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1
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Antonello J, Roy P. Damage-Associated Molecular Patterns (DAMPs) In Vascular Diseases. J Biol Chem 2025:110241. [PMID: 40381697 DOI: 10.1016/j.jbc.2025.110241] [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: 03/10/2025] [Revised: 05/02/2025] [Accepted: 05/07/2025] [Indexed: 05/20/2025] Open
Abstract
Research into the role of chronic sterile inflammation (i.e. a prolonged inflammatory state not caused by an infectious agent), in vascular disease progression has continued to grow over the last few decades. DAMPs have a critical role in this research due to their ability to link stress-causing cardiovascular risk factors to inflammatory phenotypes seen in vascular disease. In this mini-review, we will briefly summarize the DAMPs and receptor signaling pathways that have been extensively studied in the context of vascular disease, including TLRs, RAGE, cGAS-STING, and the NLRP3 inflammasome. In particular, we will discuss how these pathways can promote the release of pro-inflammatory cytokines and chemokines as well as vascular remodeling. Next, we will summarize the results of studies which have linked the various pro-inflammatory effects of DAMPs with the phenotypes in the context of vascular diseases including atherosclerosis, fibrosis, aneurysm, ischemia, and hypertension. Finally, we will discuss some pre-clinical and clinical trials that have targeted DAMPs, their receptors, or the products of their signaling pathways, and discuss the outlook and future directions for the field at large.
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Affiliation(s)
| | - Partha Roy
- Bioengineering, University of Pittsburgh; Pathology, University of Pittsburgh.
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2
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Nazeam JA, Black I, Mulamoottil VA, Selim NM, El Shiekh RA, Abu-Elfotuh K, Hamdan AME, Gowifel AMH, Hafez SM, Mohamed EK, Atwa AM, El Hefnawy HM, Azadi P. Okra seed polysaccharides mitigate neuroinflammation and cognitive impairment via modulation of Nrf2/HO-1, HMGB1/RAGE/TLR4/NF-κB, NLRP3/Caspase-1, JAK-2/STAT-3, AMPK/SIRT1/m-TOR, PI3K/AKT/CREB/BDNF/TrkB and PERK/CHOP/Bcl-2 axes. Int Immunopharmacol 2025; 148:114110. [PMID: 39862637 DOI: 10.1016/j.intimp.2025.114110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 11/23/2024] [Accepted: 01/15/2025] [Indexed: 01/27/2025]
Abstract
Global healthcare systems are under tremendous strain due to the increasing prevalence of neurodegenerative disorders. Growing data suggested that overconsumption of high-fat/high-carbohydrates diet (HFHCD) is associated with enhanced incidence of metabolic alterations, neurodegeneration, and cognitive dysfunction. Functional foods have gained prominence in curbing metabolic and neurological deficits. Consequently, this study endeavored to explore effects of purified Okra seed polysaccharides (OP) (Abelmoschus esculentus (L.) Moench) against HFHCD-induced metabolic alterations and cognitive dysfunction, with elucidating underlying contributed mechanistic pathways. OP hydrolysate was analyzed using GC-MS analysis. The biological study encompassed two phases, the first phase I (model establishment phase), for 3 months, involved a control group, fed standard diet, and HFHCD group. The second phase (phase II) where HFHCD fed rats were re-divided into 3 equal subgroups, 1st subgroup received HFHCD, whereas second and third subgroups received OP, 200 or 400 mg/kg/day, respectively, for 28 days. GC-MS characterized OP as an arabinogalactouranan and revealed the monosaccharide composition as galacturonic acid: arabinose: glucose: galactose: rhamnose: xylose in ratio of 28.2: 23.3: 11.5: 4.2: 3.5: 2.0. The findings demonstrated that OP dose-dependently mitigated HFHCD-induced rise in body weights, lipid profiles, levels of blood glucose and disruption in behavioral outcomes, neurotransmitters, together with histopathological alterations in brain. Moreover, OP dose-dependently improved redox, neuroinflammatory, endoplasmic reticulum (ER) stress, autophagic and apoptotic biomarkers. OP can be regarded as promising functional food candidate to hamper HFHCD-induced metabolic alterations and cognitive deficit, via enhancing Nrf2/HO-1, AMPK/SIRT1 and PI3K/AKT/CREB axes, long with dampening of HMGB1/RAGE/TLR4, NLRP3/Caspase-1, JAK-2/STAT-3 and PERK/CHOP axes.
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Affiliation(s)
- Jilan A Nazeam
- Department of Pharmacognosy, Faculty of Pharmacy, October 6 University, Giza, Egypt; Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
| | - Ian Black
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
| | | | - Nabil M Selim
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Giza 11562, Egypt.
| | - Riham A El Shiekh
- Pharmacognosy Department, Faculty of Pharmacy, Cairo University, Giza 11562, Egypt.
| | - Karema Abu-Elfotuh
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt; Al-Ayen Iraqi University, Thi-Qar 64001, Iraq.
| | - Ahmed M E Hamdan
- Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia; Prince Fahad bin Sultan Chair for Biomedical Research, University of Tabuk, Saudi Arabia.
| | - Ayah M H Gowifel
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt.
| | - Shaimaa M Hafez
- Department of Anatomy and Embryology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt.
| | - Ehsan K Mohamed
- Biochemistry Department, Egyptian Drug Authority (EDA), Formerly National Organization of Drug Control and Research (NODCAR), Giza, Egypt
| | - Ahmed M Atwa
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo-Suez Road, Cairo 11829, Egypt; Department of Pharmacology and Toxicology, College of Pharmacy, Al-Ayen Iraqi University, Thi-Qar, 64001, Iraq.
| | | | - Parastoo Azadi
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, USA.
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3
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Pedreañez A, Mosquera-Sulbaran JA, Tene D. Role of the receptor for advanced glycation end products in the severity of SARS-CoV-2 infection in diabetic patients. Diabetol Int 2024; 15:732-744. [PMID: 39469543 PMCID: PMC11512988 DOI: 10.1007/s13340-024-00746-1] [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: 03/19/2024] [Accepted: 07/17/2024] [Indexed: 10/30/2024]
Abstract
Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a severe disease in older adults and in individuals with associated comorbidities such as diabetes mellitus. Patients with diabetes infected with SARS-CoV-2 are more likely to develop severe pneumonia, hospitalization, and mortality compared with infected non-diabetic patients. During diabetes, hyperglycemia contributes to the maintenance of a low-grade inflammatory state which has been implicated in the microvascular and macrovascular complications associated with this pathology. The receptor for advanced glycation end products (RAGE) is a multi-ligand pattern recognition receptor, expressed on a wide variety of cells, which participates as an important mediator of inflammatory responses in many diseases, including lung diseases. This review highlights the role of RAGE in the pathophysiology of COVID-19 with special emphasis on diabetic patients. These data could explain the severity of the disease, positioning it as a key therapeutic target in the clinical management of this infection.
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Affiliation(s)
- Adriana Pedreañez
- Cátedra de Inmunología, Escuela de Bioanálisis, Facultad de Medicina, Universidad del Zulia, Apartado Postal: 23, Maracaibo 4001-A, Maracaibo, Zulia Venezuela
| | - Jesús A. Mosquera-Sulbaran
- Instituto de Investigaciones Clínicas “Dr. Américo Negrette”, Facultad de Medicina, Universidad del Zulia, Maracaibo, Venezuela
| | - Diego Tene
- Universidad Nacional del Chimborazo, Facultad de Ciencias de la Salud, Riobamba, Ecuador
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4
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Vitorakis N, Piperi C. Pivotal role of AGE-RAGE axis in brain aging with current interventions. Ageing Res Rev 2024; 100:102429. [PMID: 39032613 DOI: 10.1016/j.arr.2024.102429] [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: 05/02/2024] [Revised: 07/10/2024] [Accepted: 07/15/2024] [Indexed: 07/23/2024]
Abstract
Brain aging is characterized by several structural, biochemical and molecular changes which can vary among different individuals and can be influenced by genetic, environmental and lifestyle factors. Accumulation of protein aggregates, altered neurotransmitter composition, low-grade chronic inflammation and prolonged oxidative stress have been shown to contribute to brain tissue damage. Among key metabolic byproducts, advanced glycation end products (AGEs), formed endogenously through non-enzymatic reactions or acquired directly from the diet or other exogenous sources, have been detected to accumulate in brain tissue, exerting detrimental effects on cellular structure and function, contributing to neurodegeneration and cognitive decline. Upon binding to signal transduction receptor RAGE, AGEs can initiate pro-inflammatory pathways, exacerbate oxidative stress and neuroinflammation, thus impairing neuronal function and cognition. AGE-RAGE signaling induces programmed cell death, disrupts the blood-brain barrier and promotes protein aggregation, further compromising brain health. In this review, we investigate the intricate relationship between the AGE-RAGE pathway and brain aging in order to detect affected molecules and potential targets for intervention. Reduction of AGE deposition in brain tissue either through novel pharmacological therapeutics, dietary modifications, and lifestyle changes, shows a great promise in mitigating cognitive decline associated with brain aging.
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Affiliation(s)
- Nikolaos Vitorakis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, Athens 11527, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 75 M. Asias Street, Athens 11527, Greece.
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5
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Wang G, Hiramoto K, Ma N, Ohnishi S, Morita A, Xu Y, Yoshikawa N, Chinzei Y, Murata M, Kawanishi S. Immunohistochemical analyses reveal FoxP3 expressions in spleen and colorectal cancer in mice treated with AOM/DSS, and their suppression by glycyrrhizin. PLoS One 2024; 19:e0307038. [PMID: 39150932 PMCID: PMC11329161 DOI: 10.1371/journal.pone.0307038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 06/27/2024] [Indexed: 08/18/2024] Open
Abstract
We previously demonstrated that glycyrrhizin (GL) suppressed inflammation and carcinogenesis in an azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced murine model of colorectal cancer (CC). In this study, we found an accumulation of regulatory T cells (Tregs) in the spleen and suppression by GL in model mice. ICR mice were divided into four groups: Control, GL, CC, and GL-treated CC (CC+GL), and were sacrificed 20 weeks after AOM/DSS treatment. We measured spleen weight, areas of white and red pulp, and CD8+ T cells (cytotoxic T lymphocytes, CTL), and CD11c-positive cells (dendritic cells) in splenic tissues and forkhead box protein 3 (FoxP3)-positive cells (Tregs) in colorectal and splenic tissues. In all cases, the CC group showed a significant increase compared with those in Control group, and GL administration significantly attenuated this increase. These results indicate that Tregs accumulated in the spleen may participate in inflammation-related carcinogenesis by suppressing CTL. We also suggest that GL which binds to high-mobility group box 1 (HMGB1), suppresses carcinogenesis with decreasing Tregs in the spleen. Furthermore, there was an expression of FoxP3 in cancer cells, indicating that it may be involved in the malignant transformation of cancer cells.
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Affiliation(s)
- Guifeng Wang
- Department of Acupuncture and Moxibustion Medical Science, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Keiichi Hiramoto
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Ning Ma
- Graduate School of Health Science, Suzuka University of Medical Science, Suzuka, Mie, Japan
- Institute of Traditional Chinese Medicine, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Shiho Ohnishi
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Akihiro Morita
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Yifei Xu
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | | | - Yasuo Chinzei
- Graduate School of Health Science, Suzuka University of Medical Science, Suzuka, Mie, Japan
| | - Mariko Murata
- Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie, Japan
| | - Shosuke Kawanishi
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan
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6
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Walid MKI, Rahman S, Smith EA. Reciprocal effect on lateral diffusion of receptor for advanced glycation endproducts and toll-like receptor 4 in the HEK293 cell membrane. EUROPEAN BIOPHYSICS JOURNAL : EBJ 2024; 53:327-338. [PMID: 39066956 DOI: 10.1007/s00249-024-01717-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 06/28/2024] [Accepted: 07/18/2024] [Indexed: 07/30/2024]
Abstract
Receptor for advanced glycation endproducts (RAGE) and toll-like receptor 4 (TLR4) are pattern-recognition receptors that bind to molecular patterns associated with pathogens, stress, and cellular damage. Diffusion plays an important role in receptor functionality in the cell membrane. However, there has been no prior investigation of the reciprocal effect of RAGE and TLR4 diffusion properties in the presence and absence of each receptor. This study reports how RAGE and TLR4 affect the mobility of each other in the human embryonic kidney (HEK) 293 cell membrane. Diffusion properties were measured using single-particle tracking (SPT) with quantum dots (QDs) that are selectively attached to RAGE or TLR4. The Brownian diffusion coefficients of RAGE and TLR4 are affected by the presence of the other receptor, leading to similar diffusion coefficients when both receptors coexist in the cell. When TLR4 is present, the average Brownian diffusion coefficient of RAGE increases by 40%, while the presence of RAGE decreases the average Brownian diffusion coefficient of TLR4 by 32%. Diffusion in confined membrane domains is not altered by the presence of the other receptor. The mobility of the cell membrane lipid remains constant whether one or both receptors are present. Overall, this work shows that the presence of each receptor can affect a subset of diffusion properties of the other receptor without affecting the mobility of the membrane.
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Affiliation(s)
| | - Sharifur Rahman
- Department of Chemistry, Iowa State University, Ames, IA, 50011, USA
| | - Emily A Smith
- Department of Chemistry, Iowa State University, Ames, IA, 50011, USA.
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7
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Hassan NF, El-Ansary MR, Selim HMRM, Ousman MS, Khattab MS, El-Ansary MRM, Gad ES, Moursi SMM, Gohar A, Gowifel AMH. Alirocumab boosts antioxidant status and halts inflammation in rat model of sepsis-induced nephrotoxicity via modulation of Nrf2/HO-1, PCSK9/HMGB1/NF-ᴋB/NLRP3 and Fractalkine/CX3CR1 hubs. Biomed Pharmacother 2024; 177:116929. [PMID: 38889644 DOI: 10.1016/j.biopha.2024.116929] [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: 04/17/2024] [Revised: 06/05/2024] [Accepted: 06/09/2024] [Indexed: 06/20/2024] Open
Abstract
Acute kidney injury (AKI) is a devastating consequence of sepsis, accompanied by high mortality rates. It was suggested that inflammatory pathways are closely linked to the pathogenesis of lipopolysaccharide (LPS)-induced AKI. Inflammatory signaling, including PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-κB, NLRP3/caspase-1 and Fractalkine/CX3CR1 are considered major forerunners in this link. Alirocumab, PCSK9 inhibitor, with remarkable anti-inflammatory features. Accordingly, this study aimed to elucidate the antibacterial effect of alirocumab against E. coli in vitro. Additionally, evaluation of the potential nephroprotective effects of alirocumab against LPS-induced AKI in rats, highlighting the potential underlying mechanisms involved in these beneficial actions. Thirty-six adult male Wistar rats were assorted into three groups (n=12). Group I; was a normal control group, whereas sepsis-mediated AKI was induced in groups II and III through single-dose intraperitoneal injection of LPS on day 16. In group III, animals were given alirocumab. The results revealed that LPS-induced AKI was mitigated by alirocumab, evidenced by amelioration in renal function tests (creatinine, cystatin C, KIM-1, and NGAL); oxidative stress biomarkers (Nrf2, HO-1, TAC, and MDA); apoptotic markers and renal histopathological findings. Besides, alirocumab pronouncedly hindered LPS-mediated inflammatory response, confirmed by diminishing HMGB1, TNF-α, IL-1β, and caspase-1 contents; the gene expression of PCSK9, RAGE, NF-ᴋB and Fractalkine/CX3CR1, along with mRNA expression of TLR4, MYD88, and NLRP3. Regarding the antibacterial actions, results showed that alirocumab displayed potential anti-bacterial activity against pathogenic gram-negative E. coli. In conclusion, alirocumab elicited nephroprotective activities against LPS-induced AKI via modulation of Nrf2/HO-1, PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-ᴋB/NLRP3/Caspase-1, Fractalkine/CX3R1 and apoptotic axes.
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Affiliation(s)
- Noha F Hassan
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt.
| | - Mona R El-Ansary
- Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt.
| | - Heba Mohammed Refat M Selim
- Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, P.O. Box 71666, Riyadh, 11597, Saudi Arabia; Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11651, Egypt.
| | - Mona S Ousman
- Emergency Medical Services, College of Applied Sciences, AlMaarefa University, P.O. Box 71666, Riyadh, Saudi Arabia.
| | - Marwa S Khattab
- Pathology Department, Faculty of Veterinary Medicine, Cairo University, Giza 1211, Egypt.
| | - Mahmoud R M El-Ansary
- Medical Microbiology and Immunology Department, Faculty of Medicine, Misr University for Science and Technology (MUST), Giza 12566, Egypt.
| | - Enas S Gad
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, Saudi Arabia; Department of Pharmacology and Toxicology, faculty of Pharmacy, Sinai University-Kantara branch, Ismailia, Egypt
| | - Suzan M M Moursi
- Medical Physiology Department, Faculty of Medicine, Zagazig University, 44519, Egypt.
| | - Asmaa Gohar
- Microbiology and Immunology Department, Faculty of Pharmacy, Ahram Canadian University, sixth of October city, Giza, Egypt; Microbiology and Immunology Department, Faculty of Pharmacy, Galala University, New Galala City, Suez, 43713, Egypt.
| | - Ayah M H Gowifel
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt.
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8
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Chen X, Zhang L, Yu C, Duan A, Jiao B, Chen Y, Dai Y, Li B. The role of HMGB1 on SiC NPs-induced inflammation response in lung epithelial-macrophage co-culture system. Food Chem Toxicol 2024; 190:114762. [PMID: 38871110 DOI: 10.1016/j.fct.2024.114762] [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: 04/23/2024] [Revised: 05/13/2024] [Accepted: 05/22/2024] [Indexed: 06/15/2024]
Abstract
In recent years, carbonized silicon nanoparticles (SiC NPs) have found widespread scientific and engineering applications, raising concerns about potential human health risks. SiC NPs may induce pulmonary damage through sustained inflammatory responses and oxidative stress, with unclear toxicity mechanisms. This study uses an in vitro co-culture model of alveolar macrophages (NR8383) and alveolar epithelial cells (RLE-6TN) to simulate the interaction between airway epithelial cells and immune cells, providing initial insights into SiC NP-triggered inflammatory responses. The research reveals that increasing SiC NP exposure prompts NR8383 cells to release high mobility group box 1 protein (HMGB1), which migrates into RLE-6TN cells and activates the receptor for advanced glycation end-products (RAGE) and Toll-like receptor 4 (TLR4). RAGE and TLR4 synergistically activate the MyD88/NF-κB inflammatory pathway, ultimately inducing inflammatory responses and oxidative stress in RLE-6TN cells, characterized by excessive ROS generation and altered cytokine levels. Pretreatment with RAGE and TLR4 inhibitors attenuates SiC-induced HMGB1 expression and downstream pathway proteins, reducing inflammatory responses and oxidative damage. This highlights the pivotal role of RAGE-TLR4 crosstalk in SiC NP-induced pulmonary inflammation, providing insights into SiC NP cytotoxicity and nanomaterial safety guidelines.
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Affiliation(s)
- Xiao Chen
- State Key Laboratory of Trauma and Chemical Poisoning, National Institute for Occupational and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China
| | - Linyuan Zhang
- State Key Laboratory of Trauma and Chemical Poisoning, National Institute for Occupational and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China
| | - Changyan Yu
- State Key Laboratory of Trauma and Chemical Poisoning, National Institute for Occupational and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China
| | - Airu Duan
- State Key Laboratory of Trauma and Chemical Poisoning, National Institute for Occupational and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China
| | - Bo Jiao
- State Key Laboratory of Trauma and Chemical Poisoning, National Institute for Occupational and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China
| | - Yuanyuan Chen
- Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, 100050, China
| | - Yufei Dai
- State Key Laboratory of Trauma and Chemical Poisoning, National Institute for Occupational and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China; Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, 100050, China.
| | - Bin Li
- State Key Laboratory of Trauma and Chemical Poisoning, National Institute for Occupational and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, 100050, China.
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Yuan J, Guo L, Ma J, Zhang H, Xiao M, Li N, Gong H, Yan M. HMGB1 as an extracellular pro-inflammatory cytokine: Implications for drug-induced organic damage. Cell Biol Toxicol 2024; 40:55. [PMID: 39008169 PMCID: PMC11249443 DOI: 10.1007/s10565-024-09893-2] [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: 02/14/2024] [Accepted: 06/18/2024] [Indexed: 07/16/2024]
Abstract
Drug-induced organic damage encompasses various intricate mechanisms, wherein HMGB1, a non-histone chromosome-binding protein, assumes a significant role as a pivotal hub gene. The regulatory functions of HMGB1 within the nucleus and extracellular milieu are interlinked. HMGB1 exerts a crucial regulatory influence on key biological processes including cell survival, inflammatory regulation, and immune response. HMGB1 can be released extracellularly from the cell during these processes, where it functions as a pro-inflammation cytokine. HMGB1 interacts with multiple cell membrane receptors, primarily Toll-like receptors (TLRs) and receptor for advanced glycation end products (RAGE), to stimulate immune cells and trigger inflammatory response. The excessive or uncontrolled HMGB1 release leads to heightened inflammatory responses and cellular demise, instigating inflammatory damage or exacerbating inflammation and cellular demise in different diseases. Therefore, a thorough review on the significance of HMGB1 in drug-induced organic damage is highly important for the advancement of pharmaceuticals, ensuring their effectiveness and safety in treating inflammation as well as immune-related diseases. In this review, we initially outline the characteristics and functions of HMGB1, emphasizing their relevance in disease pathology. Then, we comprehensively summarize the prospect of HMGB1 as a promising therapeutic target for treating drug-induced toxicity. Lastly, we discuss major challenges and propose potential avenues for advancing the development of HMGB1-based therapeutics.
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Affiliation(s)
- JianYe Yuan
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
- Xiangya School of Medicine, Central South University, Changsha, China
- Department of Pathology, The Eight Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Lin Guo
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
| | - JiaTing Ma
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
| | - HeJian Zhang
- Xiangya School of Medicine, Central South University, Changsha, China
| | - MingXuan Xiao
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
| | - Ning Li
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Hui Gong
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
| | - Miao Yan
- Department of Pharmacy, the Second Xiangya Hospital, Central South University, Changsha, China.
- Institute of Clinical Pharmacy, Central South University, Changsha, China.
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China.
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10
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Baronaitė I, Šulskis D, Kopu̅stas A, Tutkus M, Smirnovas V. Formation of Calprotectin Inhibits Amyloid Aggregation of S100A8 and S100A9 Proteins. ACS Chem Neurosci 2024; 15:1915-1925. [PMID: 38634811 PMCID: PMC11066842 DOI: 10.1021/acschemneuro.4c00093] [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: 02/09/2024] [Revised: 03/31/2024] [Accepted: 04/10/2024] [Indexed: 04/19/2024] Open
Abstract
Calcium-binding S100A8 and S100A9 proteins play a significant role in various disorders due to their pro-inflammatory functions. Substantially, they are also relevant in neurodegenerative disorders via the delivery of signals for the immune response. However, at the same time, they can aggregate and accelerate the progression of diseases. Natively, S100A8 and S100A9 exist as homo- and heterodimers, but upon aggregation, they form amyloid-like oligomers, fibrils, or amorphous aggregates. In this study, we aimed to elucidate the aggregation propensities of S100A8, S100A9, and their heterodimer calprotectin by investigating aggregation kinetics, secondary structures, and morphologies of the aggregates. For the first time, we followed the in vitro aggregation of S100A8, which formed spherical aggregates, unlike the fibrillar structures of S100A9 under the same conditions. The aggregates were sensitive to amyloid-specific ThT and ThS dyes and had a secondary structure composed of β-sheets. Similarly to S100A9, S100A8 protein was stabilized by calcium ions, resulting in aggregation inhibition. Finally, the formation of S100A8 and S100A9 heterodimers stabilized the proteins in the absence of calcium ions and prevented their aggregation.
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Affiliation(s)
- Ieva Baronaitė
- Institute
of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania
| | - Darius Šulskis
- Institute
of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania
| | - Aurimas Kopu̅stas
- Institute
of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania
- Department
of Molecular Compound Physics, Center for
Physical Sciences and Technology, LT- 10257 Vilnius, Lithuania
| | - Marijonas Tutkus
- Institute
of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania
- Department
of Molecular Compound Physics, Center for
Physical Sciences and Technology, LT- 10257 Vilnius, Lithuania
| | - Vytautas Smirnovas
- Institute
of Biotechnology, Life Sciences Center, Vilnius University, LT-10257 Vilnius, Lithuania
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11
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Rojas A, Lindner C, Schneider I, Gonzalez I, Uribarri J. The RAGE Axis: A Relevant Inflammatory Hub in Human Diseases. Biomolecules 2024; 14:412. [PMID: 38672429 PMCID: PMC11048448 DOI: 10.3390/biom14040412] [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: 03/04/2024] [Revised: 03/21/2024] [Accepted: 03/25/2024] [Indexed: 04/28/2024] Open
Abstract
In 1992, a transcendental report suggested that the receptor of advanced glycation end-products (RAGE) functions as a cell surface receptor for a wide and diverse group of compounds, commonly referred to as advanced glycation end-products (AGEs), resulting from the non-enzymatic glycation of lipids and proteins in response to hyperglycemia. The interaction of these compounds with RAGE represents an essential element in triggering the cellular response to proteins or lipids that become glycated. Although initially demonstrated for diabetes complications, a growing body of evidence clearly supports RAGE's role in human diseases. Moreover, the recognizing capacities of this receptor have been extended to a plethora of structurally diverse ligands. As a result, it has been acknowledged as a pattern recognition receptor (PRR) and functionally categorized as the RAGE axis. The ligation to RAGE leads the initiation of a complex signaling cascade and thus triggering crucial cellular events in the pathophysiology of many human diseases. In the present review, we intend to summarize basic features of the RAGE axis biology as well as its contribution to some relevant human diseases such as metabolic diseases, neurodegenerative, cardiovascular, autoimmune, and chronic airways diseases, and cancer as a result of exposure to AGEs, as well as many other ligands.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile; (A.R.); (I.G.)
| | - Cristian Lindner
- Department of Radiology, Faculty of Medicine, University of Concepción, Concepción 4030000, Chile;
| | - Ivan Schneider
- Centre of Primary Attention, South Metropolitan Health Service, Santiago 3830000, Chile;
| | - Ileana Gonzalez
- Biomedical Research Laboratories, Faculty of Medicine, Catholic University of Maule, Talca 34600000, Chile; (A.R.); (I.G.)
| | - Jaime Uribarri
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10021, USA
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12
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Araldi D, Khomula EV, Bonet IJM, Bogen O, Green PG, Levine JD. Role of pattern recognition receptors in chemotherapy-induced neuropathic pain. Brain 2024; 147:1025-1042. [PMID: 37787114 PMCID: PMC10907096 DOI: 10.1093/brain/awad339] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 07/25/2023] [Accepted: 09/12/2023] [Indexed: 10/04/2023] Open
Abstract
Progress in the development of effective chemotherapy is producing a growing population of patients with acute and chronic painful chemotherapy-induced peripheral neuropathy (CIPN), a serious treatment-limiting side effect for which there is currently no US Food and Drug Administration-approved treatment. CIPNs induced by diverse classes of chemotherapy drugs have remarkably similar clinical presentations, leading to the suggestion they share underlying mechanisms. Sensory neurons share with immune cells the ability to detect damage associated molecular patterns (DAMPs), molecules produced by diverse cell types in response to cellular stress and injury, including by chemotherapy drugs. DAMPs, in turn, are ligands for pattern recognition receptors (PRRs), several of which are found on sensory neurons, as well as satellite cells, and cells of the immune system. In the present experiments, we evaluated the role of two PRRs, TLR4 and RAGE, present in dorsal root ganglion (DRG), in CIPN. Antisense (AS)-oligodeoxynucleotides (ODN) against TLR4 and RAGE mRNA were administered intrathecally before ('prevention protocol') or 3 days after ('reversal protocol') the last administration of each of three chemotherapy drugs that treat cancer by different mechanisms (oxaliplatin, paclitaxel and bortezomib). TLR4 and RAGE AS-ODN prevented the development of CIPN induced by all three chemotherapy drugs. In the reversal protocol, however, while TLR4 AS-ODN completely reversed oxaliplatin- and paclitaxel-induced CIPN, in rats with bortezomib-induced CIPN it only produced a temporary attenuation. RAGE AS-ODN, in contrast, reversed CIPN induced by all three chemotherapy drugs. When a TLR4 antagonist was administered intradermally to the peripheral nociceptor terminal, it did not affect CIPN induced by any of the chemotherapy drugs. However, when administered intrathecally, to the central terminal, it attenuated hyperalgesia induced by all three chemotherapy drugs, compatible with a role of TLR4 in neurotransmission at the central terminal but not sensory transduction at the peripheral terminal. Finally, since it has been established that cultured DRG neurons can be used to study direct effects of chemotherapy on nociceptors, we also evaluated the role of TLR4 in CIPN at the cellular level, using patch-clamp electrophysiology in DRG neurons cultured from control and chemotherapy-treated rats. We found that increased excitability of small-diameter DRG neurons induced by in vivo and in vitro exposure to oxaliplatin is TLR4-dependent. Our findings suggest that in addition to the established contribution of PRR-dependent neuroimmune mechanisms, PRRs in DRG cells also have an important role in CIPN.
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Affiliation(s)
- Dionéia Araldi
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Eugen V Khomula
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Ivan J M Bonet
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Oliver Bogen
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Paul G Green
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
- Department of Preventative and Restorative Dental Sciences, Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Jon D Levine
- Department of Oral and Maxillofacial Surgery, UCSF Pain and Addiction Research Center, University of California at San Francisco, San Francisco, CA 94143, USA
- Department of Medicine, Division of Neuroscience, University of California at San Francisco, San Francisco, CA 94143, USA
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13
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Fan A, Gao M, Tang X, Jiao M, Wang C, Wei Y, Gong Q, Zhong J. HMGB1/RAGE axis in tumor development: unraveling its significance. Front Oncol 2024; 14:1336191. [PMID: 38529373 PMCID: PMC10962444 DOI: 10.3389/fonc.2024.1336191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 02/15/2024] [Indexed: 03/27/2024] Open
Abstract
High mobility group protein 1 (HMGB1) plays a complex role in tumor biology. When released into the extracellular space, it binds to the receptor for advanced glycation end products (RAGE) located on the cell membrane, playing an important role in tumor development by regulating a number of biological processes and signal pathways. In this review, we outline the multifaceted functions of the HMGB1/RAGE axis, which encompasses tumor cell proliferation, apoptosis, autophagy, metastasis, and angiogenesis. This axis is instrumental in tumor progression, promoting tumor cell proliferation, autophagy, metastasis, and angiogenesis while inhibiting apoptosis, through pivotal signaling pathways, including MAPK, NF-κB, PI3K/AKT, ERK, and STAT3. Notably, small molecules, such as miRNA-218, ethyl pyruvate (EP), and glycyrrhizin exhibit the ability to inhibit the HMGB1/RAGE axis, restraining tumor development. Therefore, a deeper understanding of the mechanisms of the HMGB1/RAGE axis in tumors is of great importance, and the development of inhibitors targeting this axis warrants further exploration.
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Affiliation(s)
- Anqi Fan
- College of Life Science, Yangtze University, Jingzhou, Hubei, China
| | - Mengxiang Gao
- College of Life Science, Yangtze University, Jingzhou, Hubei, China
| | - Xuhuan Tang
- Department of Immunology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Mengya Jiao
- Department of Immunology, School of Basic Medicine, Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonostic Infectious Disease, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chenchen Wang
- National Demonstration Center for Experimental Basic Medical Education, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yingying Wei
- Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Quan Gong
- Department of Immunology, School of Medicine, Yangtze University, Jingzhou, Hubei, China
| | - Jixin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
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14
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Govindarajah V, Sakabe M, Good S, Solomon M, Arasu A, Chen N, Zhang X, Grimes HL, Kendler A, Xin M, Reynaud D. Gestational diabetes in mice induces hematopoietic memory that affects the long-term health of the offspring. J Clin Invest 2024; 134:e169730. [PMID: 37988162 PMCID: PMC10786695 DOI: 10.1172/jci169730] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 11/16/2023] [Indexed: 11/23/2023] Open
Abstract
Gestational diabetes is a common medical complication of pregnancy that is associated with adverse perinatal outcomes and an increased risk of metabolic diseases and atherosclerosis in adult offspring. The mechanisms responsible for this delayed pathological transmission remain unknown. In mouse models, we found that the development of atherosclerosis in adult offspring born to diabetic pregnancy can be in part linked to hematopoietic alterations. Although they do not show any gross metabolic disruptions, the adult offspring maintain hematopoietic features associated with diabetes, indicating the acquisition of a lasting diabetic hematopoietic memory. We show that the induction of this hematopoietic memory during gestation relies on the activity of the advanced glycation end product receptor (AGER) and the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which lead to increased placental inflammation. In adult offspring, we find that this memory is associated with DNA methyltransferase 1 (DNMT1) upregulation and epigenetic changes in hematopoietic progenitors. Together, our results demonstrate that the hematopoietic system can acquire a lasting memory of gestational diabetes and that this memory constitutes a pathway connecting gestational health to adult pathologies.
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Affiliation(s)
| | | | - Samantha Good
- Division of Experimental Hematology and Cancer Biology and
| | | | - Ashok Arasu
- Division of Experimental Hematology and Cancer Biology and
| | - Nong Chen
- Division of Experimental Hematology and Cancer Biology and
| | - Xuan Zhang
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA
| | - H. Leighton Grimes
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center (CCHMC), Cincinnati, Ohio, USA
- Department of Pediatrics and
| | - Ady Kendler
- Department of Pathology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Mei Xin
- Division of Experimental Hematology and Cancer Biology and
- Department of Pediatrics and
| | - Damien Reynaud
- Division of Experimental Hematology and Cancer Biology and
- Department of Pediatrics and
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15
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Rubas NC, Peres R, Kunihiro BP, Allan NP, Phankitnirundorn K, Wells RK, McCracken T, Lee RH, Umeda L, Conching A, Juarez R, Maunakea AK. HMGB1 mediates microbiome-immune axis dysregulation underlying reduced neutralization capacity in obesity-related post-acute sequelae of SARS-CoV-2. Sci Rep 2024; 14:355. [PMID: 38172612 PMCID: PMC10764757 DOI: 10.1038/s41598-023-50027-1] [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: 05/23/2023] [Accepted: 12/14/2023] [Indexed: 01/05/2024] Open
Abstract
While obesity is a risk factor for post-acute sequelae of SARS-CoV-2 infection (PASC, "long-COVID"), the mechanism(s) underlying this phenomenon remains poorly understood. To address this gap in knowledge, we performed a 6-week longitudinal study to examine immune activity and gut microbiome dysbiosis in post-acute stage patients recovering from SARS-CoV-2 infection. Self-reported symptom frequencies and blood samples were collected weekly, with plasma assessed by ELISA and Luminex for multiple biomarkers and immune cell profiling. DNA from stool samples were collected at the early stage of recovery for baseline assessments of gut microbial composition and diversity using 16S-based metagenomic sequencing. Multiple regression analyses revealed obesity-related PASC linked to a sustained proinflammatory immune profile and reduced adaptive immunity, corresponding with reduced gut microbial diversity. In particular, enhanced signaling of the high mobility group box 1 (HMGB1) protein was found to associate with this dysregulation, with its upregulated levels in plasma associated with significantly impaired viral neutralization that was exacerbated with obesity. These findings implicate HMGB1 as a candidate biomarker of PASC, with potential applications for risk assessment and targeted therapies.
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Affiliation(s)
- Noelle C Rubas
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
- Deparment of Molecular Biosciences and Bioengineering, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Rafael Peres
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Braden P Kunihiro
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Nina P Allan
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Krit Phankitnirundorn
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Riley K Wells
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
- Deparment of Molecular Biosciences and Bioengineering, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Trevor McCracken
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Rosa H Lee
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Lesley Umeda
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA
- Deparment of Molecular Biosciences and Bioengineering, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | | | - Ruben Juarez
- Hawai'i Integrated Analytics, Honolulu, HI, USA
- Deparment of Economics and UHERO, University of Hawai'i at Mānoa, Honolulu, HI, USA
| | - Alika K Maunakea
- Department of Biochemistry, Anatomy, and Physiology, University of Hawai'i at Mānoa, Honolulu, HI, USA.
- Hawai'i Integrated Analytics, Honolulu, HI, USA.
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16
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Yang Q, Li M, Hou Y, He H, Sun S. High-mobility group box 1 emerges as a therapeutic target for asthma. Immun Inflamm Dis 2023; 11:e1124. [PMID: 38156383 PMCID: PMC10739362 DOI: 10.1002/iid3.1124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/22/2023] [Accepted: 11/23/2023] [Indexed: 12/30/2023] Open
Abstract
High-mobility group box 1 (HMGB1) is a highly conserved nonhistone nuclear protein found in the calf thymus and participates in a variety of intracellular processes such as DNA transcription, replication and repair. In the cytoplasm, HMGB1 promotes mitochondrial autophagy and is involved in in cellular stress response. Once released into the extracellular, HMGB1 becomes an inflammatory factor that triggers inflammatory responses and a variety of immune responses. In addition, HMGB1 binding with the corresponding receptor can activate the downstream substrate to carry out several biological effects. Meanwhile, HMGB1 is involved in various signaling pathways, such as the HMGB1/RAGE pathway, HMGB1/NF-κB pathway, and HMGB1/JAK/STAT pathway, which ultimately promote inflammation. Moreover, HMGB1 may be involved in the pathogenesis of asthma by regulating downstream signaling pathways through corresponding receptors and mediates a number of signaling pathways in asthma, such as HMGB1/TLR4/NF-κB, HMGB1/RAGE, HMGB1/TGF-β, and so forth. Accordingly, HMGB1 emerges as a therapeutic target for asthma.
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Affiliation(s)
- Qianni Yang
- Department of Pulmonary and Critical Care MedicineFirst Affiliated Hospital, Kunming Medical UniversityKunmingChina
- 2021 Class 2 of AnesthesiologyKunming Medical UniversityKunmingChina
| | - Min Li
- Department of Pulmonary and Critical Care MedicineFirst Affiliated Hospital, Kunming Medical UniversityKunmingChina
| | - Yunjiao Hou
- Department of Pulmonary and Critical Care MedicineFirst Affiliated Hospital, Kunming Medical UniversityKunmingChina
| | - Huilin He
- Department of Pulmonary and Critical Care MedicineFirst Affiliated Hospital, Kunming Medical UniversityKunmingChina
| | - Shibo Sun
- Department of Pulmonary and Critical Care MedicineFirst Affiliated Hospital, Kunming Medical UniversityKunmingChina
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17
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Curren B, Ahmed T, Howard DR, Ashik Ullah M, Sebina I, Rashid RB, Al Amin Sikder M, Namubiru P, Bissell A, Ngo S, Jackson DJ, Toussaint M, Edwards MR, Johnston SL, McSorley HJ, Phipps S. IL-33-induced neutrophilic inflammation and NETosis underlie rhinovirus-triggered exacerbations of asthma. Mucosal Immunol 2023; 16:671-684. [PMID: 37506849 DOI: 10.1016/j.mucimm.2023.07.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 06/04/2023] [Accepted: 07/19/2023] [Indexed: 07/30/2023]
Abstract
Rhinovirus-induced neutrophil extracellular traps (NETs) contribute to acute asthma exacerbations; however, the molecular factors that trigger NETosis in this context remain ill-defined. Here, we sought to implicate a role for IL-33, an epithelial cell-derived alarmin rapidly released in response to infection. In mice with chronic experimental asthma (CEA), but not naïve controls, rhinovirus inoculation induced an early (1 day post infection; dpi) inflammatory response dominated by neutrophils, neutrophil-associated cytokines (IL-1α, IL-1β, CXCL1), and NETosis, followed by a later, type-2 inflammatory phase (3-7 dpi), characterised by eosinophils, elevated IL-4 levels, and goblet cell hyperplasia. Notably, both phases were ablated by HpARI (Heligmosomoides polygyrus Alarmin Release Inhibitor), which blocks IL-33 release and signalling. Instillation of exogenous IL-33 recapitulated the rhinovirus-induced early phase, including the increased presence of NETs in the airway mucosa, in a PAD4-dependent manner. Ex vivo IL-33-stimulated neutrophils from mice with CEA, but not naïve mice, underwent NETosis and produced greater amounts of IL-1α/β, IL-4, and IL-5. In nasal samples from rhinovirus-infected people with asthma, but not healthy controls, IL-33 levels correlated with neutrophil elastase and dsDNA. Our findings suggest that IL-33 blockade ameliorates the severity of an asthma exacerbation by attenuating neutrophil recruitment and the downstream generation of NETs.
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Affiliation(s)
- Bodie Curren
- QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia; School of Biomedical Sciences, The University of Queensland, Queensland 4072, Australia
| | - Tufael Ahmed
- QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia; School of Biomedical Sciences, Queensland University of Technology, Queensland 4000, Australia
| | - Daniel R Howard
- QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia; School of Biomedical Sciences, The University of Queensland, Queensland 4072, Australia
| | - Md Ashik Ullah
- QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
| | - Ismail Sebina
- QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia; School of Biomedical Sciences, The University of Queensland, Queensland 4072, Australia; School of Biomedical Sciences, Queensland University of Technology, Queensland 4000, Australia
| | - Ridwan B Rashid
- QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia; School of Biomedical Sciences, The University of Queensland, Queensland 4072, Australia
| | - Md Al Amin Sikder
- QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia; School of Biomedical Sciences, The University of Queensland, Queensland 4072, Australia
| | - Patricia Namubiru
- QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia; School of Biomedical Sciences, The University of Queensland, Queensland 4072, Australia
| | - Alec Bissell
- QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
| | - Sylvia Ngo
- QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia
| | - David J Jackson
- School of Immunology & Microbial Sciences, King's College London, London, UK; National Heart and Lung Institute, Imperial College London, London, UK
| | - Marie Toussaint
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Michael R Edwards
- National Heart and Lung Institute, Imperial College London, London, UK
| | | | - Henry J McSorley
- Division of Cell Signalling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK
| | - Simon Phipps
- QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia; School of Biomedical Sciences, The University of Queensland, Queensland 4072, Australia; School of Biomedical Sciences, Queensland University of Technology, Queensland 4000, Australia; Australian Infectious Diseases Research Centre, The University of Queensland, 4072 Queensland, Australia.
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18
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Richards CM, McRae SA, Ranger AL, Klegeris A. Extracellular histones as damage-associated molecular patterns in neuroinflammatory responses. Rev Neurosci 2023; 34:533-558. [PMID: 36368030 DOI: 10.1515/revneuro-2022-0091] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 10/18/2022] [Indexed: 07/20/2023]
Abstract
The four core histones H2A, H2B, H3, H4, and the linker histone H1 primarily bind DNA and regulate gene expression within the nucleus. Evidence collected mainly from the peripheral tissues illustrates that histones can be released into the extracellular space by activated or damaged cells. In this article, we first summarize the innate immune-modulatory properties of extracellular histones and histone-containing complexes, such as nucleosomes, and neutrophil extracellular traps (NETs), described in peripheral tissues. There, histones act as damage-associated molecular patterns (DAMPs), which are a class of endogenous molecules that trigger immune responses by interacting directly with the cellular membranes and activating pattern recognition receptors (PRRs), such as toll-like receptors (TLR) 2, 4, 9 and the receptor for advanced glycation end-products (RAGE). We then focus on the available evidence implicating extracellular histones as DAMPs of the central nervous system (CNS). It is becoming evident that histones are present in the brain parenchyma after crossing the blood-brain barrier (BBB) or being released by several types of brain cells, including neurons, microglia, and astrocytes. However, studies on the DAMP-like effects of histones on CNS cells are limited. For example, TLR4 is the only known molecular target of CNS extracellular histones and their interactions with other PRRs expressed by brain cells have not been observed. Nevertheless, extracellular histones are implicated in the pathogenesis of a variety of neurological disorders characterized by sterile neuroinflammation; therefore, detailed studies on the role these proteins and their complexes play in these pathologies could identify novel therapeutic targets.
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Affiliation(s)
- Christy M Richards
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna V1V 1V7, BC, Canada
| | - Seamus A McRae
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna V1V 1V7, BC, Canada
| | - Athena L Ranger
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna V1V 1V7, BC, Canada
| | - Andis Klegeris
- Department of Biology, University of British Columbia Okanagan Campus, Kelowna V1V 1V7, BC, Canada
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19
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Vo TTT, Kong G, Kim C, Juang U, Gwon S, Jung W, Nguyen H, Kim SH, Park J. Exploring scavenger receptor class F member 2 and the importance of scavenger receptor family in prediagnostic diseases. Toxicol Res 2023; 39:341-353. [PMID: 37398563 PMCID: PMC10313632 DOI: 10.1007/s43188-023-00176-2] [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] [Received: 12/31/2022] [Revised: 03/09/2023] [Accepted: 03/14/2023] [Indexed: 07/04/2023] Open
Abstract
Scavenger Receptor Class F Member 2 (SCARF2), also known as the Type F Scavenger Receptor Family gene, encodes for Scavenger Receptor Expressed by Endothelial Cells 2 (SREC-II). This protein is a crucial component of the scavenger receptor family and is vital in protecting mammals from infectious diseases. Although research on SCARF2 is limited, mutations in this protein have been shown to cause skeletal abnormalities in both SCARF2-deficient mice and individuals with Van den Ende-Gupta syndrome (VDEGS), which is also associated with SCARF2 mutations. In contrast, other scavenger receptors have demonstrated versatile responses and have been found to aid in pathogen elimination, lipid transportation, intracellular cargo transportation, and work in tandem with various coreceptors. This review will concentrate on recent progress in comprehending SCARF2 and the functions played by members of the Scavenger Receptor Family in pre-diagnostic diseases.
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Affiliation(s)
- Thuy-Trang T. Vo
- Department of Pharmacology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015 Republic of Korea
- Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015 Republic of Korea
| | - Gyeyeong Kong
- Department of Pharmacology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015 Republic of Korea
- Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015 Republic of Korea
| | - Chaeyeong Kim
- Department of Pharmacology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015 Republic of Korea
- Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015 Republic of Korea
| | - Uijin Juang
- Department of Pharmacology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015 Republic of Korea
- Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015 Republic of Korea
| | - Suhwan Gwon
- Department of Pharmacology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015 Republic of Korea
- Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015 Republic of Korea
| | - Woohyeong Jung
- Department of Pharmacology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015 Republic of Korea
- Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015 Republic of Korea
| | - Huonggiang Nguyen
- Department of Pharmacology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015 Republic of Korea
- Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015 Republic of Korea
| | - Seon-Hwan Kim
- Department of Neurosurgery, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015 Republic of Korea
| | - Jongsun Park
- Department of Pharmacology, College of Medicine, Chungnam National University, 266 Munhwa-ro, Jung-gu, Daejeon, 35015 Republic of Korea
- Department of Medical Science, Metabolic Syndrome and Cell Signaling Laboratory, Institute for Cancer Research, College of Medicine, Chungnam National University, Daejeon, 35015 Republic of Korea
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20
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Takami Y, Tanaka M, Izawa T, Kuwamura M, Yamate J. The effect of lipopolysaccharide on liver homeostasis and diseases based on the mutual interaction of macrophages, autophagy, and damage-associated molecular patterns in male F344/DuCrlCrlj rats. Vet Pathol 2023; 60:461-472. [PMID: 37199489 DOI: 10.1177/03009858231173364] [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: 05/19/2023]
Abstract
Lipopolysaccharide (LPS) has dose-dependent biphasic functions (cell protective versus cell toxic). To clarify the different effects of LPS on liver homeostasis or liver diseases, comparisons were made between low and high doses of LPS, in terms of the mutual relation of hepatic macrophages, autophagy, and damage-associated molecular patterns (DAMPs) in male F344/DuCrlCrlj rats. Rats injected with low dose (0.1 mg/kg) or high dose (2.0 mg/kg) of LPS were examined at 6, 10, and 24 hours following single injections. Histologically, focal hepatocellular necrosis was occasionally present in high-dose animals, whereas there were no significant changes in low-dose animals. In low-dose animals, Kupffer cells reacting to CD163 and CD204 were hypertrophic and regarded as M2 macrophages, which promote resolution of inflammation and tissue repair, whereas in high-dose animals, infiltration of M1 macrophages expressing CD68 and major histocompatibility complex class II, which enhance cell injury, was seen. Hepatocytes with high-mobility-group box-1 (HMGB1) (one of DAMPs)-positive cytoplasmic granules appeared more frequently in high-dose animals than in low-dose animals, indicating the translocation of nuclear HMGB1 into the cytoplasm. However, although light-chain 3 beta-positive autophagosomes in hepatocytes increased in both doses, abnormally vacuolated autophagosomes were only seen in injured hepatocytes in the high-dose group, indicating possible extracellular release of HMGB1, which might result in cell injury and inflammation. These findings suggested that low-dose LPS induced a favorable mutual relationship among hepatic macrophages, autophagy, and DAMPs leading to cytoprotection of hepatocytes, whereas failures of the relationship in high-dose LPS caused hepatocyte injury.
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Affiliation(s)
- Yuki Takami
- Osaka Metropolitan University, Izumisano, Japan
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21
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Oseni SO, Naar C, Pavlović M, Asghar W, Hartmann JX, Fields GB, Esiobu N, Kumi-Diaka J. The Molecular Basis and Clinical Consequences of Chronic Inflammation in Prostatic Diseases: Prostatitis, Benign Prostatic Hyperplasia, and Prostate Cancer. Cancers (Basel) 2023; 15:3110. [PMID: 37370720 DOI: 10.3390/cancers15123110] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 05/23/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023] Open
Abstract
Chronic inflammation is now recognized as one of the major risk factors and molecular hallmarks of chronic prostatitis, benign prostatic hyperplasia (BPH), and prostate tumorigenesis. However, the molecular mechanisms by which chronic inflammation signaling contributes to the pathogenesis of these prostate diseases are poorly understood. Previous efforts to therapeutically target the upstream (e.g., TLRs and IL1-Rs) and downstream (e.g., NF-κB subunits and cytokines) inflammatory signaling molecules in people with these conditions have been clinically ambiguous and unsatisfactory, hence fostering the recent paradigm shift towards unraveling and understanding the functional roles and clinical significance of the novel and relatively underexplored inflammatory molecules and pathways that could become potential therapeutic targets in managing prostatic diseases. In this review article, we exclusively discuss the causal and molecular drivers of prostatitis, BPH, and prostate tumorigenesis, as well as the potential impacts of microbiome dysbiosis and chronic inflammation in promoting prostate pathologies. We specifically focus on the importance of some of the underexplored druggable inflammatory molecules, by discussing how their aberrant signaling could promote prostate cancer (PCa) stemness, neuroendocrine differentiation, castration resistance, metabolic reprogramming, and immunosuppression. The potential contribution of the IL1R-TLR-IRAK-NF-κBs signaling molecules and NLR/inflammasomes in prostate pathologies, as well as the prospective benefits of selectively targeting the midstream molecules in the various inflammatory cascades, are also discussed. Though this review concentrates more on PCa, we envision that the information could be applied to other prostate diseases. In conclusion, we have underlined the molecular mechanisms and signaling pathways that may need to be targeted and/or further investigated to better understand the association between chronic inflammation and prostate diseases.
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Affiliation(s)
- Saheed Oluwasina Oseni
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
| | - Corey Naar
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Mirjana Pavlović
- Department of Computer and Electrical Engineering, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Waseem Asghar
- Department of Computer and Electrical Engineering, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - James X Hartmann
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Gregg B Fields
- Department of Chemistry & Biochemistry, and I-HEALTH, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - Nwadiuto Esiobu
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
| | - James Kumi-Diaka
- Department of Biological Sciences, Florida Atlantic University, Boca Raton, FL 33431, USA
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22
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Reynaert NL, Vanfleteren LEGW, Perkins TN. The AGE-RAGE Axis and the Pathophysiology of Multimorbidity in COPD. J Clin Med 2023; 12:jcm12103366. [PMID: 37240472 DOI: 10.3390/jcm12103366] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 04/24/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a disease of the airways and lungs due to an enhanced inflammatory response, commonly caused by cigarette smoking. Patients with COPD are often multimorbid, as they commonly suffer from multiple chronic (inflammatory) conditions. This intensifies the burden of individual diseases, negatively affects quality of life, and complicates disease management. COPD and comorbidities share genetic and lifestyle-related risk factors and pathobiological mechanisms, including chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) is an important driver of chronic inflammation. Advanced glycation end products (AGEs) are RAGE ligands that accumulate due to aging, inflammation, oxidative stress, and carbohydrate metabolism. AGEs cause further inflammation and oxidative stress through RAGE, but also through RAGE-independent mechanisms. This review describes the complexity of RAGE signaling and the causes of AGE accumulation, followed by a comprehensive overview of alterations reported on AGEs and RAGE in COPD and in important co-morbidities. Furthermore, it describes the mechanisms by which AGEs and RAGE contribute to the pathophysiology of individual disease conditions and how they execute crosstalk between organ systems. A section on therapeutic strategies that target AGEs and RAGE and could alleviate patients from multimorbid conditions using single therapeutics concludes this review.
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Affiliation(s)
- Niki L Reynaert
- Department of Respiratory Medicine, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, 6229 ER Maastricht, The Netherlands
| | - Lowie E G W Vanfleteren
- COPD Center, Department of Respiratory Medicine and Allergology, Sahlgrenska University Hospital, 413 45 Gothenburg, Sweden
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden
| | - Timothy N Perkins
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
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23
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Yan L, Li Y, Tan T, Qi J, Fang J, Guo H, Ren Z, Gou L, Geng Y, Cui H, Shen L, Yu S, Wang Z, Zuo Z. RAGE-TLR4 Crosstalk Is the Key Mechanism by Which High Glucose Enhances the Lipopolysaccharide-Induced Inflammatory Response in Primary Bovine Alveolar Macrophages. Int J Mol Sci 2023; 24:ijms24087007. [PMID: 37108174 PMCID: PMC10138623 DOI: 10.3390/ijms24087007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/04/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
The receptor of advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4) are important receptors for inflammatory responses induced by high glucose (HG) and lipopolysaccharide (LPS) and show crosstalk phenomena in inflammatory responses. However, it is unknown whether RAGE and TLR4 can influence each other's expression through a crosstalk mechanism and whether the RAGE-TLR4 crosstalk related to the molecular mechanism of HG enhances the LPS-induced inflammatory response. In this study, the implications of LPS with multiple concentrations (0, 1, 5, and 10 μg/mL) at various treatment times (0, 3, 6, 12, and 24 h) in primary bovine alveolar macrophages (BAMs) were explored. The results showed that a 5 μg/mL LPS treatment at 12 h had the most significant increment on the pro-inflammatory cytokine interleukin 1β (IL-1β), IL-6, and tumor necrosis factor (TNF)-α levels in BAMs (p < 0.05) and that the levels of TLR4, RAGE, MyD88, and NF-κB p65 mRNA and protein expression were upregulated (p < 0.05). Then, the effect of LPS (5 μg/mL) and HG (25.5 mM) co-treatment in BAMs was explored. The results further showed that HG significantly enhanced the release of IL-1β, IL-6, and TNF-α caused by LPS in the supernatant (p < 0.01) and significantly increased the levels of RAGE, TLR4, MyD88, and NF-κB p65 mRNA and protein expression (p < 0.01). Pretreatment with FPS-ZM1 and TAK-242, the inhibitors of RAGE and TLR4, significantly alleviated the HG + LPS-induced increment of RAGE, TLR4, MyD88, and NF-κB p65 mRNA and protein expression in the presence of HG and LPS (p < 0.01). This study showed that RAGE and TLR4 affect each other's expression through crosstalk during the combined usage of HG and LPS and synergistically activate the MyD88/NF-κB signaling pathway to promote the release of pro-inflammatory cytokines in BAMs.
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Affiliation(s)
- Longfei Yan
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Yanran Li
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Tianyu Tan
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Jiancheng Qi
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Jing Fang
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Hongrui Guo
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Zhihua Ren
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Liping Gou
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Yi Geng
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Hengmin Cui
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Liuhong Shen
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Shumin Yu
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
| | - Zhisheng Wang
- Institute of Animal Nutrition, Sichuan Agricultural University, Chengdu 611134, China
| | - Zhicai Zuo
- College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611134, China
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24
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An D, Qi X, Li K, Xu W, Wang Y, Chen X, Sha S, Wu C, Du Y, Chen L. Blockage of TRPV4 Downregulates the Nuclear Factor-Kappa B Signaling Pathway to Inhibit Inflammatory Responses and Neuronal Death in Mice with Pilocarpine-Induced Status Epilepticus. Cell Mol Neurobiol 2023; 43:1283-1300. [PMID: 35840809 PMCID: PMC11414440 DOI: 10.1007/s10571-022-01249-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 06/25/2022] [Indexed: 11/03/2022]
Abstract
The blockage of transient receptor potential vanilloid 4 (TRPV4) inhibits inflammation and reduces hippocampal neuronal injury in a pilocarpine-induced mouse model of temporal lobe epilepsy. However, the underlying mechanisms remain largely unclear. NF-κB signaling pathway is responsible for the inflammation and neuronal injury during epilepsy. Here, we explored whether TRPV4 blockage could affect the NF-κB pathway in mice with pilocarpine-induced status epilepticus (PISE). Application of a TRPV4 antagonist markedly attenuated the PISE-induced increase in hippocampal HMGB1, TLR4, phospho (p)-IκK (p-IκK), and p-IκBα protein levels, as well as those of cytoplasmic p-NF-κB p65 (p-p65) and nuclear NF-κB p65 and p50; in contrast, the application of GSK1016790A, a TRPV4 agonist, showed similar changes to PISE mice. Administration of the TLR4 antagonist TAK-242 or the NF-κB pathway inhibitor BAY 11-7082 led to a noticeable reduction in the hippocampal protein levels of cleaved IL-1β, IL-6 and TNF, as well as those of cytoplasmic p-p65 and nuclear p65 and p50 in GSK1016790A-injected mice. Finally, administration of either TAK-242 or BAY 11-7082 greatly increased neuronal survival in hippocampal CA1 and CA2/3 regions in GSK1016790A-injected mice. Therefore, TRPV4 activation increases HMGB1 and TLR4 expression, leading to IκK and IκBα phosphorylation and, consequently, NF-κB activation and nuclear translocation. The resulting increase in pro-inflammatory cytokine production is responsible for TRPV4 activation-induced neuronal injury. We conclude that blocking TRPV4 can downregulate HMGB1/TLR4/IκK/κBα/NF-κB signaling following PISE onset, an effect that may underlie the anti-inflammatory response and neuroprotective ability of TRPV4 blockage in mice with PISE.
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Affiliation(s)
- Dong An
- Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China
- Center for Analysis and Testing, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiuting Qi
- Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Kunpeng Li
- Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Weixing Xu
- Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Yue Wang
- Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xi Chen
- Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Sha Sha
- Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China
| | - Chunfeng Wu
- Department of Neurology, Children's Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Yimei Du
- Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
| | - Lei Chen
- Department of Physiology, Nanjing Medical University, Nanjing, People's Republic of China.
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25
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Rojas A, Lindner C, Schneider I, González I, Morales MA. Contributions of the receptor for advanced glycation end products axis activation in gastric cancer. World J Gastroenterol 2023; 29:997-1010. [PMID: 36844144 PMCID: PMC9950863 DOI: 10.3748/wjg.v29.i6.997] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/26/2022] [Accepted: 01/11/2023] [Indexed: 02/10/2023] Open
Abstract
Compelling shreds of evidence derived from both clinical and experimental research have demonstrated the crucial contribution of receptor for advanced glycation end products (RAGE) axis activation in the development of neoplasms, including gastric cancer (GC). This new actor in tumor biology plays an important role in the onset of a crucial and long-lasting inflammatory milieu, not only by supporting phenotypic changes favoring growth and dissemination of tumor cells, but also by functioning as a pattern-recognition receptor in the inflammatory response to Helicobacter pylori infection. In the present review, we aim to highlight how the overexpression and activation of the RAGE axis contributes to the proliferation and survival of GC cells as and their acquisition of more invasive phenotypes that promote dissemination and metastasis. Finally, the contribution of some single nucleotide polymorphisms in the RAGE gene as susceptibility or poor prognosis factors is also discussed.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Cristian Lindner
- Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Iván Schneider
- Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Ileana González
- Biomedical Research Laboratories, Medicine Faculty, Catholic University of Maule, Talca 34600000, Chile
| | - Miguel Angel Morales
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, University of Chile, Santiago 8320000, Chile
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26
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MiR-146a-5p Contributes to Microglial Polarization Transitions Associated With AGEs. Mol Neurobiol 2023; 60:3020-3033. [PMID: 36780120 DOI: 10.1007/s12035-023-03252-8] [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: 09/04/2022] [Accepted: 01/30/2023] [Indexed: 02/14/2023]
Abstract
M1/M2 polarization transitions of microglial phenotypes determine the states of neuroinflammation, which is critical in the pathophysiology of diabetic encephalopathy. This study aims to investigate the effects of advanced glycation end products (AGEs) on the microglial polarization state, the role of miR-146a-5p in the regulation of microglial polarization, and the underlying signaling pathways. BV-2 cells were incubated with N-ε-carboxymethyl lysine (CML), one kind of Advanced Glycation End Products (AGEs), to induce polarization. CD11b and iNOS and CD206 and Arg-1 were used to evaluate M1 and M2 microglia, respectively. The mRNA and protein expression levels of miR-146a-5p, transcription factor NF-κB, and inflammasome NLRP3 were measured. High and low expression of miR-146a-5p in the BV-2 cell line was generated by lentivirus transfection technology. RAGE, TLR-4, and NF-κB antagonists were applied to evaluate the underlying signaling pathways. Compared with the control group, CML upregulated the M1 phenotype and downregulated the M2 phenotype. These effects were reversed by overexpression of miR-146a. Furthermore, the expression of inflammasome NLRP3 and NF-κB was upregulated in the CML group and was reduced after miR-146a overexpression. And then overexpression of miR-146a effects was reversed by inhibition miR-146a expression. An NF-κB antagonist (PDTC), a RAGE antagonist (FPS-ZMI), and a TLR-4 antagonist (TLI-095) all reversed the polarization state induced by CML. In summary, CML induced polarization transitions to M1 phenotype and promoted inflammasome NLRP3 expression in BV-2 cells. The RAGE or TLR-4/miR-146a/NLRP3/NF-кB pathway might participate in the regulation of CML-induced BV-2 polarization.
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27
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Bigagli E, D’Ambrosio M, Cinci L, Fiorindi C, Agostiniani S, Bruscoli E, Nannoni A, Lodovici M, Scaringi S, Giudici F, Luceri C. Impact of Preoperative Immunonutrition on Oxidative Stress and Gut Barrier Function in Surgical Patients with Crohn's Disease. Nutrients 2023; 15:nu15040882. [PMID: 36839239 PMCID: PMC9960923 DOI: 10.3390/nu15040882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/02/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Several international guidelines recommend a peri-operative immunonutrition (IN) support for patients care in elective colorectal surgery, to reduce postoperative complications, particularly infections. In Crohn's patients, is also used to mitigate the severity of the disease. We performed a pilot study on 16 Crohn's patients undergoing intestinal surgery for active disease, not responsive to pharmacological treatment; half of them received an oral nutritional supplement enriched with immunonutrients (IN patients) for 7 days prior to surgery, in addition to normal food intake. Markers of oxidative stress (Advanced Glycated End-products (AGEs) and Advanced Oxidation Protein Products (AOPPs) were measured both in plasma and tissue samples wherein the Receptor for Advanced Glycation End products (RAGE) and Tight Junction Protein 1 (TJP1) gene expression were also determined. Plasma AGEs were significantly and positively correlated with tissue levels of AGEs (p = 0.0354) and AOPPs (p = 0.0043) while they were negatively correlated with TJP1 expression (p = 0.0159). The expression of RAGE was also negatively correlated with that of TJP1 gene (p = 0.0146). IN patients exhibited significantly lower AGEs plasma levels (p = 0.0321) and a higher mucosal TJP1 expression (p = 0.0182). No patient had postoperative complications and the length of hospital stay was similar in the two groups, but IN patients, showed a significantly shorter time to resume fluid and solid diet. These preliminary data suggest that IN might support patient's recovery by improving intestinal mucosa barrier function through the regulation of AGEs/RAGE signaling.
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Affiliation(s)
- Elisabetta Bigagli
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
| | - Mario D’Ambrosio
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
| | - Lorenzo Cinci
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
| | - Camilla Fiorindi
- Department of Health Science, University of Firenze, 50134 Firenze, Italy
| | - Sara Agostiniani
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
| | - Elisa Bruscoli
- Department of Health Science, University of Firenze, 50134 Firenze, Italy
| | - Anita Nannoni
- Department of Health Science, University of Firenze, 50134 Firenze, Italy
| | - Maura Lodovici
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
| | - Stefano Scaringi
- Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy
| | - Francesco Giudici
- Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy
- Correspondence: (F.G.); (C.L.)
| | - Cristina Luceri
- Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Firenze, 50134 Firenze, Italy
- Correspondence: (F.G.); (C.L.)
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28
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Salehi M, Amiri S, Ilghari D, Hasham LFA, Piri H. The Remarkable Roles of the Receptor for Advanced Glycation End Products (RAGE) and Its Soluble Isoforms in COVID-19: The Importance of RAGE Pathway in the Lung Injuries. Indian J Clin Biochem 2022; 38:159-171. [PMID: 35999871 PMCID: PMC9387879 DOI: 10.1007/s12291-022-01081-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/22/2022] [Indexed: 11/29/2022]
Abstract
The respiratory symptoms of acute respiratory distress syndrome (ARDS) in the coronavirus disease 2019 (COVID-19) patients is associated with accumulation of pre-inflammatory molecules such as advanced glycation end-products (AGES), calprotectin, high mobility group box family-1 (HMGB1), cytokines, angiotensin converting enzyme 2 (ACE2), and other molecules in the alveolar space of lungs and plasma. The receptor for advanced glycation end products (RAGEs), which is mediated by the mitogen-activated protein kinase (MAPK), plays a critical role in the severity of chronic inflammatory diseases such as diabetes mellitus (DM) and ARDS. The RAGE gene is most expressed in the alveolar epithelial cells (AECs) of the pulmonary system. Several clinical trials are now being conducted to determine the possible association between the levels of soluble isoforms of RAGE (sRAGE and esRAGE) and the severity of the disease in patients with ARDS and acute lung injury (ALI). In the current article, we reviewed the most recent studies on the RAGE/ligands axis and sRAGE/esRAGE levels in acute respiratory illness, with a focus on COVID-19–associated ARDS (CARDS) patients. According to the research conducted so far, sRAGE/esRAGE measurements in patients with CARDS can be used as a powerful chemical indicator among other biomarkers for assessment of early pulmonary involvement. Furthermore, inhibiting RAGE/MAPK and Angiotensin II receptor type 1 (ATR1) in CARDS patients can be a powerful strategy for diminishing cytokine storm and severe respiratory symptoms.
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Affiliation(s)
- Mitra Salehi
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Shahin Amiri
- Department of Medical Biotechnology, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
- Student Research Committee, Pasteur Institute of Iran, Tehran, Iran
| | - Dariush Ilghari
- Midland Memorial Hospital, 400 Rosalind Redfern Grover Pkwy, Midland, TX 79701 USA
| | | | - Hossein Piri
- Department of Biochemistry and Genetics, School of Medicine, Qazvin University of Medical Sciences, Qazvin, Iran
- Cellular and Molecular Research Center, Research Institute for Prevention of Non Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
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29
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Takasawa S, Tsuchida C, Sakuramoto-Tsuchida S, Uchiyama T, Makino M, Yamauchi A, Itaya-Hironaka A. Upregulation of REG IV gene in human intestinal epithelial cells by lipopolysaccharide via downregulation of microRNA-24. J Cell Mol Med 2022; 26:4710-4720. [PMID: 35946046 PMCID: PMC9443949 DOI: 10.1111/jcmm.17498] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Revised: 07/03/2022] [Accepted: 07/06/2022] [Indexed: 01/10/2023] Open
Abstract
The pathophysiology of inflammatory bowel diseases (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members (REG Iα, REG Iβ and REG IV) are expressed in Crohn's disease (CD) and ulcerative colitis (UC) and involved as proliferative mucosal factors in IBD. We revealed that REG Iα and REG Iβ were induced in cell culture system by IL‐6/IL‐22. Although REG IV was upregulated in IBD biopsy samples, the upregulation of REG IV was not at all induced in cell culture by autoimmune‐related cytokines such as IL‐6, IL‐22 and TNFα. Here, we analysed REG IV expression in LS‐174 T and HT‐29 human intestinal epithelial cells by real‐time RT–PCR and elisa. REG IV expression was induced by lipopolysaccharide (LPS). However, LPS did not activate REG IV promoter activity. As the LPS‐induced upregulation of REG IV was considered to be regulated post‐transcriptionally, we searched targeted microRNA (miR), which revealed that REG IV mRNA has a potential target sequence for miR‐24. We measured the miR‐24 level of LPS‐treated cells and found that the level was significantly lower. The LPS‐induced increase of REG IV mRNA was abolished by the introduction of miR‐24 mimic but not by non‐specific control RNA.
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Affiliation(s)
- Shin Takasawa
- Department of Biochemistry, Nara Medical University, Kashihara, Japan
| | | | | | - Tomoko Uchiyama
- Department of Biochemistry, Nara Medical University, Kashihara, Japan.,Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan
| | - Mai Makino
- Department of Biochemistry, Nara Medical University, Kashihara, Japan
| | - Akiyo Yamauchi
- Department of Biochemistry, Nara Medical University, Kashihara, Japan
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30
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Rojas A, Schneider I, Lindner C, Gonzalez I, Morales M. The RAGE/multiligand axis: a new actor in tumor biology. Biosci Rep 2022; 42:BSR20220395. [PMID: 35727208 PMCID: PMC9251583 DOI: 10.1042/bsr20220395] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/02/2022] [Accepted: 06/21/2022] [Indexed: 01/06/2023] Open
Abstract
The receptor for advanced glycation end-products (RAGE) is a multiligand binding and single-pass transmembrane protein which actively participates in several chronic inflammation-related diseases. RAGE, in addition to AGEs, has a wide repertoire of ligands, including several damage-associated molecular pattern molecules or alarmins such as HMGB1 and members of the S100 family proteins. Over the last years, a large and compelling body of evidence has revealed the active participation of the RAGE axis in tumor biology based on its active involvement in several crucial mechanisms involved in tumor growth, immune evasion, dissemination, as well as by sculpturing of the tumor microenvironment as a tumor-supportive niche. In the present review, we will detail the consequences of the RAGE axis activation to fuel essential mechanisms to guarantee tumor growth and spreading.
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Affiliation(s)
- Armando Rojas
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Ivan Schneider
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Cristian Lindner
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Ileana Gonzalez
- Biomedical Research Labs., Universidad Catolica del Maule, Facultad de Medicina, 3605 San Miguel Ave., Talca, Chile
| | - Miguel A. Morales
- Department of Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Universidad de Chile, Santiago 8320000, Chile, Santiago, Chile
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31
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Simpson J, Spann KM, Phipps S. MLKL Regulates Rapid Cell Death-independent HMGB1 Release in RSV Infected Airway Epithelial Cells. Front Cell Dev Biol 2022; 10:890389. [PMID: 35712662 PMCID: PMC9194532 DOI: 10.3389/fcell.2022.890389] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 05/09/2022] [Indexed: 11/13/2022] Open
Abstract
Respiratory syncytial virus (RSV)-induced bronchiolitis is a significant contributor to infant morbidity and mortality. Previously, we identified that necroptosis, a pro-inflammatory form of cell death mediated by receptor-interacting serine/threonine-protein kinase 1 (RIPK1) and RIPK3, and mixed lineage kinase domain like protein (MLKL), occurs in RSV-infected human airway epithelial cells (hAECs), mediating the release of the alarmin high mobility group box 1 (HMGB1). Here, we show that RSV infection of hAECs induces the biphasic release of HMGB1 at 6 (“early”) and 24 (“late”) hours post infection (hpi). The early phase of HMGB1 release at 6 hpi is cell death-independent, however, this release is nonetheless attenuated by inhibition of MLKL (primarily associated with necroptosis). The early release of HMGB1 promotes the late phase of HMGB1 release via the activation of RAGE (receptor for advanced glycation endproducts) and occurs with cell death. Treatment of hAECS with exogenous HMGB1 combined with a pan-caspase inhibitor induces hAEC necroptosis, and is attenuated by the RAGE antagonist, FPS-ZM1. Together, these findings demonstrate that RSV infection of hAECs leads to the early release of HMGB1, followed by a paracrine feed-forward amplification loop that further increases HMGB1 levels and promotes cell death. As the inhibition of MLKL or targeting of HMGB1/RAGE pathway attenuates the release of pro-inflammatory HMGB1 and decreases viral load, this suggests that the pharmacological targeting of these pathways may be of benefit for the treatment of severe RSV bronchiolitis.
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Affiliation(s)
- Jennifer Simpson
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- School of Biomedical Science, University of Queensland, Brisbane, QLD, Australia
| | - Kirsten M. Spann
- Centre for Immunology and Infection Control, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia
| | - Simon Phipps
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- School of Biomedical Science, University of Queensland, Brisbane, QLD, Australia
- Australian Infectious Diseases Research Centre, Brisbane, QLD, Australia
- *Correspondence: Simon Phipps,
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32
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HMGB1 Promotes Lymphangiogenesis through the Activation of RAGE on M2 Macrophages in Laryngeal Squamous Cell Carcinoma. DISEASE MARKERS 2022; 2022:4487435. [PMID: 35280439 PMCID: PMC8916867 DOI: 10.1155/2022/4487435] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/20/2022] [Accepted: 02/04/2022] [Indexed: 11/17/2022]
Abstract
Background. Receptor for advanced glycation end products (RAGE) is implicated in tumor biology. Released high mobility group box protein 1 (HMGB1) ligand binding to RAGE receptor in tumor cells promotes tumor progression. The mechanisms of HMGB1-RAGE signaling in M2 macrophages involved in lymphangiogenesis in laryngeal carcinoma remain poorly understood. Here, we assessed the effect of HMGB1-RAGE signaling on M2 macrophages in lymphangiogenesis. Methods. HMGB1, CD163, and D2-40 in laryngeal squamous cell carcinoma (LSCC,
), laryngeal precursor lesions (LPLs,
), and vocal polyp (VP,
) were analyzed by immunohistochemistry. THP-1 cell-expressed RAGE gene was knocked down and then polarized to M0 macrophages and M2 macrophages. IL-23, TNF-α, TGF-β, and IL-10 were measured by ELISA; IL-1β, IL-12, IL-10, and CCL-13 were evaluated by RT-qPCR, and CD206, CD163, and RAGE were evaluated by western blot to evaluate whether classical M2 macrophages were obtained. Conditioned media from RAGE+/- M0 macrophages and RAGE+/- M2 macrophages incubated in the presence or absence of HMGB1, anti-Toll-like receptor (TLR)2, anti-TLR4 antibodies, and anti-VEGF-C antibodies were collected separately for human dermal lymphatic endothelial cells (HDLEC) for proliferation, migration, lymphangiogenesis assay, and VEGF-C concentration analysis. Results. HMGB1 and M2 macrophage densities were increased in LSCC (
). HMGB1 and M2 macrophage densities were significantly correlated with lymphatic vessel density (LVD) in LSCC (
). The HMGB1 overexpression and higher M2 macrophage density were involved in lymph node metastasis (
) and poor prognosis (
). In vitro, conditioned medium from HMGB1-stimulated RAGE+ M2 macrophages activated lymphangiogenesis by upregulating the VEGF compared to controls (
). On the contrary, RAGE knockdown obviously decreased the corresponding effects of HMGB1-preconditioned M2 macrophages upon HDLEC (
). HMGB1-TLR pathway does not significantly increase HDLEC proliferation, migration, and lymphangiogenesis on M2 macrophages. Conclusions. HMGB1 promotes lymphangiogenesis by activation of RAGE on M2 macrophages. Targeting RAGE may provide an effective therapeutic strategy against M2 macrophages in LSCC patients with lymph node metastasis.
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33
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High Mobility Group Box 1: Biological Functions and Relevance in Oxidative Stress Related Chronic Diseases. Cells 2022; 11:cells11050849. [PMID: 35269471 PMCID: PMC8909428 DOI: 10.3390/cells11050849] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/03/2022] [Accepted: 02/26/2022] [Indexed: 01/27/2023] Open
Abstract
In the early 1970s, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and named high-mobility group (HMG) proteins. High-mobility group box 1 (HMGB1) is the most studied HMG protein that detects and coordinates cellular stress response. The biological function of HMGB1 depends on its subcellular localization and expression. It plays a critical role in the nucleus and cytoplasm as DNA chaperone, chromosome gatekeeper, autophagy maintainer, and protector from apoptotic cell death. HMGB1 also functions as an extracellular alarmin acting as a damage-associated molecular pattern molecule (DAMP). Recent findings describe HMGB1 as a sophisticated signal of danger, with a pleiotropic function, which is useful as a clinical biomarker for several disorders. HMGB1 has emerged as a mediator in acute and chronic inflammation. Furthermore, HMGB1 targeting can induce beneficial effects on oxidative stress related diseases. This review focus on HMGB1 redox status, localization, mechanisms of release, binding with receptors, and its activities in different oxidative stress-related chronic diseases. Since a growing number of reports show the key role of HMGB1 in socially relevant pathological conditions, to our knowledge, for the first time, here we analyze the scientific literature, evaluating the number of publications focusing on HMGB1 in humans and animal models, per year, from 2006 to 2021 and the number of records published, yearly, per disease and category (studies on humans and animal models).
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Jang H, Lee S, Yoo I, Choi Y, Han J, Cheon Y, Ka H. Calcium-binding proteins S100A8, S100A9, and S100A12: expression and regulation at the maternal-conceptus Interface in pigs†. Biol Reprod 2022; 106:1098-1111. [PMID: 35178550 DOI: 10.1093/biolre/ioac039] [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: 06/18/2021] [Revised: 12/01/2021] [Accepted: 02/15/2022] [Indexed: 11/12/2022] Open
Abstract
Among the many calcium-binding proteins, S100A8, S100A9, and S100A12 play important roles in inflammation, innate immunity, and antimicrobial function, but their expression, regulation, and function at the maternal-conceptus interface in pigs are not fully understood. Therefore, we determined the expression and regulation of S100A8, S100A9, S100A12, and their receptor AGER at the maternal-conceptus interface in pigs. We found that S100A8, S100A9, and S100A12 mRNAs were expressed in the endometrium during the estrous cycle and pregnancy, with the greatest levels on Day (D) 12 of pregnancy, and AGER appeared at greater levels on D15 and D30 of pregnancy than on other days. The expression of S100A8, S100A9, and S100A12 was predominantly localized to epithelial cells in the endometrium, and they were detected in early-stage conceptus and later chorioallantoic tissues during pregnancy. AGER expression was localized to endometrial epithelial and stromal cells and chorionic epithelial cells. In endometrial explant tissues, the expression of S100A8, S100A9, and S100A12 was induced by estrogen, S100A8 by interleukin-1β, and AGER by interferon-γ. We further found that on D12 of pregnancy, the expression of S100A8, S100A9, and S100A12 decreased significantly in the endometria of gilts carrying conceptuses derived from somatic cell nuclear transfer. These results indicate that the expression of S100A8, S100A9, and S100A12 is dynamically regulated in response to conceptus-derived signals at the maternal-conceptus interface, suggesting that S100A8, S100A9, and S100A12 could play a critical role in regulating endometrial epithelial cell function and conceptus implantation to support the establishment and maintenance of pregnancy in pigs.
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Affiliation(s)
- Hwanhee Jang
- Department of Biological Science and Technology, Yonsei University, Wonju, 26493, Republic of Korea
| | - Soohyung Lee
- Department of Biological Science and Technology, Yonsei University, Wonju, 26493, Republic of Korea
| | - Inkyu Yoo
- Department of Biological Science and Technology, Yonsei University, Wonju, 26493, Republic of Korea
| | - Yohan Choi
- Department of Biological Science and Technology, Yonsei University, Wonju, 26493, Republic of Korea
| | - Jisoo Han
- Department of Biological Science and Technology, Yonsei University, Wonju, 26493, Republic of Korea
| | - Yugyeong Cheon
- Department of Biological Science and Technology, Yonsei University, Wonju, 26493, Republic of Korea
| | - Hakhyun Ka
- Department of Biological Science and Technology, Yonsei University, Wonju, 26493, Republic of Korea
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35
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Ye Z, Izadi A, Gurkoff GG, Rickerl K, Sharp F, Ander B, Bauer SZ, Lui A, Lyeth BG, Liu D. Combined Inhibition of Fyn and c-Src Protects Hippocampal Neurons and Improves Spatial Memory via ROCK after Traumatic Brain Injury. J Neurotrauma 2022; 39:520-529. [PMID: 35109711 PMCID: PMC8978569 DOI: 10.1089/neu.2021.0311] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Our previous studies demonstrated that TBI and ventricular administration of thrombin caused hippocampal neuron loss and cognitive dysfunction via activation of Src family kinases (SFKs). Based on SFK localization in brain, we hypothesized SFK subtypes Fyn and c-Src as well as SFK downstream molecule Rho-associated protein kinase (ROCK) contribute to cell death and cognitive dysfunction after TBI. We administered nanoparticle wrapped siRNA-Fyn and siRNA-c-Src, or ROCK inhibitor Y-27632 to adult rats subjected to moderate lateral fluid percussion (LFP) induced TBI. Spatial memory function was assessed from 12 to 16 days, and NeuN stained hippocampal neurons were assessed 16 days after TBI. The combination of siRNA-Fyn and siRNA-c-Src, but neither alone, prevented hippocampal neuron loss and spatial memory deficits after TBI. The ROCK inhibitor Y-27632 also prevented hippocampal neuronal loss and spatial memory deficits after TBI. The data suggest that the combined actions of three kinases (Fyn, c-Src, ROCK) mediate hippocampal neuronal cell death and spatial memory deficits produced by LFP-TBI, and that inhibiting this pathway prevents the TBI-induced cell death and memory deficits.
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Affiliation(s)
- Zhouheng Ye
- University of California at Davis Medical Center, Department of Neurology, Davis, California, United States;
| | - Ali Izadi
- University of California, Davis, Neurological Surgery, 1515 Newton Ct, Room 502, Davis, California, United States, 95618;
| | - Gene Gabriel Gurkoff
- University of California, Davis, Neurological Surgery, 1515 Newton Ct, Room 502, Davis, California, United States, 95618;
| | - Kaitlin Rickerl
- University of California at Davis Medical Center, Department of Neurology, Davis, California, United States;
| | - Frank Sharp
- University of California Davis, MIND Institute, Davis, United States;
| | - Bradley Ander
- University of California at Davis Medical Center, Department of Neurology and the M.I.N.D. Institute, Sacramento, California, United States;
| | - Sawyer Z Bauer
- University of California at Davis Medical Center, Department of Neurology, Davis, California, United States;
| | - Austin Lui
- University of California at Davis Medical Center, Department of Neurology, Davis, California, United States;
| | - Bruce G Lyeth
- U.C. Davis, Neurological Surgery, One Shields Ave, Davis, California, United States, 95616;
| | - DaZhi Liu
- University of California at Davis Medical Center, Department of Neurology, Davis, California, United States;
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36
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Taban Q, Mumtaz PT, Masoodi KZ, Haq E, Ahmad SM. Scavenger receptors in host defense: from functional aspects to mode of action. Cell Commun Signal 2022; 20:2. [PMID: 34980167 PMCID: PMC8721182 DOI: 10.1186/s12964-021-00812-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 11/27/2021] [Indexed: 12/17/2022] Open
Abstract
Scavenger receptors belong to a superfamily of proteins that are structurally heterogeneous and encompass the miscellaneous group of transmembrane proteins and soluble secretory extracellular domain. They are functionally diverse as they are involved in various disorders and biological pathways and their major function in innate immunity and homeostasis. Numerous scavenger receptors have been discovered so far and are apportioned in various classes (A-L). Scavenger receptors are documented as pattern recognition receptors and known to act in coordination with other co-receptors such as Toll-like receptors in generating the immune responses against a repertoire of ligands such as microbial pathogens, non-self, intracellular and modified self-molecules through various diverse mechanisms like adhesion, endocytosis and phagocytosis etc. Unlike, most of the scavenger receptors discussed below have both membrane and soluble forms that participate in scavenging; the role of a potential scavenging receptor Angiotensin-Converting Enzyme-2 has also been discussed whereby only its soluble form might participate in preventing the pathogen entry and replication, unlike its membrane-bound form. This review majorly gives an insight on the functional aspect of scavenger receptors in host defence and describes their mode of action extensively in various immune pathways involved with each receptor type. Video abstract.
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Affiliation(s)
- Qamar Taban
- Division of Animal Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, Sher-e- Kashmir University of Agricultural Sciences and Technology - Kashmir, Shuhama, 190006, India.,Department of Biotechnology, University of Kashmir, Hazratbal Srinagar, Kashmir, India
| | | | - Khalid Z Masoodi
- Division of Plant Biotechnology, Transcriptomics Laboratory, SKUAST-K, Shalimar, India
| | - Ehtishamul Haq
- Department of Biotechnology, University of Kashmir, Hazratbal Srinagar, Kashmir, India
| | - Syed Mudasir Ahmad
- Division of Animal Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, Sher-e- Kashmir University of Agricultural Sciences and Technology - Kashmir, Shuhama, 190006, India.
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37
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Chen S, Gou M, Chen W, Xiu M, Fan H, Tan Y, Tian L. Alterations in innate immune defense distinguish first-episode schizophrenia patients from healthy controls. Front Psychiatry 2022; 13:1024299. [PMID: 36311523 PMCID: PMC9606407 DOI: 10.3389/fpsyt.2022.1024299] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 09/26/2022] [Indexed: 11/21/2022] Open
Abstract
Innate immune components involved in host defense have been implicated in schizophrenia (SCZ). However, studies exploring their clinical utility in SCZ diagnosis are limited. The main purpose of this study was to evaluate whether circulating endotoxin, high mobility group box 1 protein (HMGB1) and complement component 4 (C4) could act as peripheral biomarkers to distinguish first-episode schizophrenia (FES, n = 42) patients from healthy controls (HCs, n = 35) in associations with psychopathological symptoms and cognitive dysfunctions. Also, their changes after 8-week antipsychotic treatment were investigated. The Positive and Negative Syndrome Scale (PANSS), Psychotic Symptom Rating Scale (PSYRATS), and MATRICS Consensus Cognitive Battery (MCCB) were administered. Receiver operating characteristic (ROC) curves were conducted to evaluate the diagnostic effectiveness of the three biological indicators. Compared to HCs, levels of endotoxin, HMGB1, and C4 were remarkably increased in FES patients after controlling for age, gender, body mass index (BMI) and education years, and the combination of the three biomarkers demonstrated desirable diagnostic performance (AUC = 0.933). Moreover, the endotoxin level was positively correlated with the severity of auditory hallucinations. After 8 weeks of treatment, HMGB1 was decreased significantly in patients but still higher than that in HCs, whereas endotoxin and C4 did not change statistically. The baseline levels of endotoxin, HMGB1, and C4, as well as their changes were not associated with changes in any PANSS subscale score and total score. Our preliminary results suggest that a composite peripheral biomarker of endotoxin, HMGB1, and C4 may have accessory diagnostic value to distinguish SCZ patients from HCs. Additionally, endotoxin might be implicated in the pathogenesis of auditory hallucinations.
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Affiliation(s)
- Song Chen
- Peking University HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China
| | - Mengzhuang Gou
- Peking University HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China
| | - Wenjin Chen
- Peking University HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China
| | - Meihong Xiu
- Peking University HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China
| | - Hongzhen Fan
- Peking University HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China
| | - Yunlong Tan
- Peking University HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China
| | - Li Tian
- Department of Physiology, Faculty of Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
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38
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Hu Z, Xiao M, Cai H, Li W, Fang W, Long X. Glycyrrhizin regulates rat TMJOA progression by inhibiting the HMGB1-RAGE/TLR4-NF-κB/AKT pathway. J Cell Mol Med 2021; 26:925-936. [PMID: 34953035 PMCID: PMC8817133 DOI: 10.1111/jcmm.17149] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 12/06/2021] [Accepted: 12/12/2021] [Indexed: 11/26/2022] Open
Abstract
To investigate the role of glycyrrhizin on the progression of temporomandibular joint osteoarthritis (TMJOA) and the underlying mechanism by regulation of the high‐mobility group box 1 (HMGB1) receptor for advanced glycation end products (RAGE)/toll‐like receptor 4 (TLR4)‐nuclear factor kappa B (NF‐κB)/protein kinase B (AKT) pathway. After a rat model of TMJOA was built by intra‐articular injection of monosodium iodoacetate, glycyrrhizin was intragastrically administered at low concentration (20 mg/kg) or high concentration (50 mg/kg). Micro‐computed tomography, histological and immunohistochemical analysis were used to reveal the progression of TMJOA. Rat TMJ chondrocytes and disc cells were cultured in inflammatory condition with different doses of glycyrrhizin. Western blot was used to evaluate the effect of glycyrrhizin on the HMGB1‐RAGE/TLR4‐NF‐κB/AKT pathway. Administration of glycyrrhizin alleviated cartilage degeneration, lowered the levels of inflammatory and catabolic mediators and reduced the production of HMGB1, RAGE and TLR4 in TMJOA animal model. Increased production of RAGE and TLR4, and activated intracellular NF‐κB and/or AKT signalling pathways in chondrocytes and disc cells were found in inflammatory condition. Upon activation, matrix metalloprotease‐3 and interleukin‐6 were upregulated. Glycyrrhizin inhibited not only HMGB1 release but also RAGE and TLR4 in inflammatory condition. Glycyrrhizin alleviated the pathological changes of TMJOA by regulating the HMGB1‐RAGE/TLR4‐NF‐kB/AKT signalling pathway. This study revealed the potential of glycyrrhizin as a novel therapeutic drug to suppress TMJ cartilage degradation.
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Affiliation(s)
- Zhihui Hu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Mian Xiao
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.,Affiliated Stomatological Hospital of Nanchang University, Nanchang, China
| | - Hengxing Cai
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Wei Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Wei Fang
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.,Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
| | - Xing Long
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.,Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Wuhan University, Wuhan, China
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39
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Aguirre JI, Castillo EJ, Kimmel DB. Biologic and pathologic aspects of osteocytes in the setting of medication-related osteonecrosis of the jaw (MRONJ). Bone 2021; 153:116168. [PMID: 34487892 PMCID: PMC8478908 DOI: 10.1016/j.bone.2021.116168] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/02/2021] [Accepted: 08/31/2021] [Indexed: 02/08/2023]
Abstract
Medication-related osteonecrosis of the jaw (MRONJ) is a potentially severe, debilitating condition affecting patients with cancer and patients with osteoporosis who have been treated with powerful antiresorptives (pARs) or angiogenesis inhibitors (AgIs). Oral risk factors associated with the development of MRONJ include tooth extraction and inflammatory dental disease (e.g., periodontitis, periapical infection). In bone tissues, osteocytes play a bidirectional role in which they not only act as the "receiver" of systemic signals from blood vessels, such as hormones and drugs, or local signals from the mineralized matrix as it is deformed, but they also play a critical role as "transmitter" of signals to the cells that execute bone modeling and remodeling (osteoclasts, osteoblasts and lining cells). When the survival capacity of osteocytes is overwhelmed, they can die. Osteocyte death has been associated with several pathological conditions. Whereas the causes and mechanisms of osteocyte death have been studied in conditions like osteonecrosis of the femoral head (ONFH), few studies of the causes and mechanisms of osteocyte death have been done in MRONJ. The three forms of cell death that affect most of the different cells in the body (apoptosis, autophagy, and necrosis) have been recognized in osteocytes. Notably, necroptosis, a form of regulated cell death with "a necrotic cell death phenotype," has also been identified as a form of cell death in osteocytes under certain pathologic conditions. Improving the understanding of osteocyte death in MRONJ may be critical for preventing disease and developing treatment approaches. In this review, we intend to provide insight into the biology of osteocytes, cell death, in general, and osteocyte death, in particular, and discuss hypothetical mechanisms involved in osteocyte death associated with MRONJ.
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Affiliation(s)
- J I Aguirre
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America.
| | - E J Castillo
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America.
| | - D B Kimmel
- Department of Physiological Sciences, University of Florida (UF), Gainesville, FL, United States of America
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40
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Somensi N, Lopes SC, Gasparotto J, Mayer Gonçalves R, Tiefensee-Ribeiro C, Oppermann Peixoto D, Ozorio Brum P, Pinho CM, Agnes JP, Santos L, de Oliveira J, Spiller F, Fonseca Moreira JC, Zanotto-Filho A, Prediger RD, Pens Gelain D. Role of toll-like receptor 4 and sex in 6-hydroxydopamine-induced behavioral impairments and neurodegeneration in mice. Neurochem Int 2021; 151:105215. [PMID: 34710535 DOI: 10.1016/j.neuint.2021.105215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/02/2021] [Accepted: 10/21/2021] [Indexed: 11/19/2022]
Abstract
Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of the nigrostriatal dopaminergic neurons that are associated with motor alterations and non-motor manifestations (such as depression). Neuroinflammation is a process with a critical role in the pathogenesis of PD. In this regard, toll-like receptor 4 (TLR4) is a central mediator of immune response in PD. Moreover, there are gender-related differences in the incidence, prevalence, and clinical features of PD. Therefore, we aimed to elucidate the role of TLR4 in the sex-dependent response to dopaminergic denervation induced by 6-hydroxydopamine (6-OHDA) in mice. Female and male adult wildtype (WT) and TLR4 knockout (TLR4-/-) mice were administered with unilateral injection of 6-OHDA in the dorsal striatum, and non-motor and motor impairments were evaluated for 30 days, followed by biochemistry analysis in the substantia nigra pars compacta (SNc), dorsal striatum, and dorsoventral cortex. Early non-motor impairments (i.e., depressive-like behavior and spatial learning deficits) induced by 6-OHDA were observed in the male WT mice but not in male TLR4-/- or female mice. Motor alterations were observed after administration of 6-OHDA in both strains, and the lack of TLR4 was also related to motor commitment. Moreover, ablation of TLR4 prevented 6-OHDA-induced dopaminergic denervation and microgliosis in the SNc, selectively in female mice. These results reinforced the existence of sex-biased alterations in PD and indicated TLR4 as a promising therapeutic target for the motor and non-motor symptoms of PD, which will help counteract the neuroinflammatory and neurodegenerative processes.
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Affiliation(s)
- Nauana Somensi
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
| | - Samantha Cristiane Lopes
- Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Juciano Gasparotto
- Instituto de Ciências Biomédicas - Universidade Federal de Alfenas, Rua Gabriel Monteiro da Silva, 700. CEP: 37130-001. Centro - Alfenas/MG, Alfenas, Minas Gerais, Brazil
| | - Rosângela Mayer Gonçalves
- Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Camila Tiefensee-Ribeiro
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Daniel Oppermann Peixoto
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Pedro Ozorio Brum
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Cibele Martins Pinho
- Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Jonathan Paulo Agnes
- Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Lucas Santos
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Jade de Oliveira
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Fernando Spiller
- Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - José Cláudio Fonseca Moreira
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Alfeu Zanotto-Filho
- Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Rui Daniel Prediger
- Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina (UFSC), Campus Universitário, Florianópolis, SC, Brazil
| | - Daniel Pens Gelain
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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Ogawa N, Nakajima S, Tamada K, Yokoue N, Tachibana H, Okazawa M, Oyama T, Abe H, Yamazaki H, Yoshimori A, Sato A, Kamiya T, Yokomizo T, Uchiumi F, Abe T, Tanuma SI. Trimebutine suppresses Toll-like receptor 2/4/7/8/9 signaling pathways in macrophages. Arch Biochem Biophys 2021; 711:109029. [PMID: 34517011 DOI: 10.1016/j.abb.2021.109029] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 08/26/2021] [Accepted: 09/08/2021] [Indexed: 12/12/2022]
Abstract
Because of the critical roles of Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) in the pathophysiology of various acute and chronic inflammatory diseases, continuous efforts have been made to discover novel therapeutic inhibitors of TLRs and RAGE to treat inflammatory disorders. A recent study by our group has demonstrated that trimebutine, a spasmolytic drug, suppresses the high mobility group box 1‒RAGE signaling that is associated with triggering proinflammatory signaling pathways in macrophages. Our present work showed that trimebutine suppresses interleukin-6 (IL-6) production in lipopolysaccharide (LPS, a stimulant of TLR4)-stimulated macrophages of RAGE-knockout mice. In addition, trimebutine suppresses the LPS-induced production of various proinflammatory cytokines and chemokines in mouse macrophage-like RAW264.7 cells. Importantly, trimebutine suppresses IL-6 production induced by TLR2-and TLR7/8/9 stimulants. Furthermore, trimebutine greatly reduces mortality in a mouse model of LPS-induced sepsis. Studies exploring the action mechanism of trimebutine revealed that it inhibits the LPS-induced activation of IL-1 receptor-associated kinase 1 (IRAK1), and the subsequent activations of extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These findings suggest that trimebutine exerts anti-inflammatory effects on TLR signaling by downregulating IRAK1‒ERK1/2‒JNK pathway and NF-κB activity, thereby indicating the therapeutic potential of trimebutine in inflammatory diseases. Therefore, trimebutine can be a novel anti-inflammatory drug-repositioning candidate and may provide an important scaffold for designing more effective dual anti-inflammatory drugs that target TLR/RAGE signaling.
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Affiliation(s)
- Natsumi Ogawa
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan
| | - Shingo Nakajima
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan
| | - Kenya Tamada
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan
| | - Natsuki Yokoue
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan
| | - Haruki Tachibana
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan
| | - Miwa Okazawa
- Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, 278-8510, Japan
| | - Takahiro Oyama
- Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, 278-8510, Japan; Hinoki Shinyaku Co., Ltd., Chiyoda-ku, Tokyo, 102-0084, Japan
| | - Hideaki Abe
- Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, 278-8510, Japan; Hinoki Shinyaku Co., Ltd., Chiyoda-ku, Tokyo, 102-0084, Japan
| | - Hiroaki Yamazaki
- Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, 278-8510, Japan; Hinoki Shinyaku Co., Ltd., Chiyoda-ku, Tokyo, 102-0084, Japan
| | - Atsushi Yoshimori
- Institute for Theoretical Medicine, Inc., Fujisawa, Kanagawa, 251-0012, Japan
| | - Akira Sato
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan
| | - Takanori Kamiya
- Hinoki Shinyaku Co., Ltd., Chiyoda-ku, Tokyo, 102-0084, Japan
| | - Takehiko Yokomizo
- Department of Biochemistry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Fumiaki Uchiumi
- Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan
| | - Takehiko Abe
- Hinoki Shinyaku Co., Ltd., Chiyoda-ku, Tokyo, 102-0084, Japan
| | - Sei-Ichi Tanuma
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan; Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, 278-8510, Japan.
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42
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Biswas I, Panicker SR, Cai XS, Giri H, Rezaie AR. Extracellular Histones Bind Vascular Glycosaminoglycans and Inhibit the Anti-Inflammatory Function of Antithrombin. Cell Physiol Biochem 2021; 55:605-617. [PMID: 34655467 DOI: 10.33594/000000438] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND/AIMS Binding of histones to molecular pattern recognition receptors on endothelial cells and leukocytes provokes proinflammatory responses and promotes activation of coagulation. Histones also bind therapeutic heparins, thereby neutralizing their anticoagulant functions. The aim of this study was to test the hypothesis that histones can interact with the antithrombin (AT)-binding vascular glycosaminoglycans (GAGs) to induce inflammation and inhibit the anti-inflammatory function of AT. METHODS We evaluated the heparin-binding function of histones by an AT-dependent protease-inhibition assay. Furthermore, we treated endothelial cells with histones in the absence and presence of AT and monitored cellular phenotypes employing established signaling assays. RESULTS Histones neutralized AT-dependent anticoagulant function of heparin in both purified protease-inhibition and plasma-based assays. Histones also disrupted endothelial cell barrier-permeability function by a GAG-dependent mechanism as evidenced by the GAG-antagonist, surfen, abrogating their disruptive effects. Further studies revealed histones and AT compete for overlapping binding-sites on GAGs, thus increasing concentrations of one protein abrogated effects of the other. Histones elicited proapoptotic effects by inducing nuclear localization of PKC-δ in endothelial cells and barrier-disruptive effects by destabilizing VE-cadherin, which were inhibited by AT, but not by a D-helix mutant of AT incapable of interacting with GAGs. Finally, histones induced release of Weibel-Palade body contents, VWF and angiopoietin-2, and promoted expression of cell adhesion molecules on endothelial cells, which were all downregulated by AT but not by D-helix mutant of AT. CONCLUSION We conclude that histones and AT compete for overlapping binding sites on vascular GAGs to modulate coagulation and inflammation.
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Affiliation(s)
- Indranil Biswas
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Sumith R Panicker
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Xiaofeng S Cai
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Hemant Giri
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Alireza R Rezaie
- Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA, .,Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
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Gonzalez I, Araya P, Schneider I, Lindner C, Rojas A. Pattern recognition receptors and their roles in the host response to Helicobacter pylori infection. Future Microbiol 2021; 16:1229-1238. [PMID: 34615380 DOI: 10.2217/fmb-2021-0106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 08/31/2021] [Indexed: 02/07/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection is highly prevalent, affecting 4.4 billion people globally. This pathogen is a risk factor in the pathogenesis of more than 75% of worldwide cases of gastric cancer. Pattern recognition receptors are essential in the innate immune response to H. pylori infection. They recognize conserved pathogen structures and myriad alarmins released by host cells in response to microbial components, cytokines or cellular stress, thus triggering a robust proinflammatory response, which is crucial in H. pylori-induced gastric carcinogenesis. In this review, we intend to highlight the main pattern recognition receptors involved in the recognition and host response to H. pylori, as well as the main structures recognized and the subsequent inflammatory response.
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Affiliation(s)
- Ileana Gonzalez
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, 3460000, Chile
| | - Paulina Araya
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, 3460000, Chile
| | - Ivan Schneider
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, 3460000, Chile
| | - Cristian Lindner
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, 3460000, Chile
| | - Armando Rojas
- Biomedical Research Labs, Medicine Faculty, Catholic University of Maule, Talca, 3460000, Chile
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McFarlin BK, Hill DW, Vingren JL, Curtis JH, Tanner EA. Dietary Polyphenol and Methylsulfonylmethane Supplementation Improves Immune, DAMP Signaling, and Inflammatory Responses During Recovery From All-Out Running Efforts. Front Physiol 2021; 12:712731. [PMID: 34531760 PMCID: PMC8438219 DOI: 10.3389/fphys.2021.712731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 07/26/2021] [Indexed: 12/01/2022] Open
Abstract
Nutritional ingredients with defined mechanisms of action can be useful in the recovery of the body from the physical demands of a habitual training plan. The purpose of this study was to determine the effect of dietary supplementation with optimized curcumin, pomegranate ellagitannins, and MSM (R + MSM) on immune-associated mRNA during early recovery (i.e., up to 8 h post-exercise) following all-out running efforts (5-km, 10-km, and 21.1-km). Subjects (N = 14) were randomized to either a supplement (R + MSM) or a control group using an open label design. The study was completed over a period of 31-day prior to a scheduled half-marathon race. Venous blood samples were collected into PAXgene tubes at baseline, subsequent samples were collected at 2, 4, and 8 h after each running effort. A 574-plex mRNA Immunology Array (NanoString) was measured for each sample and ROSALIND® Advanced Analysis Software was used to examined changes in 31 annotated immune response pathways and specific mRNA changes. The greatest change in immune pathways occurred at 2 h (GSS > 3) followed by 4 h (GSS 2–3) and 8 h (GSS 1–2). R + MSM was associated with an increase in innate immunity (CAMP, LTF, TIRAP, CR1, IL1R1, CXCR1, PDCDILG2, and GNLY) and a blunted/smaller increase in damage-associated molecular pattern (DAMP) signaling/inflammation (TLR4, TLR5, S100A8, S100A9, and IFP35). We also found changes in immune-associated mRNA that have not been previously linked to exercise recovery (SOCS1, SOCS2, MME, CECAM6, MX1, IL-1R2, KLRD1, KLRK1, and LAMP3). Collectively these results demonstrate that supplementation with a combination of optimized curcumin, pomegranate ellagitannins, and methylsulfonylmethane resulted in changes that may improve biological recovery from all-out running efforts.
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Affiliation(s)
- Brian K McFarlin
- Applied Physiology Laboratory, Department of Kinesiology, Health Promotion, and Recreation, College of Education, University of North Texas, Denton, TX, United States.,Department of Biological Sciences, College of Science, University of North Texas, Denton, TX, United States
| | - David W Hill
- Applied Physiology Laboratory, Department of Kinesiology, Health Promotion, and Recreation, College of Education, University of North Texas, Denton, TX, United States
| | - Jakob L Vingren
- Applied Physiology Laboratory, Department of Kinesiology, Health Promotion, and Recreation, College of Education, University of North Texas, Denton, TX, United States.,Department of Biological Sciences, College of Science, University of North Texas, Denton, TX, United States
| | - John H Curtis
- Applied Physiology Laboratory, Department of Kinesiology, Health Promotion, and Recreation, College of Education, University of North Texas, Denton, TX, United States
| | - Elizabeth A Tanner
- Applied Physiology Laboratory, Department of Kinesiology, Health Promotion, and Recreation, College of Education, University of North Texas, Denton, TX, United States.,Department of Biological Sciences, College of Science, University of North Texas, Denton, TX, United States
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Munro P, Rekima S, Loubat A, Duranton C, Pisani DF, Boyer L. Impact of thermogenesis induced by chronic β3-adrenergic receptor agonist treatment on inflammatory and infectious response during bacteremia in mice. PLoS One 2021; 16:e0256768. [PMID: 34437647 PMCID: PMC8389438 DOI: 10.1371/journal.pone.0256768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 08/15/2021] [Indexed: 11/19/2022] Open
Abstract
White adipocytes store energy differently than brown and brite adipocytes which dissipate energy under the form of heat. Studies have shown that adipocytes are able to respond to bacteria thanks to the presence of Toll-like receptors at their surface. Despite this, little is known about the involvement of each class of adipocytes in the infectious response. We treated mice for one week with a β3-adrenergic receptor agonist to induce activation of brown adipose tissue and brite adipocytes within white adipose tissue. Mice were then injected intraperitoneally with E. coli to generate acute infection. The metabolic, infectious and inflammatory parameters of the mice were analysed during 48 hours after infection. Our results shown that in response to bacteria, thermogenic activity promoted a discrete and local anti-inflammatory environment in white adipose tissue characterized by the increase of the IL-1RA secretion. More generally, activation of brown and brite adipocytes did not modify the host response to infection including no additive effect with fever and an equivalent bacteria clearance and inflammatory response. In conclusion, these results suggest an IL-1RA-mediated immunomodulatory activity of thermogenic adipocytes in response to acute bacterial infection and open a way to characterize their effect along more chronic infection as septicaemia.
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Affiliation(s)
| | - Samah Rekima
- Université Côte d’Azur, CNRS, Inserm, iBV, Nice, France
| | - Agnès Loubat
- Université Côte d’Azur, CNRS, Inserm, iBV, Nice, France
| | | | - Didier F. Pisani
- Université Côte d’Azur, CNRS, LP2M, Nice, France
- * E-mail: (DFP); (LB)
| | - Laurent Boyer
- Université Côte d’Azur, Inserm, C3M, Nice, France
- * E-mail: (DFP); (LB)
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High Mobility Group Box 1 in Pig Amniotic Membrane Experimentally Infected with E. coli O55. Biomolecules 2021; 11:biom11081146. [PMID: 34439812 PMCID: PMC8393629 DOI: 10.3390/biom11081146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/27/2021] [Accepted: 07/29/2021] [Indexed: 12/15/2022] Open
Abstract
Intra-amniotic infections (IAI) are one of the reasons for preterm birth. High mobility group box 1 (HMGB1) is a nuclear protein with various physiological functions, including tissue healing. Its excessive extracellular release potentiates inflammatory reaction and can revert its action from beneficial to detrimental. We infected the amniotic fluid of a pig on the 80th day of gestation with 1 × 104 colony forming units (CFUs) of E. coli O55 for 10 h, and evaluated the appearance of HMGB1, receptor for glycation endproducts (RAGE), and Toll-like receptor (TLR) 4 in the amniotic membrane and fluid. Sham-infected amniotic fluid served as a control. The expression and release of HMGB1 were evaluated by Real-Time PCR, immunofluorescence, immunohistochemistry, and ELISA. The infection downregulated HMGB1 mRNA expression in the amniotic membrane, changed the distribution of HMGB1 protein in the amniotic membrane, and increased its level in amniotic fluid. All RAGE mRNA, protein expression in the amniotic membrane, and soluble RAGE level in the amniotic fluid were downregulated. TLR4 mRNA and protein expression and soluble TLR4 were all upregulated. HMGB1 is a potential target for therapy to suppress the exaggerated inflammatory response. This controlled expression and release can, in some cases, prevent the preterm birth of vulnerable infants. Studies on suitable animal models can contribute to the development of appropriate therapy.
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Molecular Characteristics of RAGE and Advances in Small-Molecule Inhibitors. Int J Mol Sci 2021; 22:ijms22136904. [PMID: 34199060 PMCID: PMC8268101 DOI: 10.3390/ijms22136904] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 12/16/2022] Open
Abstract
Receptor for advanced glycation end-products (RAGE) is a member of the immunoglobulin superfamily. RAGE binds and mediates cellular responses to a range of DAMPs (damage-associated molecular pattern molecules), such as AGEs, HMGB1, and S100/calgranulins, and as an innate immune sensor, can recognize microbial PAMPs (pathogen-associated molecular pattern molecules), including bacterial LPS, bacterial DNA, and viral and parasitic proteins. RAGE and its ligands stimulate the activations of diverse pathways, such as p38MAPK, ERK1/2, Cdc42/Rac, and JNK, and trigger cascades of diverse signaling events that are involved in a wide spectrum of diseases, including diabetes mellitus, inflammatory, vascular and neurodegenerative diseases, atherothrombosis, and cancer. Thus, the targeted inhibition of RAGE or its ligands is considered an important strategy for the treatment of cancer and chronic inflammatory diseases.
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Mollace A, Coluccio ML, Donato G, Mollace V, Malara N. Cross-talks in colon cancer between RAGE/AGEs axis and inflammation/immunotherapy. Oncotarget 2021; 12:1281-1295. [PMID: 34194625 PMCID: PMC8238251 DOI: 10.18632/oncotarget.27990] [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] [Received: 04/14/2021] [Accepted: 06/02/2021] [Indexed: 12/19/2022] Open
Abstract
The tumour microenvironment is the result of the activity of many types of cells in various metabolic states, whose metabolites are shared between cells. This cellular complexity results in an availability profile of nutrients and reactive metabolites such as advanced glycation end products (AGE). The tumour microenvironment is not favourable to immune cells due to hypoxia and for the existence of significant competition between various types of cells for a limited nutrient pool. However, it is now known that cancer cells can influence the host's immune reaction through the expression and secretion of numerous molecules. The microenvironment can therefore present itself in different patterns that contribute to shaping immune surveillance. Colorectal cancer (CRC) is one of the most important causes of death in cancer patients. Recently, immunotherapy has begun to give encouraging results in some groups of patients suffering from this neoplasm. The analysis of literature data shows that the RAGE (Receptor for advanced glycation end products) and its numerous ligands contribute to connect the energy metabolic pathway, which appears prevalently disconnected by mitochondrial running, with the immune reaction, conditioned by local microbiota and influencing tumour growth. Understanding how metabolism in cancer and immune cells shapes response and resistance to therapy, will provide novel potential strategies to increase both the number of tumour types treated by immunotherapy and the rate of immunotherapy response. The analysis of literature data shows that an immunotherapy approach based on the knowledge of RAGE and its ligands is not only possible, but also desirable in the treatment of CRC.
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Affiliation(s)
- Annachiara Mollace
- Department of Health Sciences, Research Centre IRC-FSH, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy
| | - Maria Laura Coluccio
- Department of Experimental and Clinical Medicine, Bionem Laboratory, Magna Græcia University of Catanzaro, 88100 Catanzaro, Italy
| | - Giuseppe Donato
- Department of Health Sciences, University Magna Græcia of Catanzaro, Campus S. Venuta, 88100 Catanzaro, Italy
| | - Vincenzo Mollace
- Department of Health Sciences, Research Centre IRC-FSH, University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy.,These authors contributed equally to this work
| | - Natalia Malara
- Department of Experimental and Clinical Medicine, Bionem Laboratory, Magna Græcia University of Catanzaro, 88100 Catanzaro, Italy.,These authors contributed equally to this work
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Kennon AM, Stewart JA. RAGE Differentially Altered in vitro Responses in Vascular Smooth Muscle Cells and Adventitial Fibroblasts in Diabetes-Induced Vascular Calcification. Front Physiol 2021; 12:676727. [PMID: 34163373 PMCID: PMC8215351 DOI: 10.3389/fphys.2021.676727] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 05/11/2021] [Indexed: 12/12/2022] Open
Abstract
The Advanced Glycation End-Products (AGE)/Receptor for AGEs (RAGE) signaling pathway exacerbates diabetes-mediated vascular calcification (VC) in vascular smooth muscle cells (VSMCs). Other cell types are involved in VC, such as adventitial fibroblasts (AFBs). We hope to elucidate some of the mechanisms responsible for differential signaling in diabetes-mediated VC with this work. This work utilizes RAGE knockout animals and in vitro calcification to measure calcification and protein responses. Our calcification data revealed that VSMCs calcification was AGE/RAGE dependent, yet AFBs calcification was not an AGE-mediated RAGE response. Protein expression data showed VSMCs lost their phenotype marker, α-smooth muscle actin, and had a higher RAGE expression over non-diabetics. RAGE knockout (RKO) VSMCs did not show changes in phenotype markers. P38 MAPK, a downstream RAGE-associated signaling molecule, had significantly increased activation with calcification in both diabetic and diabetic RKO VSMCs. AFBs showed a loss in myofibroblast marker, α-SMA, due to calcification treatment. RAGE expression decreased in calcified diabetic AFBs, and P38 MAPK activation significantly increased in diabetic and diabetic RKO AFBs. These findings point to potentially an alternate receptor mediating the calcification response in the absence of RAGE. Overall, VSMCs and AFBs respond differently to calcification and the application of AGEs.
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Affiliation(s)
- Amber M Kennon
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Mississippi, MS, United States
| | - James A Stewart
- Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, Mississippi, MS, United States
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Cheng TL, Lin YS, Hong YK, Ma CY, Tsai HW, Shi GY, Wu HL, Lai CH. Role of tumor endothelial marker 1 (Endosialin/CD248) lectin-like domain in lipopolysaccharide-induced macrophage activation and sepsis in mice. Transl Res 2021; 232:150-162. [PMID: 33737161 DOI: 10.1016/j.trsl.2021.03.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 11/16/2022]
Abstract
Deleterious hyper-inflammation resulting from macrophage activation may aggravate sepsis and lead to lethality. Tumor endothelial marker 1 (TEM1), a type I transmembrane glycoprotein containing six functional domains, has been implicated in cancer and chronic sterile inflammatory disorders. However, the role of TEM1 in acute sepsis remains to be determined. Herein we explored the functional significance of the TEM1 lectin-like domain (TEM1D1) in monocyte/macrophage activation and sepsis using TEM1D1-deleted (TEM1LeD/LeD) transgenic mice and recombinant TEM1D1 (rTEM1D1) protein. Under stimulation with lipopolysaccharides (LPS) or several other toll-like receptor agonists, TEM1LeD/LeD macrophages produced lower levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 than wild-type TEM1wt/wt macrophages. Compared with TEM1wt/wt macrophages, LPS-macrophage binding and intracellular mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-κB activation were suppressed in TEM1LeD/LeD macrophages. In vivo, TEM1D1 deletion improved survival in LPS-challenged mice with reduction of circulating TNF-α and IL-6 and alleviation of lung injury and pulmonary leukocyte accumulation. In contrast, rTEM1D1 could bind to LPS and markedly suppress LPS-macrophage binding, MAPK/NF-κB signaling in macrophages and proinflammatory cytokine production. Treatment with rTEM1D1 improved survival and attenuated circulating TNF-α and IL-6, lung injury and pulmonary accumulation of leukocytes in LPS-challenged mice. These findings demonstrated differential roles for the TEM1 lectin-like domain in macrophages and soluble TEM1 lectin-like domain in sepsis. TEM1 in macrophages mediates LPS-induced inflammation via its lectin-like domain, whereas rTEM1D1 interferes with LPS-induced macrophage activation and sepsis.
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Affiliation(s)
- Tsung-Lin Cheng
- Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Orthopedic Research Center, College of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan; Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yu-Syuan Lin
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Kai Hong
- Department of Dermatology, National Cheng Kung University hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; International Center for Wound Repair and Regeneration, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chih-Yuan Ma
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Guey-Yueh Shi
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Hua-Lin Wu
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; International Center for Wound Repair and Regeneration, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chao-Han Lai
- Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee.
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