpression of TLR4 on innate immune response remained unclear. In this study, TLR4 overexpressing ovine macrophages were obtained from peripheral blood, and it was found that the overexpression of TLR4 initially promoted the production of proinflammatory cytokines TNFα and IL-6 by activating TLR4-mediated IRAK4-dependent NF-κB and MAPK (JNK and ERK1/2) signaling following LPS stimulation. However, this effect was later impaired due to increased internalization of TLR4 into endosomal compartment of the macrophages. Then the overexpression of TLR4 triggered TBK1-dependent interferon-regulatory factor-3 (IRF-3) expression, which in turn led to the induction of IFN-β and IFN-inducible genes (i.e.IP10, IRG1 and GARG16). Understandably, an increased IFN-β level facilitated phosphorylation of STAT1 to induce expression of innate antiviral genes Mx1 and ISG15, suggesting that TLR4 overexpressing macrophages were equipped better against viral infection. Correspondingly, the bacterial burden in these macrophages, after infection with live S. Typhimurium, was decreased significantly. In summary, the results indicated that overexpression of TLR4 could enhance innate inflammatory responses, initiate the innate antiviral immunity, and control effectively S. Typhimurium growth in ovine macrophages.
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Affiliation(s)
- Shao Wei
- Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China; National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Dongbing Yang
- Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China; National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Jifan Yang
- Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Xiaosheng Zhang
- Institute of Animal Science and Veterinary Medicine, Tianjin Academy of Agricultural Sciences, Tianjin, China
| | - Jinlong Zhang
- Institute of Animal Science and Veterinary Medicine, Tianjin Academy of Agricultural Sciences, Tianjin, China
| | - Juncai Fu
- State Key Laboratory of Animal Nutrition, China Agricultural University, Beijing, China
| | - Guangbin Zhou
- Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, College of Animal Science and Technology, Sichuan Agricultural University, China
| | - Haijun Liu
- Institute of Animal Science and Veterinary Medicine, Tianjin Academy of Agricultural Sciences, Tianjin, China
| | - Zhengxing Lian
- Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China; National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Hongbing Han
- Beijing Key Laboratory for Animal Genetic Improvement, College of Animal Science and Technology, China Agricultural University, Beijing, China; National Engineering Laboratory for Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing, China.
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Jannasch O, Meyer F, Fuellert A, König B, Eder F, Tautenhahn J. Vacuum-assisted closure (VAC) for postoperative secondary peritonitis: Effect on bacterial load as well as local and systemic cytokine response (initial results). POLISH JOURNAL OF SURGERY 2018; 90:27-35. [PMID: 30426943 DOI: 10.5604/01.3001.0012.1751] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND It is still a matter of debate what the best management of peritonitis is following eliminating the source of infection. This particularly concerns the amplitude of local and systemic inflammatory response as well as bacterial clearence at the infectious site. AIM To investigate the effects of vacuum-assisted closure (VAC) vs. relaparotomy on demand (ROD) onto the i) severity and course of disease, ii) surgical outcome, iii) intraperitoneal bacterial load as well as iv) local and systemic inflammatory and immune response in postoperative secondary peritonitis. METHODS Over a defined time period, all consecutive patients of the reporting surgical department with a secondary peritonitis (assessed by Mannheim's Peritonitis Index [MPI] and APPACHE II score) were enrolled in this systematic unicenter clinical prospective observational pilot study reflecting daily surgical practice and as a contribution to internal quality assurance. Patients were subclassified into VAC or ROD group according to surgeon's individual decision at the time point of primary surgical intervention with the intent to sanitize the source of infection. Early postoperative result was assessed by 30-d and in-hospital mortality. Bacterial load was characterized by microbiological culture of intraperitoneal fluid collection obtained on postoperative days (POD) 0 (primary surgical intervention), 1, 4, 7, 10, 13 and following description of the microbial spectrum including semiquantitative assessment of bacterial load. Local and systemic inflammatory and immune response was determined by ELISA-based analysis of CrP, PCT and the representative cytokines such as TNF-α, IL-1β, IL-6, IL-8, and IL-10 of serum and peritoneal fluid samples. RESULTS Over a 26-months investigation period, 18 patients (sex ratio, male:female=9:9) were eligible for study criteria: n=8 were enrolled in the VAC (m:f=4:4) and n=10 in the ROD group (m:f=5:5). With regard to early postoperative results represented by mortality, there is no significant difference between both patients groups. Despite the relatively low number of cases enrolled in this study, a trend for more severe findings associated with the VAC group could be detected based on MPI score. There was also a trend of higher APACHE II scores in the VAC group from the 7th POD on and, in addition, patients of this group had a longer hospital stay. For patients with persisting infection, there were no relevant differences comparing VAC therapy and ROD. Cytokines released, in particular, at the beginning of the inflammation cascade with proinflammatory characteristics, showed higher values within the peritoneal fluid whereas CrP and PCT were found to be higher within the serum samples. Summary & Conclusion: Comparing data of various local and systemic inflammatory and immune parameters, there were only a few correlations. This may indicate a compartimentation of the inflammatory process within the abdominal cavity. Based on the observed inter-individual variation of this pilot study data, the clinically applicable benefit appears questionable. In this context, a reliable effect of VAC therapy onto reduction of bacterial burden within the abdominal cavity could not clearly be detected.
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Affiliation(s)
- Olof Jannasch
- Elisabeth Hospital at Kassel (Germany) Dept. of Gemeral and Abdominal Surgery
| | - Frank Meyer
- University Hospital at Magdeburg, Magdeburg (Germany) Dept. of General, Abdominal and Vascular Surgery
| | - Angela Fuellert
- Municipal Hospital ("Klinikum") at Magdeburg (Germany) Dept. of Vascular Surgery
| | - Brigitte König
- University Hospital at Leipzig (Germany) Institute of Microbiology
| | - Frank Eder
- Municipal Hospital (AMEOS-Klinikum) at Halberstadt (Germany) Dept. of General, Abdominal and Vascular Surgery
| | - Jörg Tautenhahn
- Municipal Hospital ("Klinikum") at Magdeburg (Germany) Dept. of Vascular Surgery
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Wang L, Yu K, Zhang X, Yu S. Dual functional roles of the MyD88 signaling in colorectal cancer development. Biomed Pharmacother 2018; 107:177-184. [PMID: 30086464 DOI: 10.1016/j.biopha.2018.07.139] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Revised: 07/24/2018] [Accepted: 07/25/2018] [Indexed: 12/12/2022] Open
Abstract
The myeloid differentiation factor 88 (MyD88), an adaptor protein in regulation of the innate immunity, functions to regulate immune responses against viral and bacterial infections in the human body. Toll-like receptors (TLRs) and interleukin 1 receptors (IL-1R) can recognize microbes or endogenous ligands and then recruit MyD88 to activate the MyD88-dependent pathway, while MyD88 mutation associated with lymphoma development and altered MyD88 signaling also involved in cancer-associated cell intrinsic and extrinsic inflammation progression and carcinogenesis. Detection of MyD88 expression was to predict prognosis of various human cancers, e.g., lymphoid, liver, and colorectal cancers. In human cancers, MyD88 protein acts as a bridge between the inflammatory signaling from the TLR/IL-1R and Ras oncogenic signaling pathway. However, the MyD88 signaling played dual functional roles in colorectal cancer, i.e., the tumor-promoting role that enhances cancer inflammation and intestinal flora imbalance to induce tumor invasion and tumor cell self-renewal, and the anti-tumor role that helps to maintain the host-microbiota homeostasis to induce tumor cell cycle arrest and immune responses against cancer cells. This review precisely discusses the up to date literature for these contrasting effects of MyD88 signaling on colorectal cancer development and progression.
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Affiliation(s)
- Lu Wang
- Department of Pharmacy, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| | - Kewei Yu
- Department of Pharmacy, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| | - Xiang Zhang
- Department of Pharmacy, Jinan Central Hospital Affiliated to Shandong University, Jinan, China
| | - Shuwen Yu
- Department of Pharmacy, Jinan Central Hospital Affiliated to Shandong University, Jinan, China.
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Kannegieter NM, Hesselink DA, Dieterich M, de Graav GN, Kraaijeveld R, Rowshani AT, Leenen PJM, Baan CC. Pharmacodynamic Monitoring of Tacrolimus-Based Immunosuppression in CD14+ Monocytes After Kidney Transplantation. Ther Drug Monit 2018. [PMID: 28640063 DOI: 10.1097/ftd.0000000000000426] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
BACKGROUND Monocytes significantly contribute to ischemia-reperfusion injury and allograft rejection after kidney transplantation. However, the knowledge about the effects of immunosuppressive drugs on monocyte activation is limited. Conventional pharmacokinetic methods for immunosuppressive drug monitoring are not cell type-specific. In this study, phosphorylation of 3 signaling proteins was measured to determine the pharmacodynamic effects of immunosuppression on monocyte activation in kidney transplant patients. METHODS Blood samples from 20 kidney transplant recipients were monitored before and during the first year after transplantation. All patients received induction therapy with basiliximab, followed by tacrolimus (TAC), mycophenolate mofetil, and prednisolone maintenance therapy. TAC whole-blood predose concentrations were determined using an antibody-conjugated magnetic immunoassay. Samples were stimulated with phorbol 12-myristate 13-acetate (PMA)/ionomycin, and phosphorylation of p38MAPK, ERK, and Akt in CD14 monocytes was quantified by phospho-specific flow cytometry. RESULTS Phosphorylation of p38MAPK and Akt in monocytes of immunosuppressed recipients was lower after 360 days compared with before transplantation in the unstimulated samples [mean reduction in median fluorescence intensity 36%; range -28% to 77% for p-p38MAPK and 20%; range -22% to 53% for p-Akt; P < 0.05]. P-ERK was only decreased at day 4 after transplantation (mean inhibition 23%; range -52% to 73%; P < 0.05). At day 4, when the highest whole-blood predose TAC concentrations were measured, p-p38MAPK and p-Akt, but not p-ERK, correlated inversely with TAC (rs = -0.65; P = 0.01 and rs = -0.58; P = 0.03, respectively). CONCLUSIONS Immunosuppressive drug combination therapy partially inhibits monocyte activation pathways after kidney transplantation. This inhibition can be determined by phospho-specific flow cytometry, which enables the assessment of the pharmacodynamic effects of immunosuppressive drugs in a cell type-specific manner.
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Affiliation(s)
- Nynke M Kannegieter
- Departments of *Internal Medicine and †Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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Xu L, Sun Y, Li M, Ge X. Dyrk2 mediated the release of proinflammatory cytokines in LPS-induced BV2 cells. Int J Biol Macromol 2018; 109:1115-1124. [PMID: 29155197 DOI: 10.1016/j.ijbiomac.2017.11.095] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 11/14/2017] [Accepted: 11/15/2017] [Indexed: 11/19/2022]
Abstract
NF-κB pathway and p38MAPK (p38mitogen-activated protein kinase) pathway have been shown to play a key role in neuroinflammation, however, the phosphorylation modification is an important process that affects the activation of above pathways. Dual-specificity tyrosine-phosphorylation-regulated kinase 2(Dyrk2), as a phosphokinase that can phosphorylate signal molecules, has been demonstrated to regulate Type I Interferon(TIF) by promoting ser527 phosphorylation of TBK1. Therefore, to investigate the role of Dyrk2 in neuroinflammation, we analyzed the effect of Dyrk2 on LPS-induced the activation of microglia. Here, we found Dyrk2 expressed in BV2 cells, and LPS induced different expression trend of Dyrk2 in the cytoplasm and nucleus. In addition, we revealed that Dyrk2 interacted with Akt, p38MAPK and NF-κB subunit p65, however, in the nucleus of BV2 cells, Dyrk2 selectively interacted with p38MAPK instead of with p65. Although the overexpression of Dyrk2 increased the expression level of phospho-p65, phospho-Akt and phospho-p38MAPK in LPS-stimulated BV2 cells, less TNF-α and IL-1β were detected. Probably, the inhibitory effect of Dyrk2 on the release of TNF-α and IL-1β was associated with the induction of phospho-Akt. In conclusion, these data suggested Dyrk2 involved in regulating LPS-induced the release of proinflammatory cytokines through its phosphokinase function.
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Affiliation(s)
- Li Xu
- Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong 226001, Jiangsu Province, People's Republic of China
| | - Yuxiang Sun
- Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong 226001, Jiangsu Province, People's Republic of China.
| | - Mengmeng Li
- Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong 226001, Jiangsu Province, People's Republic of China
| | - Xin Ge
- Jiangsu Province Key Laboratory of Neuroregeneration, Nantong University, Nantong 226001, Jiangsu Province, People's Republic of China
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Bai D, Zhao Y, Zhu Q, Zhou Y, Zhao Y, Zhang T, Guo Q, Lu N. LZ205, a newly synthesized flavonoid compound, exerts anti-inflammatory effect by inhibiting M1 macrophage polarization through regulating PI3K/AKT/mTOR signaling pathway. Exp Cell Res 2018; 364:84-94. [DOI: 10.1016/j.yexcr.2018.01.033] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Revised: 01/20/2018] [Accepted: 01/24/2018] [Indexed: 01/26/2023]
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Enterococcus faecalis Promotes Innate Immune Suppression and Polymicrobial Catheter-Associated Urinary Tract Infection. Infect Immun 2017; 85:IAI.00378-17. [PMID: 28893918 DOI: 10.1128/iai.00378-17] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 09/01/2017] [Indexed: 12/18/2022] Open
Abstract
Enterococcus faecalis, a member of the human gastrointestinal microbiota, is an opportunistic pathogen associated with hospital-acquired wound, bloodstream, and urinary tract infections. E. faecalis can subvert or evade immune-mediated clearance, although the mechanisms are poorly understood. In this study, we examined E. faecalis-mediated subversion of macrophage activation. We observed that E. faecalis actively prevents NF-κB signaling in mouse RAW264.7 macrophages in the presence of Toll-like receptor agonists and during polymicrobial infection with Escherichia coliE. faecalis and E. coli coinfection in a mouse model of catheter-associated urinary tract infection (CAUTI) resulted in a suppressed macrophage transcriptional response in the bladder compared to that with E. coli infection alone. Finally, we demonstrated that coinoculation of E. faecalis with a commensal strain of E. coli into catheterized bladders significantly augmented E. coli CAUTI. Taken together, these results support the hypothesis that E. faecalis suppression of NF-κB-driven responses in macrophages promotes polymicrobial CAUTI pathogenesis, especially during coinfection with less virulent or commensal E. coli strains.
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Xu Z, Tong Z, Neelakantan P, Cai Y, Wei X. Enterococcus faecalis immunoregulates osteoclastogenesis of macrophages. Exp Cell Res 2017; 362:152-158. [PMID: 29129564 DOI: 10.1016/j.yexcr.2017.11.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 11/07/2017] [Accepted: 11/08/2017] [Indexed: 12/17/2022]
Abstract
Persistent apical periodontitis (PAP) is characterized by refractory inflammation and progressive bone destruction. Enterococcus faecalis infection is considered an important etiological factor for the development of PAP, although the exact mechanisms remain unknown. This study aimed at investigating the role of E. faecalis in cell proliferation, inflammatory reactions and osteoclast differentiation of macrophages using an in vitro infection model of osteoclast precursor RAW264.7 cells. A cell viability assay of cultured RAW264.7 cells exposed to live E. faecalis at a multiplicity of infection of 100 for 2h, indicated that the infection exhibited no cytotoxic effect. Transmission electron microscopy images revealed no apoptotic changes but a rise of metabolic activity and phagocytic features in the infected RAW264.7 cells. Confocal laser scanning microscopic and flow cytometric analysis indicated that the phagocytosis of RAW264.7 cells was activated by E. faecalis infection. Furthermore, quantitative real-time PCR assays demonstrated that the expression of inflammatory cytokines was remarkably elevated in infected RAW264.7 cells. Differentiation of infected RAW264.7 cells into osteoclasts was remarkably attenuated, and expression of osteoclast marker genes as well as fusogenic genes significantly dropped. In summary, E. faecalis appears to attenuate osteoclastic differentiation of RAW264.7 precursor cells, rather stimulates them to function as macrophages.
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Affiliation(s)
- Zhezhen Xu
- Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56 Lingyuan Xi Road, Guangzhou 510055, Guangdong, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China.
| | - Zhongchun Tong
- Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56 Lingyuan Xi Road, Guangzhou 510055, Guangdong, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China.
| | - Prasanna Neelakantan
- Discipline of Endodontology, Faculty of Dentistry, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
| | - Yanling Cai
- Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56 Lingyuan Xi Road, Guangzhou 510055, Guangdong, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China.
| | - Xi Wei
- Department of Operative Dentistry and Endodontics, Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, 56 Lingyuan Xi Road, Guangzhou 510055, Guangdong, China; Guangdong Province Key Laboratory of Stomatology, No. 74, 2nd Zhongshan Road, Guangzhou 510080, Guangdong, China.
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Gao Q, Yin F, Zhang C, Yue Y, Sun P, Min M, Peng S, Shi Z, Lv J. Cloning, characterization, and function of MyD88 in silvery pomfret ( Pampus argenteus ) in response to bacterial challenge. Int J Biol Macromol 2017; 103:327-337. [DOI: 10.1016/j.ijbiomac.2017.05.039] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 05/07/2017] [Accepted: 05/09/2017] [Indexed: 02/07/2023]
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Short-Term Regulation of Fc γR-Mediated Phagocytosis by TLRs in Macrophages: Participation of 5-Lipoxygenase Products. Mediators Inflamm 2017; 2017:2086840. [PMID: 28894350 PMCID: PMC5574301 DOI: 10.1155/2017/2086840] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 06/08/2017] [Indexed: 12/19/2022] Open
Abstract
TLRs recognize a broad spectrum of microorganism molecules, triggering a variety of cellular responses. Among them, phagocytosis is a critical process for host defense. Leukotrienes (LTs), lipid mediators produced from 5-lipoxygenase (5-LO) enzyme, increase FcγR-mediated phagocytosis. Here, we evaluated the participation of TLR2, TLR3, TLR4, and TLR9 in FcγR-mediated phagocytosis and whether this process is modulated by LTs. Rat alveolar macrophages (AMs), murine bone marrow-derived macrophages (BMDMs), and peritoneal macrophages (PMs) treated with TLR2, TLR3, and TLR4 agonists, but not TLR9, enhanced IgG-opsonized sheep red blood cell (IgG-sRBC) phagocytosis. Pretreatment of AMs or BMDMs with drugs that block LT synthesis impaired the phagocytosis promoted by TLR ligands, and TLR potentiation was also abrogated in PMs and BMDMs from 5-LO−/− mice. LTB4 production induced by IgG engagement was amplified by TLR ligands, while cys-LTs were amplified by activation of TLR2 and TLR4, but not by TLR3. We also noted higher ERK1/2 phosphorylation in IgG-RBC-challenged cells when preincubated with TLR agonists. Furthermore, ERK1/2 inhibition by PD98059 reduced the phagocytic activity evoked by TLR agonists. Together, these data indicate that TLR2, TLR3, and TLR4 ligands, but not TLR9, amplify IgG-mediated phagocytosis by a mechanism which requires LT production and ERK-1/2 pathway activation.
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