1
|
Woolls MK, Mott MD, Poole CS, Gregory JA, Ivester HM, Allen IC. Innate Immunity Never "NODs" Off: NLRs Regulate the Host Anti-Viral Immune Response. Immunol Rev 2025; 330:e13429. [PMID: 39878363 PMCID: PMC11776368 DOI: 10.1111/imr.13429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/14/2024] [Revised: 11/22/2024] [Accepted: 12/02/2024] [Indexed: 01/31/2025]
Abstract
A robust innate immune response is essential in combating viral pathogens. However, it is equally critical to quell overzealous immune signaling to limit collateral damage and enable inflammation resolution. Pattern recognition receptors are critical regulators of these processes. The cytosolic nucleotide-binding domain leucine-rich repeat (NLR; NOD-like receptor) family of pattern recognition receptors plays essential roles in the sensing of viral pathogen-associated molecular patterns and is best characterized for itsr pro-inflammatory biological functions. Specifically, these include the formation of multi-protein complexes, defined as inflammasomes or NODosomes that regulate the production of IL-1beta, IL-18, and pyroptosis, or the induction of NF-ΚB signaling. While these biological effects are inherently pro-inflammatory, it is also important to recognize that other NLR family members conversely function to negatively regulate inflammation through modulating signaling initiated by other families of pattern recognition receptors. Mechanistically, these unique NLRs also form multiprotein complexes that act to attenuate a variety of biological signaling pathways, such as the inhibition of NF-ΚB. This inhibition facilitates inflammation resolution and functions to restore cellular homeostasis. Despite extensive characterization of individual NLR family members, the mechanisms of immune system regulation are highly nuanced and remain enigmatic. This is especially true for non-inflammasome-forming, regulatory NLRs. Here, we discuss recent findings associated with NLR family members that play essential roles in the host immune response to viruses and mechanisms by which these pattern recognition receptors may function to regulate antiviral immunity.
Collapse
Affiliation(s)
- Mackenzie K. Woolls
- Graduate Program in Translational Biology, Medicine, and HealthVirginia TechRoanokeVirginiaUSA
| | - Madeline D. Mott
- Graduate Program in Translational Biology, Medicine, and HealthVirginia TechRoanokeVirginiaUSA
| | - Cassandra S. Poole
- Biomedical and Veterinary Sciences Graduate Program, Virginia Maryland College of Veterinary MedicineVirginia TechBlacksburgVirginiaUSA
| | - Julia A. Gregory
- Department of Biological Sciences Undergraduate Program, College of Biological SciencesVirginia TechBlacksburgVirginiaUSA
| | - Hannah M. Ivester
- Graduate Program in Translational Biology, Medicine, and HealthVirginia TechRoanokeVirginiaUSA
| | - Irving Coy Allen
- Graduate Program in Translational Biology, Medicine, and HealthVirginia TechRoanokeVirginiaUSA
- Biomedical and Veterinary Sciences Graduate Program, Virginia Maryland College of Veterinary MedicineVirginia TechBlacksburgVirginiaUSA
- Department of Basic Science EducationVirginia Tech Carilion School of MedicineRoanokeVirginiaUSA
- The Virginia Tech Center for Emerging, Zoonotic and Arthropod‐Borne PathogensVirginia TechBlacksburgVirginiaUSA
| |
Collapse
|
2
|
Garg S, Rai G, Singh S, Gauba P, Ali J, Dang S. An insight into the role of innate immune cells in breast tumor microenvironment. Breast Cancer 2025; 32:79-100. [PMID: 39460874 DOI: 10.1007/s12282-024-01645-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/07/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024]
Abstract
The immune background of breast cancer is highly heterogeneous and the immune system of the human body plays a dual role by both promoting and suppressing its progression. Innate immune cells are the first line of defense in the immune system and impart protection by identifying and interacting with foreign pathogens and cancer cells. Different innate immune cells like natural killer cells, macrophages, dendritic cells, and myeloid suppressor cells take part in hosting the cancer cells. Autophagy is another key component inside the tumor microenvironment and is linked to the disintegration and recycling of cellular components. Within the tumor microenvironment autophagy is involved with Pattern Recognition Receptors and inflammation. Various clinical studies have shown prominent results where innate immune cells and autophagy in combination are used for pathogen as well as cancer cell clearance. However, it is necessary to comprehend the complex tumor microenvironment so that different therapeutic approaches can be developed to enhance the suppressive actions of the cells toward breast cancer cells. In this review article, the complex interaction between immune cells and breast cancer cells and their role in developing effective immunotherapies to improve patient outcomes are discussed in detail.
Collapse
Affiliation(s)
- Sandini Garg
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
| | - Garima Rai
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
| | - Sakshi Singh
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
| | - Pammi Gauba
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India
| | - Javed Ali
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India
| | - Shweta Dang
- Department of Biotechnology, Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India.
| |
Collapse
|
3
|
Koskimäki F, Ahokas O, Kajanne R, Saviauk KR, Elnahas A, Reigo A, Reis K, Esko T, Palta P, Leinonen S, Kettunen J, Liinamaa J, Karjalainen MK, Saarela V. Genome-wide association study of anterior uveitis. Br J Ophthalmol 2024:bjo-2024-326037. [PMID: 39732499 DOI: 10.1136/bjo-2024-326037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/20/2024] [Accepted: 12/01/2024] [Indexed: 12/30/2024]
Abstract
BACKGROUND/AIMS The purpose of this study is to define genetic factors associated with anterior uveitis through genome-wide association study (GWAS). METHODS In this GWAS meta-analysis, we combined data from the FinnGen, Estonian Biobank and UK Biobank with a total of 12 205 anterior uveitis cases and 917 145 controls. We performed a phenome-wide association study (PheWAS) to investigate associations across phenotypes and traits. We also evaluated genetic correlations of anterior uveitis. RESULTS We identified six anterior uveitis-associated loci. Genome-wide significant (p<5 × 10-8) associations were identified for the first time at three loci (innate immunity activator (INAVA), nucleotide-binding domain, leucine-rich repeat family, pyrin domain containing 3 and nitric oxide synthase 2). We detected associations at three loci previously reported to be associated with uveitis (endoplasmic reticulum aminopeptidase 1 (ERAP1), the trinucleotide repeat containing 18 (TNRC18) and the HLA region) and also replicated associations at two loci previously associated with acute anterior uveitis (IL23R and HDAC2-AS2). In PheWAS, we further detected that lead single nucleotide polymorphisms (SNPs) at three of the anterior uveitis-associated loci (ERAP1, INAVA and TNRC18) are associated with other immunity-related phenotypes, including ankylosing spondylitis and inflammatory bowel disease. Additionally, we detected a moderate genetic correlation between anterior uveitis and inflammatory bowel disease (rg =0.39, p=8 × 10-5). CONCLUSION We identified six anterior uveitis-associated loci, including three novel loci with genome-wide significance. Our findings deepen our understanding of the genetic basis of anterior uveitis and the genetic connections between anterior uveitis and immune-related disorders, providing a foundation for further research and potential therapeutic interventions.
Collapse
Affiliation(s)
- Fredrika Koskimäki
- Department of Ophthalmology and Medical Research Center, Oulu University Hospital; Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland
| | - Oona Ahokas
- Department of Ophthalmology and Medical Research Center, Oulu University Hospital; Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland
- Department of Mathematical Sciences, University of Oulu, Oulu, Finland
| | | | | | - Abdelrahman Elnahas
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Anu Reigo
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Kadri Reis
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Tõnu Esko
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Priit Palta
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Sanna Leinonen
- Tays Eye Centre, Tampere University Hospital, Tampere, Finland
| | - Johannes Kettunen
- Research Unit of Population Health, Faculty of Medicine, University of Oulu; Biocenter Oulu, University of Oulu, Oulu, Finland
- Finnish Institute for Health and Welfare (THL), Helsinki, Finland
| | - Johanna Liinamaa
- Department of Ophthalmology and Medical Research Center, Oulu University Hospital; Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland
| | - Minna K Karjalainen
- Research Unit of Population Health, Faculty of Medicine, University of Oulu; Northern Finland Birth Cohorts, Arctic Biobank, Infrastructure for Population Studies, Faculty of Medicine, University of Oulu, Oulu, Finland
- Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
| | - Ville Saarela
- Department of Ophthalmology and Medical Research Center, Oulu University Hospital; Research Unit of Clinical Medicine, University of Oulu, Oulu, Finland
| |
Collapse
|
4
|
Vinnitskaya EV, Sandler YG, Saliev KG, Ivanov AN, Sbikina ES, Khaymenova TY, Bordin DS. Efficacy of human placenta hydrolyzate in the treatment of patients with metabolic associated fatty liver disease at the stage of fibrosis (pilot study). TERAPEVT ARKH 2024; 96:107-116. [DOI: 10.26442/00403660.2024.02.202582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/03/2025]
Abstract
Background. Despite active research, drug treatment options for metabolic associated fatty liver disease (MAFLD) are limited, and there are no currently approved drugs for patients with MAFLD. Treatment of patients at risk of developing non-alcoholic steatohepatitis and progressive liver fibrosis (LF) is of particular relevance, since they determine the clinical outcomes of the disease.
Aim. To evaluate the clinical efficacy of complex polypeptide drug (CPD), human placenta hydrolyzate, containing low molecular weight regulatory peptides, amino acids, vitamins, macro- and microelements in patients with MAFLD at the LF stage.
Materials and methods. A single-center, placebo-controlled pilot study. Patients with MAFLD at LF stage 1≤F≤3 according to METAVIR were included (n=10, of which 8 were women, median age was 55 years old). Patients were randomized into 2 groups: 5 people received CPD therapy for 12 weeks (intravenous infusion of 6 ml 2 times a week); another 5 people initially received placebo x 2 times a week (12 weeks), with transfer to the open phase for CPD therapy in the same regimen. The dynamics laboratory and instrumental data was assessed, as well as determine the presence of fibrosis by non-invasive tests – measurement of liver stiffness by transient elastography and use of serum biomarker (SM) by FibroTest and detection of steatosis with controlled attenuation parameter for transient elastography and SM by SteatoTest. The quality of life of patients was assessed using questionnaire SF-36 and well-being via Visual Analogue Scale. Statistical processing of the material was carried out using the methods of nonparametric analysis, using the Statistica 13.3 software.
Results. Patients in the CPD group compared with the baseline data and with the placebo group showed a statistically significant improvement: 1) transaminases (ALT, AST), lipid profile indicators (cholesterol), ferritin; 2) indicators of LF, based on a decrease in liver stiffness by transient elastography and SM of Fibrotest, as well as the degree of steatosis based on controlled attenuation parameter and SM of Steatotest; 3) in well-being and quality of life (according to testing: SF-36 physical, mental well-being and general condition of the VAS). CPD was well tolerated, no side effects were noted.
Conclusion. In patients with MAFLD during CPD therapy, a decrease in the level of liver enzymes was noted, as well as in LF and liver steatosis according to noninvasive methods. Randomized controlled trials are required to confirm these findings.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Dmitry S. Bordin
- Loginov Moscow Clinical Scientific Center
- Russian University of Medicine
- Tver State Medical University
| |
Collapse
|
5
|
Nomani H, Deng Z, Navetta-Modrov B, Yang J, Yun M, Aroniadis O, Gorevic P, Aksentijevich I, Yao Q. Implications of combined NOD2 and other gene mutations in autoinflammatory diseases. Front Immunol 2023; 14:1265404. [PMID: 37928541 PMCID: PMC10620916 DOI: 10.3389/fimmu.2023.1265404] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/22/2023] [Accepted: 10/09/2023] [Indexed: 11/07/2023] Open
Abstract
NOD-like receptors (NLRs) are intracellular sensors associated with systemic autoinflammatory diseases (SAIDs). We investigated the largest monocentric cohort of patients with adult-onset SAIDs for coinheritance of low frequency and rare mutations in NOD2 and other autoinflammatory genes. Sixty-three patients underwent molecular testing for SAID gene panels after extensive clinical workups. Whole exome sequencing data from the large Atherosclerosis Risk in Communities (ARIC) study of individuals of European-American ancestry were used as control. Of 63 patients, 44 (69.8%) were found to carry combined gene variants in NOD2 and another gene (Group 1), and 19 (30.2%) were carriers only for NOD2 variants (Group 2). The genetic variant combinations in SAID patients were digenic in 66% (NOD2/MEFV, NOD2/NLRP12, NOD2/NLRP3, and NOD2/TNFRSF1A) and oligogenic in 34% of cases. These variant combinations were either absent or significantly less frequent in the control population. By phenotype-genotype correlation, approximately 40% of patients met diagnostic criteria for a specific SAID, and 60% had mixed diagnoses. There were no statistically significant differences in clinical manifestations between the two patient groups except for chest pain. Due to overlapping phenotypes and mixed genotypes, we have suggested a new term, "Mixed NLR-associated Autoinflammatory Disease ", to describe this disease scenario. Gene variant combinations are significant in patients with SAIDs primarily presenting with mixed clinical phenotypes. Our data support the proposition that immunological disease expression is modified by genetic background and environmental exposure. We provide a preliminary framework in diagnosis, management, and interpretation of the clinical scenario.
Collapse
Affiliation(s)
- Hafsa Nomani
- Division of Rheumatology, Allergy and Immunology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
| | - Zuoming Deng
- Biodata Mining and Discovery Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, United States
| | - Brianne Navetta-Modrov
- Division of Rheumatology, Allergy and Immunology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
| | - Jie Yang
- Department of Family, Population and Preventive Medicine, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
| | - Mark Yun
- Division of Rheumatology, Allergy and Immunology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
| | - Olga Aroniadis
- Division of Gastroenterology and Hepatology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
| | - Peter Gorevic
- Division of Rheumatology, Allergy and Immunology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
| | - Ivona Aksentijevich
- Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
| | - Qingping Yao
- Division of Rheumatology, Allergy and Immunology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, United States
| |
Collapse
|
6
|
Hirano SI, Ichikawa Y, Sato B, Takefuji Y, Satoh F. Clinical Use and Treatment Mechanism of Molecular Hydrogen in the Treatment of Various Kidney Diseases including Diabetic Kidney Disease. Biomedicines 2023; 11:2817. [PMID: 37893190 PMCID: PMC10603947 DOI: 10.3390/biomedicines11102817] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/31/2023] [Revised: 10/13/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
As diabetes rates surge globally, there is a corresponding rise in the number of patients suffering from diabetic kidney disease (DKD), a common complication of diabetes. DKD is a significant contributor to chronic kidney disease, often leading to end-stage renal failure. However, the effectiveness of current medical treatments for DKD leaves much to be desired. Molecular hydrogen (H2) is an antioxidant that selectively reduces hydroxyl radicals, a reactive oxygen species with a very potent oxidative capacity. Recent studies have demonstrated that H2 not only possesses antioxidant properties but also exhibits anti-inflammatory effects, regulates cell lethality, and modulates signal transduction. Consequently, it is now being utilized in clinical applications. Many factors contribute to the onset and progression of DKD, with mitochondrial dysfunction, oxidative stress, and inflammation being strongly implicated. Recent preclinical and clinical trials reported that substances with antioxidant properties may slow the progression of DKD. Hence, we undertook a comprehensive review of the literature focusing on animal models and human clinical trials where H2 demonstrated effectiveness against a variety of renal diseases. The collective evidence from this literature review, along with our previous findings, suggests that H2 may have therapeutic benefits for patients with DKD by enhancing mitochondrial function. To substantiate these findings, future large-scale clinical studies are needed.
Collapse
Affiliation(s)
- Shin-ichi Hirano
- Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura 247-0056, Japan; (Y.I.); (B.S.); (F.S.)
| | - Yusuke Ichikawa
- Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura 247-0056, Japan; (Y.I.); (B.S.); (F.S.)
| | - Bunpei Sato
- Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura 247-0056, Japan; (Y.I.); (B.S.); (F.S.)
| | - Yoshiyasu Takefuji
- Keio University, 2-15-45 Mita, Minato-ku, Tokyo 108-8345, Japan;
- Faculty of Data Science, Musashino University, 3-3-3 Ariake, Koto-ku, Tokyo 135-8181, Japan
| | - Fumitake Satoh
- Department of Research and Development, MiZ Company Limited, 2-19-15 Ofuna, Kamakura 247-0056, Japan; (Y.I.); (B.S.); (F.S.)
| |
Collapse
|
7
|
Arrindell J, Desnues B. Vimentin: from a cytoskeletal protein to a critical modulator of immune response and a target for infection. Front Immunol 2023; 14:1224352. [PMID: 37475865 PMCID: PMC10354447 DOI: 10.3389/fimmu.2023.1224352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/17/2023] [Accepted: 06/20/2023] [Indexed: 07/22/2023] Open
Abstract
Vimentin is an intermediate filament protein that plays a role in cell processes, including cell migration, cell shape and plasticity, or organelle anchorage. However, studies from over the last quarter-century revealed that vimentin can be expressed at the cell surface and even secreted and that its implications in cell physiology largely exceed structural and cytoskeletal functions. Consequently, vimentin contributes to several pathophysiological conditions such as cancer, autoimmune and inflammatory diseases, or infection. In this review, we aimed at covering these various roles and highlighting vimentin implications in the immune response. We also provide an overview of how some microbes including bacteria and viruses have acquired the ability to circumvent vimentin functions in order to interfere with host responses and promote their uptake, persistence, and egress from host cells. Lastly, we discuss the therapeutic approaches associated with vimentin targeting, leading to several beneficial effects such as preventing infection, limiting inflammatory responses, or the progression of cancerous events.
Collapse
Affiliation(s)
- Jeffrey Arrindell
- Aix Marseille Univ, Institut de Recherche pour le Développement (IRD), Assistance Publique-Hôpitaux de Marseille (AP-HM), Microbes Evolution Phylogeny and Infections (MEPHI), Marseille, France
- Institut Hospitalo-Universitaire (IHU)-Méditerranée Infection, Marseille, France
| | - Benoit Desnues
- Aix Marseille Univ, Institut de Recherche pour le Développement (IRD), Assistance Publique-Hôpitaux de Marseille (AP-HM), Microbes Evolution Phylogeny and Infections (MEPHI), Marseille, France
- Institut Hospitalo-Universitaire (IHU)-Méditerranée Infection, Marseille, France
| |
Collapse
|
8
|
Paik S, Song GY, Jo EK. Ginsenosides for therapeutically targeting inflammation through modulation of oxidative stress. Int Immunopharmacol 2023; 121:110461. [PMID: 37331298 DOI: 10.1016/j.intimp.2023.110461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/05/2023] [Revised: 05/20/2023] [Accepted: 06/04/2023] [Indexed: 06/20/2023]
Abstract
Ginsenosides are steroid glycosides derived from ginseng plants such as Panax ginseng, Panax quinquefolium, and Panax notoginseng. Advances in recent studies have identified numerous physiological functions of each type of ginsenoside, i.e., immunomodulatory, antioxidative, and anti-inflammatory functions, in the context of inflammatory diseases. Accumulating evidence has revealed the molecular mechanisms by which the single or combined ginsenoside(s) exhibit anti-inflammatory effects, although it remains largely unclear. It is well known that excessive production of reactive oxygen species (ROS) is associated with pathological inflammation and cell death in a variety of cells, and that inhibition of ROS generation ameliorates the local and systemic inflammatory responses. The mechanisms by which ginsenosides attenuate inflammation are largely unknown; however, targeting ROS is suggested as one of the crucial mechanisms for the ginsenosides to control the pathological inflammation in the immune and non-immune cells. This review will summarize the latest progress in ginsenoside studies, particularly in the context of antioxidant mechanisms for its anti-inflammatory effects. A better understanding of the distinct types and the combined action of ginsenosides will pave the way for developing potential preventive and therapeutic modalities in treating various inflammation-related diseases.
Collapse
Affiliation(s)
- Seungwha Paik
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon, 35015, South Korea; Department of Medical Science, Chungnam National University School of Medicine, Daejeon, 35015, South Korea.
| | - Gyu Yong Song
- Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, 35015, South Korea; College of Pharmacy, Chungnam National University, Daejeon, 34134, South Korea
| | - Eun-Kyeong Jo
- Department of Microbiology, Chungnam National University School of Medicine, Daejeon, 35015, South Korea; Department of Medical Science, Chungnam National University School of Medicine, Daejeon, 35015, South Korea; Infection Control Convergence Research Center, Chungnam National University School of Medicine, Daejeon, 35015, South Korea.
| |
Collapse
|
9
|
Abstract
With a global burden of 844 million, chronic kidney disease (CKD) is now considered a public health priority. Cardiovascular risk is pervasive in this population, and low-grade systemic inflammation is an established driver of adverse cardiovascular outcomes in these patients. Accelerated cellular senescence, gut microbiota-dependent immune activation, posttranslational lipoprotein modifications, neuroimmune interactions, osmotic and nonosmotic sodium accumulation, acute kidney injury, and precipitation of crystals in the kidney and the vascular system all concur in determining the unique severity of inflammation in CKD. Cohort studies documented a strong link between various biomarkers of inflammation and the risk of progression to kidney failure and cardiovascular events in patients with CKD. Interventions targeting diverse steps of the innate immune response may reduce the risk of cardiovascular and kidney disease. Among these, inhibition of IL-1β (interleukin-1 beta) signaling by canakinumab reduced the risk for cardiovascular events in patients with coronary heart disease, and this protection was equally strong in patients with and without CKD. Several old (colchicine) and new drugs targeting the innate immune system, like the IL-6 (interleukin 6) antagonist ziltivekimab, are being tested in large randomized clinical trials to thoroughly test the hypothesis that mitigating inflammation may translate into better cardiovascular and kidney outcomes in patients with CKD.
Collapse
Affiliation(s)
- Carmine Zoccali
- Renal Research Institute New York and Institute of Molecular Biology and genetics (BIOGEM), Ariano Irpino, Italy and Associazione Ipertensione, Nefrologia, Trapianto (IPNET), Reggio Calabria Italy (C.Z.)
| | - Francesca Mallamaci
- Division of Nephrology and Transplantation, Grande Ospedale Metropolitano, Reggio Calabria, Italy and National Research Council (CNR), Clinical Epidemiology of Hypertension and Renal Diseases Unit of the Institute of Clinical Physiology, Reggio Calabria, Italy (F.M.)
| |
Collapse
|
10
|
Qiu H, Wang W, Hu K, Liu W, Pan S, Lv Q, Xu G, Yu Q. EuHD1 protects against inflammatory injury driven by NLRP3 inflammasome. Int Immunopharmacol 2023; 115:109712. [PMID: 37724954 DOI: 10.1016/j.intimp.2023.109712] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/27/2022] [Revised: 12/19/2022] [Accepted: 01/06/2023] [Indexed: 01/21/2023]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) possessing anti-inflammatory, analgesic and antipyretic activities, are widely used in the treatment of osteoarthritis, rheumatism and rheumatoid arthritis. However, its long-term or large use will cause serious gastrointestinal injury or cardiovascular adverse reactions, which limits its clinical application. We have synthesized a new class of NSAIDs, EuHD1, which can release hydrogen sulfide and have better gastrointestinal safety. However, the anti-inflammatory molecular mechanism of the drug is still unclear. In this paper, we explored the mechanism of EuHD1 on NLRP3 inflammasome and its effects on acute lung injury and acute liver injury in mice. In vitro results demonstrated that EuHD1 inhibited macrophage pyroptosis and LDH release induced by LPS combined with ATP. In addition, EuHD1 blocked NLRP3 inflammasome activation and suppressed following Caspase-1 activation and secretion of mature IL-1β. EuHD1 restrained intracellular ROS production and the formation of ASC oligomers, which inhibited the assembly and activation of NLRP3 inflammasome. In vivo results further showed that EuHD1 alleviated LPS-induced acute lung injury in mice, and inhibited the production of mature IL-1β and Caspase-1 (p20). Besides, EuHD1 improved D-GalN/LPS-induced acute liver injury, and inhibited SOD/MDA levels and oxidative stress injury, and blocked the activation of NLRP3 inflammasome. In summary, we found that EuHD1 inhibits the assembly and activation of NLRP3 inflammasome through restraining the production of ROS and the formation of ASC oligomers, and has therapeutic effects on acute lung injury and liver injury in mice, indicating that EuHD1 has the potential to treat NLRP3 inflammasome-related diseases.
Collapse
Affiliation(s)
- Huanhuan Qiu
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, China
| | - Wei Wang
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, China
| | - Kejun Hu
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Wangwang Liu
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Shumin Pan
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Qi Lv
- College of Life Science, Nanjing Normal University, Nanjing, China
| | - Guanglin Xu
- College of Life Science, Nanjing Normal University, Nanjing, China; Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, China.
| | - Qingfeng Yu
- School of Science, China Pharmaceutical University, Nanjing, China.
| |
Collapse
|
11
|
Azimi S, Saghafi F, Mohammadi MH, Moghimi MH, Akhavan SA, Khataminia M, Shirvani M, Sohrevardi SM, Jamialahmadi T, Sahebnasagh A, Sahebkar A. The Potential of Cannabidiol for Acute Respiratory Distress Syndrome in COVID-19. Curr Pharm Des 2023; 29:2291-2296. [PMID: 37818584 DOI: 10.2174/0113816128275803230920094909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/05/2023] [Accepted: 08/22/2023] [Indexed: 10/12/2023]
Abstract
COVID-19 disease manifests itself in a wide range of signs and symptoms, beginning with mild symptoms, such as fever, cough, and dyspnea, progressing to acute respiratory distress syndrome (ARDS) and death in some cases. The cytokine storm, or an excess of cytokines released locally, is assumed to be the primary cause of ARDS and mortality in COVID-19 patients. To enhance the survival rate of COVID-19 patients, early management of the cytokine storm with immunomodulators is crucial. Although the effectiveness of some immunosuppressants, such as corticosteroids and tocilizumab, has been studied in clinical trials, the administration of these drugs should be exercised cautiously. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid from Cannabis sativa extracts with anti-inflammatory properties. This review is intended to discuss the possible utility of CBD for the management of COVID-19 patients, particularly those with ARDS.
Collapse
Affiliation(s)
- Saeid Azimi
- Student Research Committee, Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fatemeh Saghafi
- Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | | | - Mohammad Hossein Moghimi
- Student Research Committee, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Seyed Ali Akhavan
- Student Research Committee, Faculty of Pharmacy, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Masoud Khataminia
- Student Research Committee, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Maria Shirvani
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Seyed Mojtaba Sohrevardi
- Department of Clinical Pharmacy, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Tannaz Jamialahmadi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Adeleh Sahebnasagh
- Department of Internal Medicine, Clinical Research Center, North Khorasan University of Medical Sciences, Bojnurd, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
12
|
Tang B, Zhong Z, Wu J, Ma J, Li L, Zhong X, Lin D, Hu J, Yu P. Evaluation of Serum NLRC4 as a Potential Prognostic Biochemical Marker in Humans with Severe Traumatic Brain Injury: A Prospective Cohort Study. Risk Manag Healthc Policy 2023; 16:439-454. [PMID: 36994425 PMCID: PMC10042254 DOI: 10.2147/rmhp.s404877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/14/2023] [Accepted: 03/15/2023] [Indexed: 03/31/2023] Open
Abstract
Objective Involvement of NLR CARD domain containing 4 (NLRC4) in neuroinflammation has been demonstrated. The aim of this study was to ascertain the prognostic role of serum NLRC4 in severe traumatic brain injury (sTBI). Methods In this prospective cohort study including 140 sTBI patients and 140 controls, serum NLRC4 levels were quantified. Follow-up time was 180 days after trauma and poor prognosis was designated as extended Glasgow outcome scale (GOSE) scores of 1-4. Severity correlations and prognosis associations were determined under multivariate models. Results Enhanced serum NLRC4 levels after sTBI, in comparison to controls (median, 0.8 ng/mL versus 0.1 ng/mL; P < 0.001), were independently correlated with Glasgow coma scale (GCS) scores (β, -0.091; 95% confidence interval (CI), -0.161-0.021; P = 0.011), Rotterdam computed tomography (CT) scores (β, 0.136; 95% CI, 0.024-0.248; P = 0.018), serum C-reactive protein levels (β, 0.016; 95% CI, 0.002-0.030; P = 0.025) and 180-day GOSE scores (β, -0.906; 95% CI, -1.632-0.180; P = 0.015); and were independently predictive of 180-day death (odds ratio, 4.307; 95% CI, 1.706-10.879; P = 0.014)), overall survival (hazard ratio, 2.360; 95% CI, 1.118-4.981; P = 0.040) and poor prognosis (odds ratio, 6.705; 95% CI, 2.889-15.561; P = 0.016). Under receiver operating characteristic curve, combination of serum NLRC4 levels, GCS scores and Rotterdam CT scores had significantly higher death predictive ability than Rotterdam CT scores (P = 0.040), but not than GCS scores (P = 0.070); and exhibited substantially higher predictive capability for poor prognosis than Rotterdam CT scores (P < 0.001) and GCS scores alone (P = 0.023). Conclusion There is a dramatical elevation of serum NLRC4 levels after sTBI, which has strong correlation with severity and inflammation, and is significantly associated with long-term death and poor outcome, substantializing serum NLRC4 as an inflammatory, prognostic biomarker in sTBI.
Collapse
Affiliation(s)
- Bei Tang
- Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China
| | - Ze Zhong
- Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China
- Correspondence: Ze Zhong, Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China, Tel/Fax +86 571 64096607, Email
| | - Jinping Wu
- Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China
| | - Jianping Ma
- Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China
| | - Li Li
- Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China
| | - Xuzheng Zhong
- Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China
| | - Dongmei Lin
- Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China
| | - Jiayuan Hu
- Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China
| | - Pingan Yu
- Department of Critical Care Medicine, The First People’s Hospital of Jiande City, Jiande, People’s Republic of China
| |
Collapse
|
13
|
Sui H, Chen Q, Yang J, Srirattanapirom S, Imamichi T. Manganese enhances DNA- or RNA-mediated innate immune response by inducing phosphorylation of TANK-binding kinase 1. iScience 2022; 25:105352. [PMID: 36325059 PMCID: PMC9619380 DOI: 10.1016/j.isci.2022.105352] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/14/2022] [Revised: 05/22/2022] [Accepted: 10/11/2022] [Indexed: 12/05/2022] Open
Abstract
Trace metals are essential for various physiological processes, but their roles in innate immunity have not been fully explored. Here, we found that manganese (Mn) significantly enhanced DNA-mediated IFN-α, IFN-β, and IFN-λ1 production. Microarray analysis demonstrated Mn highly upregulated 351 genes, which were involved in multiple biological functions related to innate immune response. Moreover, we found that Mn2+ alone activates phosphorylation of TANK-binding kinase 1 (TBK1). Inhibiting ataxia telangiectasia mutated (ATM) kinase using ATM inhibitor or siRNA suppressed Mn-enhanced DNA-mediated immune response with decreasing phosphorylation of TBK-1, suggesting that ATM involves in Mn-dependent phosphorylation of TBK1. Given that TBK1 is an essential mediator in DNA- or RNA-mediated signaling pathways, we further demonstrated that Mn2+ suppressed infection of HSV-1 (DNA virus) or Sendai virus (RNA virus) into human macrophages by enhancing antiviral immunity. Our finding highlights a beneficial role of Mn in nucleic-acid-based preventive or therapeutic reagents against infectious diseases.
Collapse
Affiliation(s)
- Hongyan Sui
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Qian Chen
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Jun Yang
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Selena Srirattanapirom
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Tomozumi Imamichi
- Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| |
Collapse
|
14
|
Zhou J, Wang Q. Daphnoretin relieves IL-1β-mediated chondrocytes apoptosis via repressing endoplasmic reticulum stress and NLRP3 inflammasome. J Orthop Surg Res 2022; 17:487. [PMID: 36384642 PMCID: PMC9670399 DOI: 10.1186/s13018-022-03316-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/21/2021] [Accepted: 09/07/2022] [Indexed: 11/17/2022] Open
Abstract
Background Osteoarthritis (OA), mainly caused by severe joint degeneration, is often accompanied by joint pain and dysfunction syndrome. Inflammatory mediators and apoptosis play key roles in the evolution of OA. It is reported that daphnoretin has significant antiviral and anti-tumor values. The present study aims at investigating the role of daphnoretin in OA. Methods The OA mouse model was constructed by performing the destabilization of the medial meniscus through surgery, and the OA cell model was induced in ATDC5 chondrocytes with IL-1β (10 ng/mL) in vitro. Chondrocyte viability and apoptosis were measured by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT), Caspase-3 activity, and flow cytometry. The levels of COX-2, iNOS, TNF-α, IL-6, Bax, Bcl2, cleaved-Caspase3, endoplasmic reticulum stress (ERS) proteins (GRP78, CHOP, ATF6, and Caspase-12), and NLRP3-ASC-Caspase1 inflammasome were determined by quantitative real-time PCR or western blot. The concentrations of TNF-α, IL-6, and PGE2 were tested by enzyme-linked immunosorbent assay. The content of nitrates was detected by the Griess method. In vivo, morphologic differences in knee joint sections and the thickness of the subchondral bone density plate in mice were observed by hematoxylin–eosin (H&E) staining and safranin O-fast green staining. Results Daphnoretin effectively choked IL-1β-induced chondrocyte apoptosis and facilitated cell viability. Daphnoretin dose-dependently abated ERS, inflammatory mediators, and the activation of NLRP3 inflammasomes in IL-1β-induced chondrocytes. What’s more, in vivo experiments confirmed that daphnoretin alleviated OA progression in a murine OA model by mitigating inflammation and ERS. Conclusion Daphnoretin alleviated IL-1β-induced chondrocyte apoptosis by hindering ERS and NLRP3 inflammasome. Graphical abstract ![]()
Collapse
|
15
|
Graphene-Based Biosensors for Molecular Chronic Inflammatory Disease Biomarker Detection. BIOSENSORS 2022; 12:bios12040244. [PMID: 35448304 PMCID: PMC9030187 DOI: 10.3390/bios12040244] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 03/08/2022] [Revised: 04/04/2022] [Accepted: 04/11/2022] [Indexed: 11/17/2022]
Abstract
Chronic inflammatory diseases, such as cancer, diabetes mellitus, stroke, ischemic heart diseases, neurodegenerative conditions, and COVID-19 have had a high number of deaths worldwide in recent years. The accurate detection of the biomarkers for chronic inflammatory diseases can significantly improve diagnosis, as well as therapy and clinical care in patients. Graphene derivative materials (GDMs), such as pristine graphene (G), graphene oxide (GO), and reduced graphene oxide (rGO), have shown tremendous benefits for biosensing and in the development of novel biosensor devices. GDMs exhibit excellent chemical, electrical and mechanical properties, good biocompatibility, and the facility of surface modification for biomolecular recognition, opening new opportunities for simple, accurate, and sensitive detection of biomarkers. This review shows the recent advances, properties, and potentialities of GDMs for developing robust biosensors. We show the main electrochemical and optical-sensing methods based on GDMs, as well as their design and manufacture in order to integrate them into robust, wearable, remote, and smart biosensors devices. We also describe the current application of such methods and technologies for the biosensing of chronic disease biomarkers. We also describe the current application of such methods and technologies for the biosensing of chronic disease biomarkers with improved sensitivity, reaching limits of detection from the nano to atto range concentration.
Collapse
|
16
|
Essential Role of NLRP3 Inflammasome in Mediating IL-1β Production and the Pathobiology of Staphylococcus aureus Endophthalmitis. Infect Immun 2022; 90:e0010322. [PMID: 35404106 DOI: 10.1128/iai.00103-22] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/28/2022] Open
Abstract
Staphylococcal endophthalmitis is one of the leading causes of blindness following ocular surgery and trauma. Dysregulated inflammation during bacterial endophthalmitis causes host-induced inflammatory damage and vision loss if it remains unchecked. Emerging evidence indicates that inflammasome plays a critical role in regulating innate immunity in various infectious and inflammatory diseases. However, the role of the inflammasome in endophthalmitis remains elusive. Here, using a mouse model of Staphylococcus (S) aureus endophthalmitis, we show that NLRP3/ASC/Caspase-1 signaling regulates IL-1β production in endophthalmitis. We also show that S. aureus and its cell wall components and toxins induce the activation of the NLRP3 inflammasome complex in mouse eyes. Moreover, we found that both infiltrating neutrophils and retinal microglia contribute toward NLRP3 activation and IL-1β production in S. aureus-infected eyes. Furthermore, our data using NLRP3-/- and IL-1β-/- mice revealed that NLRP3 and IL-1β deficiency leads to increased intraocular bacterial burden and retinal tissue damage. Altogether, our study demonstrated an essential role of NLRP3 inflammasome activation in regulating innate immune responses in bacterial endophthalmitis.
Collapse
|
17
|
Lam M, Mansell A, Tate MD. Another One Fights the Dust - Targeting the NLRP3 Inflammasome for the Treatment of Silicosis. Am J Respir Cell Mol Biol 2022; 66:601-611. [PMID: 35290170 DOI: 10.1165/rcmb.2021-0545tr] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/24/2022] Open
Abstract
Silicosis is a multifaceted lung disease, characterised by persistent inflammation and structural remodelling. Despite its poor prognosis, there are no treatments currently available for patients with silicosis. Recent pre-clinical findings in models of lung fibrosis have suggested a major role for the nucleotide binding domain and leucine-rich repeat pyrin domain containing 3 (NLRP3) inflammasome in silica-driven inflammation and fibrosis. This review outlines the beneficial effects of targeting the NLRP3 inflammasome in in vitro cell experiments and in in vivo animal models, whereby inflammation and fibrosis are abrogated following NLRP3 inflammasome inhibition. While preclinical evidence is promising, studies which explore NLRP3 inflammasomes in the clinical setting are warranted. In particular, there is still a need to identify biomarkers which may be helpful for the early detection of silicosis and to fully elucidate mechanisms underlying these beneficial effects to further develop or repurpose existing anti-NLRP3 drugs as novel treatments that limit disease progression.
Collapse
Affiliation(s)
- Maggie Lam
- Hudson Institute of Medical Research Centre for Innate Immunity and Infectious Diseases, 366840, Clayton, Victoria, Australia.,Monash University , Department of Molecular and Translational Sciences, Clayton, Victoria, Australia
| | - Ashley Mansell
- Hudson Institute of Medical Research Centre for Innate Immunity and Infectious Diseases, 366840, Clayton, Victoria, Australia.,Monash Univerisity, Department of Molecular and Translational Sciences, Clayton, Victoria, Australia.,Adiso Therapeutics Inc, Concord, Massachusetts, United States
| | - Michelle D Tate
- Hudson Institute of Medical Research Centre for Innate Immunity and Infectious Diseases, 366840, Clayton, Victoria, Australia.,Monash University, Department of Molecular and Translational Sciences, Clayton, Victoria, Australia;
| |
Collapse
|
18
|
Lee SH, Choi MR, Chung J, Choi SH, Park SK, Kim YM. Povidone iodine suppresses LPS-induced inflammation by inhibiting TLR4/MyD88 formation in airway epithelial cells. Sci Rep 2022; 12:3681. [PMID: 35256715 PMCID: PMC8901750 DOI: 10.1038/s41598-022-07803-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/08/2021] [Accepted: 02/22/2022] [Indexed: 11/29/2022] Open
Abstract
Povidone-iodine (PVP-I) is an antiseptic and a disinfectant with broad-spectrum antimicrobial activity against various pathogens. However, it is unclear whether PVP-I nasal instillation can suppress mucosal inflammation in non-eosinophilic chronic rhinosinusitis (CRS) mice. This study aimed to explore the anti-inflammatory effects and underlying molecular mechanism of PVP-I on lipopolysaccharide-stimulated airway epithelial cells and investigate whether nasal instillation of PVP-I can suppress mucosal inflammation in non-eosinophilic CRS mice. Inflammation-related molecules in the nasal epithelial cells and non-eosinophilic CRS mice were measured by enzyme-linked immunosorbent assay, western blotting, quantitative real-time polymerase chain reaction, immunoprecipitation, and histopathological analysis. PVP-I blocked expressions of various inflammation-related molecules, such as NLRP3, NF-κB-p65, caspase-1, and IL-1β. Translocation of NF-κB to the nucleus, and assembly of NLRP3/ASC complexes in the nasal epithelial cells and non-eosinophilic CRS mice were also restricted. Notably, PVP-I strongly blocked the receptor co-localization of TLR4 and MyD88 in the epithelial cells of nasal mucosa. We demonstrated that PVP-I significantly attenuated inflammatory molecules and cytokines via blocking the formation of TLR4 and MyD88 complexes during LPS-induced mucosal inflammation in non-eosinophilic CRS.
Collapse
Affiliation(s)
- Seung Hoon Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon, 35015, South Korea
| | - Mi-Ra Choi
- Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon, 35015, South Korea.,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Jaein Chung
- Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon, 35015, South Korea.,Department of Otorhinolaryngology-Head and Neck Surgery, Chungnam National University Hospital, Daejeon, South Korea
| | - Seung-Hyeon Choi
- Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon, 35015, South Korea.,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Soo Kyoung Park
- Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon, 35015, South Korea
| | - Yong Min Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon, 35015, South Korea. .,Department of Medical Science, Chungnam National University School of Medicine, Daejeon, South Korea. .,Department of Otorhinolaryngology-Head and Neck Surgery, Chungnam National University Hospital, Daejeon, South Korea.
| |
Collapse
|
19
|
Ma H, Xu F, Liu C, Seeram NP. A Network Pharmacology Approach to Identify Potential Molecular Targets for Cannabidiol's Anti-Inflammatory Activity. Cannabis Cannabinoid Res 2021; 6:288-299. [PMID: 33998855 PMCID: PMC8380804 DOI: 10.1089/can.2020.0025] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/21/2022] Open
Abstract
Introduction: Published preclinical and clinical studies support the anti-inflammatory activity of CBD, but the molecular targets (e.g., genes and proteins) that are involved in its mechanisms of action remain unclear. Herein, a network-based pharmacology analysis was performed to aid in the identification of potential molecular targets for CBD's anti-inflammatory activity. Materials and Methods: Target genes and proteins were obtained from several online databases, including Swiss target prediction, Online Mendelian Inheritance in Man, and the DrugBank database. A compound-target-disease network was constructed with Cytoscape tool, and a network of protein-protein interactions was established with the Search Tool for the Retrieval of Interacting Genes/Proteins database. Lead proteins identified from the compound-target-disease network were further studied for their interactions with CBD by computational docking. In addition, biological pathways involved in CBD's anti-inflammatory activity were identified with the Gene Ontology enrichment and the Kyoto Encyclopedia of Genes and Genomes analysis. Results: A panel of proteins, including cellular tumor antigen p53, NF-kappa-B essential modulator, tumor necrosis factor (TNF) receptor, transcription factor p65, NF-kappa-B p105, NF-kappa-B inhibitor alpha, inhibitor of nuclear factor kappa-B kinase subunit alpha, and epidermal growth factor receptor, were identified as lead targets involved in CBD's anti-inflammatory activity. This finding was further supported by molecular docking, which showed interactions between the lead proteins and CBD. In addition, several signaling pathways, including TNF, toll-like receptor, mitogen-activated protein kinases, nuclear factor kappa-light-chain-enhancer of activated B cells, and nucleotide-binding oligomerization domain-like receptors, were identified as key regulators in the mediation of CBD's anti-inflammatory activity. Conclusion: A network-based pharmacology analysis identified potential molecular targets and signaling pathways for CBD's anti-inflammatory activity. Findings from this study add to the growing body of data supporting the utilization of CBD as a promising anti-inflammatory natural product.
Collapse
Affiliation(s)
- Hang Ma
- Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
| | - Feng Xu
- Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, People's Republic of China
| | - Chang Liu
- Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
| | - Navindra P. Seeram
- Bioactive Botanical Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island, USA
| |
Collapse
|
20
|
Potential Therapeutic Applications of Hydrogen in Chronic Inflammatory Diseases: Possible Inhibiting Role on Mitochondrial Stress. Int J Mol Sci 2021; 22:ijms22052549. [PMID: 33806292 PMCID: PMC7961517 DOI: 10.3390/ijms22052549] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/26/2021] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 01/10/2023] Open
Abstract
Mitochondria are the largest source of reactive oxygen species (ROS) and are intracellular organelles that produce large amounts of the most potent hydroxyl radical (·OH). Molecular hydrogen (H2) can selectively eliminate ·OH generated inside of the mitochondria. Inflammation is induced by the release of proinflammatory cytokines produced by macrophages and neutrophils. However, an uncontrolled or exaggerated response often occurs, resulting in severe inflammation that can lead to acute or chronic inflammatory diseases. Recent studies have reported that ROS activate NLRP3 inflammasomes, and that this stimulation triggers the production of proinflammatory cytokines. It has been shown in literature that H2 can be based on the mechanisms that inhibit mitochondrial ROS. However, the ability for H2 to inhibit NLRP3 inflammasome activation via mitochondrial oxidation is poorly understood. In this review, we hypothesize a possible mechanism by which H2 inhibits mitochondrial oxidation. Medical applications of H2 may solve the problem of many chronic inflammation-based diseases, including coronavirus disease 2019 (COVID-19).
Collapse
|
21
|
Zefferino R, Di Gioia S, Conese M. Molecular links between endocrine, nervous and immune system during chronic stress. Brain Behav 2021; 11:e01960. [PMID: 33295155 PMCID: PMC7882157 DOI: 10.1002/brb3.1960] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 04/28/2020] [Revised: 08/17/2020] [Accepted: 10/30/2020] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION The stress response is different in various individuals, however, the mechanisms that could explain these distinct effects are not well known and the molecular correlates have been considered one at the time. Particular harmful conditions occur if the subject, instead to cope the stressful events, succumb to them, in this case, a cascade reaction happens that through different signaling causes a specific reaction named "sickness behaviour." The aim of this article is to review the complex relations among important molecules belonging to Central nervous system (CNS), immune system (IS), and endocrine system (ES) during the chronic stress response. METHODS After having verified the state of art concerning the function of cortisol, norepinephrine (NE), interleukin (IL)-1β and melatonin, we describe as they work together. RESULTS We propose a speculative hypothesis concerning the complex interplay of these signaling molecules during chronic stress, highlighting the role of IL-1β as main biomarker of this effects, indeed, during chronic stress its increment transforms this inflammatory signal into a nervous signal (NE), in turn, this uses the ES (melatonin and cortisol) to counterbalance again IL-1β. During cortisol resistance, a vicious loop occurs that increments all mediators, unbalancing IS, ES, and CNS networks. This IL-1β increase would occur above all when the individual succumbs to stressful events, showing the Sickness Behaviour Symptoms. IL-1β might, through melatonin and vice versa, determine sleep disorders too. CONCLUSION The molecular links here outlined could explain how stress plays a role in etiopathogenesis of several diseases through this complex interplay.
Collapse
Affiliation(s)
- Roberto Zefferino
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Sante Di Gioia
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Massimo Conese
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| |
Collapse
|
22
|
Kalungi A, Kinyanda E, Womersley JS, Joloba ML, Ssembajjwe W, Nsubuga RN, Kaleebu P, Levin J, Kidd M, Seedat S, Hemmings SMJ. TERT rs2736100 and TERC rs16847897 genotypes moderate the association between internalizing mental disorders and accelerated telomere length attrition among HIV+ children and adolescents in Uganda. BMC Med Genomics 2021; 14:15. [PMID: 33407441 PMCID: PMC7789327 DOI: 10.1186/s12920-020-00857-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/09/2020] [Accepted: 12/14/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Internalizing mental disorders (IMDs) (depression, anxiety and post-traumatic stress disorder) have been associated with accelerated telomere length (TL) attrition; however, this association has not been investigated in the context of genetic variation that has been found to influence TL. We have previously reported an association between IMDs and accelerated TL attrition among Ugandan HIV+ children and adolescents. This study investigated the moderating effects of selected single nucleotide polymorphisms in the telomerase reverse transcriptase gene (TERT) (rs2736100, rs7726159, rs10069690 and rs2853669) and the telomerase RNA component gene (TERC) (rs12696304, rs16847897 and rs10936599) on the association between IMDs and TL, among Ugandan HIV+ children (aged 5-11 years) and adolescents (aged 12-17 years). RESULTS We found no significant interaction between IMDs as a group and any of the selected SNPs on TL at baseline. We observed significant interactions of IMDs with TERT rs2736100 (p = 0.007) and TERC rs16847897 (p = 0.012), respectively, on TL at 12 months. CONCLUSIONS TERT rs2736100 and TERC rs16847897 moderate the association between IMDs and TL among Ugandan HIV+ children and adolescents at 12 months. Understanding the nature of this association may shed light on the pathophysiological mechanisms underlying advanced cellular aging in IMDs.
Collapse
Affiliation(s)
- Allan Kalungi
- Department of Psychiatry, Stellenbosch University, Cape Town, South Africa.
- Mental Health Section, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda.
- Department of Medical Microbiology, Makerere University, Kampala, Uganda.
- Department of Psychiatry, College of Health Sciences, Makerere University, Kampala, Uganda.
| | - Eugene Kinyanda
- Mental Health Section, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda
- Department of Psychiatry, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Jacqueline S Womersley
- Department of Psychiatry, Stellenbosch University, Cape Town, South Africa
- South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Moses L Joloba
- Department of Medical Microbiology, Makerere University, Kampala, Uganda
- School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Wilber Ssembajjwe
- Mental Health Section, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda
- Statistics and Data Science Section, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda
| | - Rebecca N Nsubuga
- Statistics and Data Science Section, MRC/UVRI and LSHTM Uganda Research Unit, Entebbe, Uganda
| | | | - Jonathan Levin
- School of Public Health, University of Witwatersrand, Johannesburg, South Africa
| | - Martin Kidd
- Centre for Statistical Consultation, Department of Statistics and Actuarial Sciences, University of Stellenbosch, Cape Town, South Africa
| | - Soraya Seedat
- Department of Psychiatry, Stellenbosch University, Cape Town, South Africa
- South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Sian M J Hemmings
- Department of Psychiatry, Stellenbosch University, Cape Town, South Africa
- South African Medical Research Council/Stellenbosch University Genomics of Brain Disorders Research Unit, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| |
Collapse
|
23
|
Snäkä T, Fasel N. Behind the Scenes: Nod-Like Receptor X1 Controls Inflammation and Metabolism. Front Cell Infect Microbiol 2020; 10:609812. [PMID: 33344269 PMCID: PMC7746548 DOI: 10.3389/fcimb.2020.609812] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/24/2020] [Accepted: 11/09/2020] [Indexed: 12/17/2022] Open
Abstract
Regulatory Nod-like receptors (NLRs) are a subgroup of the cytosolic NLR family of pathogen recognition receptors (PRRs). These receptors can tune the innate immune responses triggered by the activation of other PRRs by either augmenting or attenuating the activated pro-inflammatory signaling cascades. Nod-like receptor X1 (NLRX1) is the only known mitochondria-associated negative regulatory NLR. NLRX1 attenuates several inflammatory pathways and modulates cellular processes such as autophagy and mitochondrial function following infection or injury. Using both in vitro expression and in vivo experimental models, NLRX1 is extensively described in the context of anti-viral signaling and host-defense against invading pathogens. More recently, NLRX1 has also gained interest in the field of cancer and metabolism where NLRX1 functions to attenuate overzealous inflammation in various inflammatory and autoimmune diseases. However, the exact function of this novel receptor is still under debate and many, often contradictory, mechanisms of action together with cellular localizations have been proposed. Thus, a better understanding of the underlying mechanism is crucial for future research and development of novel therapeutical approaches. Here, we summarize the current findings on NLRX1 and discuss its role in both infectious and inflammatory context.
Collapse
Affiliation(s)
- Tiia Snäkä
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| | - Nicolas Fasel
- Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
| |
Collapse
|
24
|
Yang SK, Han YC, He JR, Yang M, Zhang W, Zhan M, Li AM, Li L, Na-Song, Liu YT, Wu XQ, Zhang Q, Wang JW, Zhang H. Mitochondria targeted peptide SS-31 prevent on cisplatin-induced acute kidney injury via regulating mitochondrial ROS-NLRP3 pathway. Biomed Pharmacother 2020; 130:110521. [DOI: 10.1016/j.biopha.2020.110521] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/29/2019] [Revised: 07/07/2020] [Accepted: 07/11/2020] [Indexed: 12/27/2022] Open
|
25
|
Electroacupuncture Alleviates Osteoarthritis by Suppressing NLRP3 Inflammasome Activation in Guinea Pigs. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2020; 2020:5476064. [PMID: 32952587 PMCID: PMC7487102 DOI: 10.1155/2020/5476064] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 02/17/2020] [Revised: 08/09/2020] [Accepted: 08/10/2020] [Indexed: 12/21/2022]
Abstract
Osteoarthritis (OA) is an increasingly prevalent disease affecting synovial joints, which includes joint degeneration, inflammation, and joint pain. The activation of nucleotide-binding and oligomerization domain-like receptor containing protein 3 (NLRP3) could promote synovial inflammation. Previous studies have shown that electroacupuncture (EA) has potential anti-inflammatory effect. However, the effect of EA treatment on OA remains unclear. The aim of this study was to investigate the effect of applied EA on OA and joint pain and its relationship with NLRP3 inflammasome. The Hartley guinea pigs with naturally occurring OA at age 18 months were chosen as the OA model and treated with EA for 4 weeks. Mechanical allodynia was quantified by using von Frey filaments. The expression of NLRP3 inflammasome and the downstream proinflammatory factors in the cartilage tissue were quantified. Our results showed that EA treatment significantly reduces mechanical allodynia, improves the articular cartilage structure, and decreases the fibrillation on the cartilage surface in guinea pigs with spontaneous osteoarthritis. Moreover, we also found that EA treatment attenuates the NLRP3 inflammasome activation and suppresses the protein expression levels of caspase-1 and IL-1β in the cartilage tissue. Our findings suggest that EA treatment attenuates OA and joint pain by suppressing NLRP3 inflammasome activation and support further investigation of the potential therapeutic tactics.
Collapse
|
26
|
Wang H, Shi X, Qiu M, Lv S, Zheng H, Niu B, Liu H. Hydrogen Sulfide Plays an Important Role by Influencing NLRP3 inflammasome. Int J Biol Sci 2020; 16:2752-2760. [PMID: 33110394 PMCID: PMC7586428 DOI: 10.7150/ijbs.47595] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/29/2020] [Accepted: 08/12/2020] [Indexed: 12/12/2022] Open
Abstract
Inflammasome is a complex composed of several proteins and an important part of the natural immune system. Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is composed of NLRP3, apoptosis associated speck like protein (ASC) and pro-caspase-1. It plays an important role in many diseases. Hydrogen sulfide (H2S) is an important signaling molecule that regulates many physiological and pathological processes. Recent studies indicated that H2S played anti-inflammatory and pro-inflammatory roles in many diseases through influencing NLRP3 inflammasome, but its mechanism was not fully understood. This article reviewed the progress about the effects of H2S on NLRP3 inflammasome and its mechanisms involved in recent years to provide theoretical basis for in-depth study.
Collapse
Affiliation(s)
- Honggang Wang
- Institute of Biomedical Informatics, Bioinformatics Center, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475000, China
| | - Xingzhuo Shi
- School of Life Science, Henan University, Kaifeng, Henan, 475000, China
| | - Mengyuan Qiu
- Institute of Biomedical Informatics, Bioinformatics Center, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475000, China
| | - Shuangyu Lv
- Institute of Biomedical Informatics, Bioinformatics Center, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475000, China
| | - Hong Zheng
- Institute of Biomedical Informatics, Bioinformatics Center, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475000, China
| | - Baohua Niu
- Institute of Biomedical Informatics, Bioinformatics Center, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475000, China
| | - Huiyang Liu
- Institute of Biomedical Informatics, Bioinformatics Center, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, 475000, China
| |
Collapse
|
27
|
Ferrero-Andrés A, Panisello-Roselló A, Roselló-Catafau J, Folch-Puy E. NLRP3 Inflammasome-Mediated Inflammation in Acute Pancreatitis. Int J Mol Sci 2020; 21:5386. [PMID: 32751171 PMCID: PMC7432368 DOI: 10.3390/ijms21155386] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/29/2020] [Revised: 07/17/2020] [Accepted: 07/28/2020] [Indexed: 12/11/2022] Open
Abstract
The discovery of inflammasomes has enriched our knowledge in the pathogenesis of multiple inflammatory diseases. The NLR pyrin domain-containing protein 3 (NLRP3) has emerged as the most versatile and well-characterized inflammasome, consisting of an intracellular multi-protein complex that acts as a central driver of inflammation. Its activation depends on a tightly regulated two-step process, which includes a wide variety of unrelated stimuli. It is therefore not surprising that the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Inflammasome-mediated inflammation has become increasingly important in acute pancreatitis, an inflammatory disorder of the pancreas that is one of the fatal diseases of the gastrointestinal tract. This review presents an update on the progress of research into the contribution of the NLRP3 inflammasome to acute pancreatic injury, examining the mechanisms of NLRP3 activation by multiple signaling events, the downstream interleukin 1 family of cytokines involved and the current state of the literature on NLRP3 inflammasome-specific inhibitors.
Collapse
Affiliation(s)
- Ana Ferrero-Andrés
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Arnau Panisello-Roselló
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Barcelona, 08036 Catalonia, Spain; (A.F.-A.); (A.P.-R.)
| | - Joan Roselló-Catafau
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
| | - Emma Folch-Puy
- Experimental Pathology Department, Institut d’Investigacions Biomèdiques de Barcelona-Consejo Superior de Investigaciones científicas (IIBB-CSIC), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, 08036 Catalonia, Spain;
| |
Collapse
|
28
|
Jaén RI, Val-Blasco A, Prieto P, Gil-Fernández M, Smani T, López-Sendón JL, Delgado C, Boscá L, Fernández-Velasco M. Innate Immune Receptors, Key Actors in Cardiovascular Diseases. JACC Basic Transl Sci 2020; 5:735-749. [PMID: 32760860 PMCID: PMC7393405 DOI: 10.1016/j.jacbts.2020.03.015] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 02/24/2020] [Revised: 03/19/2020] [Accepted: 03/19/2020] [Indexed: 02/07/2023]
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death in the industrialized world. Most CVDs are associated with increased inflammation that arises mainly from innate immune system activation related to cardiac damage. Sustained activation of the innate immune system frequently results in maladaptive inflammatory responses that promote cardiovascular dysfunction and remodeling. Much research has focused on determining whether some mediators of the innate immune system are potential targets for CVD therapy. The innate immune system has specific receptors-termed pattern recognition receptors (PRRs)-that not only recognize pathogen-associated molecular patterns, but also sense danger-associated molecular signals. Activation of PRRs triggers the inflammatory response in different physiological systems, including the cardiovascular system. The classic PRRs, toll-like receptors (TLRs), and the more recently discovered nucleotide-binding oligomerization domain-like receptors (NLRs), have been recently proposed as key partners in the progression of several CVDs (e.g., atherosclerosis and heart failure). The present review discusses the key findings related to the involvement of TLRs and NLRs in the progression of several vascular and cardiac diseases, with a focus on whether some NLR subtypes (nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing receptor 3 and nucleotide-binding oligomerization domain-containing protein 1) can be candidates for the development of new therapeutic strategies for several CVDs.
Collapse
Key Words
- AMI, acute myocardial infarction
- CARD, caspase activation and recruitment domain
- CVD, cardiovascular disease
- Ca2+, calcium ion
- DAMPs, danger-associated molecular patterns
- DAP, D-glutamyl-meso-diaminopimelic acid
- ER, endoplasmic reticulum
- HF, heart failure
- I/R, ischemia/reperfusion
- IL, interleukin
- MAPK, mitogen-activated protein kinase
- NF-κB, nuclear factor κ-light-chain-enhancer of activated B cells
- NLR, nucleotide-binding oligomerization domain-like receptors
- NLRP, nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing receptor
- NLRP3
- NOD, Nucleotide-binding oligomerization domain-containing protein
- NOD1
- PAMP, pathogen-associated molecular pattern
- ROS, reactive oxygen species
- SR, sarcoplasmic reticulum
- TLR, toll-like receptor
- cardiovascular disease
- innate immune system
- nucleotide-binding oligomerization domain-like receptors
- toll-like receptors
Collapse
Affiliation(s)
- Rafael I. Jaén
- Biomedical Research Institute “Alberto Sols” CSIC-UAM, Madrid, Spain
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
| | - Almudena Val-Blasco
- Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Patricia Prieto
- Biomedical Research Institute “Alberto Sols” CSIC-UAM, Madrid, Spain
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
- Pharmacology, Pharmacognosy and Botany department, Faculty of Pharmacy, Complutense University of Madrid, Madrid, Spain
- Dr. Patricia Prieto, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza de Ramón y Cajal s/n, 28040 Madrid, Spain. @IIBmCSICUAM
| | - Marta Gil-Fernández
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
- Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
| | - Tarik Smani
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
- Department of Medical Physiology and Biophysics, Institute of Biomedicine of Seville, University of Seville, Sevilla, Spain
| | - José Luis López-Sendón
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
- Servicio de Cardiología, Hospital Universitario La Paz, Madrid, Spain
| | - Carmen Delgado
- Biomedical Research Institute “Alberto Sols” CSIC-UAM, Madrid, Spain
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
| | - Lisardo Boscá
- Biomedical Research Institute “Alberto Sols” CSIC-UAM, Madrid, Spain
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
| | - María Fernández-Velasco
- CIBER Cardiovascular (CIBER-CV, ISCIII), Madrid, Spain
- Innate Immune Response Group, IdiPAZ, La Paz University Hospital, Madrid, Spain
- Address for correspondence: Dr. María Fernández-Velasco, Instituto de Investigación Hospital la Paz, IdiPAZ, Paseo de la Castellana 261, 28046 Madrid, Spain. @IdipazScience@CIBER_CV@Mfvlorenzo
| |
Collapse
|
29
|
Chung CJ, Bao BY, Lin YC, Huang YL, Shiue HS, Ao PL, Pu YS, Huang CY, Hsueh YM. Polymorphism of nucleotide binding domain-like receptor protein 3 (NLRP3) increases susceptibility of total urinary arsenic to renal cell carcinoma. Sci Rep 2020; 10:6640. [PMID: 32313131 PMCID: PMC7171170 DOI: 10.1038/s41598-020-63469-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/23/2019] [Accepted: 03/29/2020] [Indexed: 12/02/2022] Open
Abstract
Our study showed that total urinary arsenic concentrations were positively correlated with renal cell carcinoma (RCC). Chronic inflammation is a key player in the development of RCC. This study explored the association between nucleotide-binding domain-like receptor protein 3 (NLRP3) genotypes and the development of RCC. We also investigated whether any of the NLRP3 genotypes modified the risk between arsenic and RCC. We recruited 350 RCC patients and 700 age-sex matched controls. RCC was confirmed by pathological assessment following surgical resection or image-guided biopsy of a renal tumor. Fifteen sites of NLRP3 gene polymorphisms were identified using the Agena Bioscience MassARRAY platform. The concentrations of the urinary arsenic species were determined by HPLC-HG-AAS. There was a significant dose-dependent association between arsenic and RCC. In addition, six of thirteen NLRP3 alleles, including rs12239046 C, rs10925025 G, rs1539019 C, rs10925026 A, rs10157379 T, and rs12143966 A, had increased odds ratios (ORs) for RCC than other NLRP3 alleles. Among these sites, we found the novel haplotype of five tag-SNPs (C-A-A-A-A) was significantly related to RCC, the OR and 95% confidence interval was 1.44 (1.08–1.92). Furthermore, participants with high total urinary arsenic levels and the NLRP3 rs1539019 C allele had significantly multiplicative and additive interactions for the risk of RCC (p interaction = 0.012). This study is the first to identify the modified effects of NLRP3 risk alleles involved in the association between arsenic and RCC risk in a population with low arsenic exposure.
Collapse
Affiliation(s)
- Chi-Jung Chung
- Department of Public Health, College of Public Health, China Medical University, Taichung, Taiwan.,Department of Medical Research, China Medical University and Hospital, Taichung, Taiwan
| | - Bo-Ying Bao
- Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan.,Sex Hormone Research Center, China Medical University Hospital, Taichung, Taiwan.,Department of Nursing, Asia University, Taichung, Taiwan
| | - Ying-Chin Lin
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan.,Department of Family Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Geriatric Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Ya-Li Huang
- Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Horng-Sheng Shiue
- Department of Chinese Medicine, College of Medicine, Chang Gung University Taoyuan, Taoyuan, Taiwan
| | - Pui-Lam Ao
- School of Public Health, College of Public Health, Taipei Medical University, Taipei, Taiwan
| | - Yeong-Shiau Pu
- Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan
| | - Chao-Yuan Huang
- Department of Urology, National Taiwan University Hospital, College of Medicine National Taiwan University, Taipei, Taiwan.
| | - Yu-Mei Hsueh
- Department of Family Medicine, Wan Fang Hospital, Taipei Medical University, Taipei City, Taiwan. .,Department of Public Health, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
| |
Collapse
|
30
|
Wang L, Zhu L, Duan C, Li L, Chen G. Total saponin of Dioscorea collettii attenuates MSU crystal‑induced inflammation via inhibiting the activation of the NALP3 inflammasome and caspase‑1 in THP‑1 macrophages. Mol Med Rep 2020; 21:2466-2474. [PMID: 32236574 PMCID: PMC7185280 DOI: 10.3892/mmr.2020.11035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/18/2019] [Accepted: 01/30/2020] [Indexed: 01/13/2023] Open
Abstract
Total saponins extracted from Dioscorea collettii (TSD), extracts of the Chinese herb Dioscorea, are thought to exhibit therapeutic benefit in gouty arthritis. However, its exact mechanism remains unclear. The current study aimed to elucidate the underlying mechanisms by investigating the effects of TSD on the inflammation induced by monosodium urate (MSU) crystals in THP-1 macrophages. The viability of THP-1 macrophages was examined using the MTT assay and the levels of inflammatory cytokines, including interleukin (IL)-1β, IL-18 and tumor necrosis factor (TNF)-α, released by the cells were quantitatively measured using ELISA kits. The results revealed that the protein level of cluster of differentiation 11b increased in THP-1 cells treated with 100 ng/ml phorbol ester, suggesting that monocytic THP-1 cells were successfully differentiated into macrophages. TSD decreased the levels of inflammatory cytokines, including TNF-α, IL-18 and IL-1β, secreted by THP-1 macrophages. As the release of IL-1β and IL-18 is dependent on the NLR family pyrin domain containing 3 (NALP3) inflammasome and caspase-1, the current study investigated the effect of TSD on the aforementioned proteins. The results revealed that TSD decreased the protein levels of NALP3 and apoptosis-associated speck-like, which serve important roles in the assembly of the NALP3 inflammasome. Furthermore, NALP3 inflammasome-related proteins were also decreased by TSD in rotenone induced THP-1 macrophages, TSD inhibited the activation of caspase-1 and rotenone-induced NALP3 inflammasome activation in THP-1 macrophages. The results obtained in the current study revealed that TSD attenuated MSU crystal-induced inflammation by inhibiting rotenone-induced activation of the NALP3 inflammasome and caspase-1, suggesting that these two proteins may be novel targets for the treatment of gouty arthritis.
Collapse
Affiliation(s)
- Lu Wang
- College of Integrative Medicine, Anhui University of Chinese Medicine, Hefei, Anhui 230012, P.R. China
| | - Liran Zhu
- Anhui Institute of Pediatric Research, Anhui Provincial Children's Hospital, Hefei, Anhui 230051, P.R. China
| | - Chenfangyuan Duan
- School of Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, P.R. China
| | - Lu Li
- College of Integrative Medicine, Anhui University of Chinese Medicine, Hefei, Anhui 230012, P.R. China
| | - Guangliang Chen
- College of Integrative Medicine, Anhui University of Chinese Medicine, Hefei, Anhui 230012, P.R. China
| |
Collapse
|
31
|
Nanomaterial Effects on Viral Infection. INTERACTION OF NANOMATERIALS WITH THE IMMUNE SYSTEM 2020. [PMCID: PMC7122331 DOI: 10.1007/978-3-030-33962-3_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Indexed: 11/16/2022]
Abstract
The potential for environmental and occupational exposures of populations to nanomaterials (NMs) has fostered concerns of associated adverse health effects, with a particular emphasis on pulmonary injury and disease. Many studies have revealed that several types of NMs can evoke a variety of biological responses, such as pulmonary inflammation and oxidative stress, which contribute to allergy, fibrosis, and granuloma formation. Less attention has been paid to health effects that may result from exposure to NMs and additional stressors such as pathogens, with a particular focus on susceptibility to viral infection. This chapter will summarize the current body of literature related to NMs and viral exposures with a primary focus on immune modulation. A summary of the studies performed and major findings to date will be discussed, highlighting proposed molecular mechanisms behind NM-driven host susceptibility, challenges, limitations, and future research needs. Specific mechanisms discussed include direct interaction between NMs and biological molecules, activation of pattern recognition receptors (PRRs) and related signaling pathways, production of oxidative stress and mitochondrial dysfunction, inflammasome activation, and modulation of lipid signaling networks.
Collapse
|
32
|
Huang D, Chen M, Wang Z, Hou L, Yu W. Electroacupuncture Pretreatment Attenuates Inflammatory Lung Injury After Cardiopulmonary Bypass by Suppressing NLRP3 Inflammasome Activation in Rats. Inflammation 2019; 42:895-903. [PMID: 30680695 DOI: 10.1007/s10753-018-0944-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/19/2022]
Abstract
Cardiopulmonary bypass (CPB) can induce inflammatory lung injury, which is a common complication during cardiac surgery. Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome-induced inflammation plays a crucial role in lung injury after CPB. Previous studies have shown that electroacupuncture (EA) has potential anti-inflammatory activity. However, the role of EA in CPB is poorly understood. The aim of this study was to determine whether EA was associated with CPB-induced inflammatory lung injury. In the present study, rats were treated with EA for 5 days before CPB. Two hours after CPB, the lung tissue, serum, and bronchoalveolar lavage fluid (BALF) were prepared for assessment. Our results showed that the expression of NLRP3 in the lung tissue increased significantly after CPB. The EA pretreatment suppressed NLRP3 inflammasome activation, reduced lung edema, and inhibited IL-1β release into the serum and BALF after CPB. Our findings suggest that EA pretreatment attenuates inflammatory lung injury after CPB by suppressing NLRP3 inflammasome activation.
Collapse
Affiliation(s)
- Dongxiao Huang
- The Third Affiliated Hospital of Soochow University, No.185 Juqian Street, Changzhou, Jiangsu, China.,Department of Anesthesiology, Wuxi People's Hospital, No.299 Qingyang Road, Wuxi, Jiangsu, China
| | - Mo Chen
- The Third Affiliated Hospital of Soochow University, No.185 Juqian Street, Changzhou, Jiangsu, China
| | - Zhankui Wang
- Department of Orthopedics, The First Clinical Medical College, Shaanxi University of Chinese Medicine, Xianyang, Shaanxi, China
| | - Lei Hou
- Department of Anesthesiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pudian Road, Shanghai, China
| | - Weifeng Yu
- Department of Anesthesiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No.160 Pudian Road, Shanghai, China. .,Department of Anesthesiology, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, No.225 Changhai Road, Shanghai, 200438, People's Republic of China.
| |
Collapse
|
33
|
McDonough A, Weinstein JR. The role of microglia in ischemic preconditioning. Glia 2019; 68:455-471. [PMID: 31386233 DOI: 10.1002/glia.23695] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/12/2019] [Revised: 07/20/2019] [Accepted: 07/23/2019] [Indexed: 12/22/2022]
Abstract
Ischemic preconditioning (IPC) is an experimental phenomenon in which a brief ischemic stimulus confers protection against a subsequent prolonged ischemic event. Initially thought to be due to mechanistic changes in neurons, our understanding of IPC has evolved to encompass a global reprogramming of the Central Nervous System (CNS) after transient ischemia/reperfusion that requires innate immune signaling pathways including Toll-like receptors (TLRs) and Type I interferons. Microglia are the CNS resident neuroimmune cells that express these key innate immune receptors. Studies suggest that microglia are required for IPC-mediated neuronal and axonal protection. Multiple paradigms targeting TLRs have converged on a distinctive Type I interferon response in microglia that is critical for preconditioning-mediated protection against ischemia. These pathways can be targeted through administration of TLR agonists, cytokines including interferon-β, and pharmaceutical agents that induce preconditioning through cross-tolerance mechanisms. Transcriptomic analyses and single cell RNA studies point to specific gene expression signatures in microglia that functionally shift these mutable cells to an immunomodulatory or protective phenotype. Although there are technological challenges and gaps in knowledge to overcome, the targeting of specific molecular signaling pathways in microglia is a promising direction for development of novel and effective pharmacotherapies for stroke. Studies on preconditioning in animal models, including nonhuman primates, show promise as prophylactic preconditioning treatments for selected at risk patient populations. In addition, our growing understanding of the mechanisms of IPC-mediated protection is identifying novel cellular and molecular targets for therapeutic interventions that could apply broadly to both acute stroke and chronic vascular cognitive impairment patients.
Collapse
Affiliation(s)
- Ashley McDonough
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington
| | - Jonathan R Weinstein
- Department of Neurology, School of Medicine, University of Washington, Seattle, Washington.,Department of Neurological Surgery, School of Medicine, University of Washington, Seattle, Washington
| |
Collapse
|
34
|
Kaneko N, Kurata M, Yamamoto T, Morikawa S, Masumoto J. The role of interleukin-1 in general pathology. Inflamm Regen 2019; 39:12. [PMID: 31182982 PMCID: PMC6551897 DOI: 10.1186/s41232-019-0101-5] [Citation(s) in RCA: 358] [Impact Index Per Article: 59.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/03/2019] [Accepted: 05/07/2019] [Indexed: 12/19/2022] Open
Abstract
Interleukin-1, an inflammatory cytokine, is considered to have diverse physiological functions and pathological significances and play an important role in health and disease. In this decade, interleukin-1 family members have been expanding and evidence is accumulating that highlights the importance of interleukin-1 in linking innate immunity with a broad spectrum of diseases beyond inflammatory diseases. In this review, we look back on the definition of "inflammation" in traditional general pathology and discuss new insights into interleukin-1 in view of its history and the molecular bases of diseases, as well as current progress in therapeutics.
Collapse
Affiliation(s)
- Naoe Kaneko
- Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, Ehime 791-0295 Japan
| | - Mie Kurata
- Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, Ehime 791-0295 Japan
| | - Toshihiro Yamamoto
- Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, Ehime 791-0295 Japan
| | - Shinnosuke Morikawa
- Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, Ehime 791-0295 Japan
| | - Junya Masumoto
- Department of Pathology, Ehime University Graduate School of Medicine and Proteo-Science Center, Shitsukawa 454, Toon, Ehime 791-0295 Japan
| |
Collapse
|
35
|
Sandall CF, MacDonald JA. Effects of phosphorylation on the NLRP3 inflammasome. Arch Biochem Biophys 2019; 670:43-57. [PMID: 30844378 DOI: 10.1016/j.abb.2019.02.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/10/2019] [Revised: 02/22/2019] [Accepted: 02/27/2019] [Indexed: 01/04/2023]
Abstract
The pyrin domain containing Nod-like receptors (NLRPs) are a family of pattern recognition receptors known to regulate an array of immune signaling pathways. Emergent studies demonstrate the potential for regulatory control of inflammasome assembly by phosphorylation, notably NLRP3. Over a dozen phosphorylation sites have been identified for NLRP3 with many more suggested by phosphoproteomic studies of the NLRP family. Well characterized NLRP3 phosphorylation events include Ser198 by c-Jun terminal kinase (JNK), Ser295 by protein kinase D (PKD) and/or protein kinase A (PKA), and Tyr861 by an unknown kinase but is dephosphorylated by protein tyrosine phosphatase non-receptor 22 (PTPN22). Since the PKA- and PKD-dependent phosphorylation of NLRP3 at Ser295 is best characterized, we provide detailed review of this aspect of NLRP3 regulation. Phosphorylation of Ser295 can attenuate ATPase activity as compared to its dephosphorylated counterpart, and this event is likely unique to NLRP3. In silico modeling of NLRP3 is useful in predicting how Ser295 phosphorylation might impact upon the structural topology of the ATP-binding domain to influence catalytic activity. It is important to gain as complete understanding as possible of the complex phosphorylation-mediated mechanisms of regulation for NLRP3 in part because of its involvement in many pathological processes.
Collapse
Affiliation(s)
- Christina F Sandall
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada
| | - Justin A MacDonald
- Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4Z6, Canada.
| |
Collapse
|
36
|
Wang Z, Hu W, Lu C, Ma Z, Jiang S, Gu C, Acuña-Castroviejo D, Yang Y. Targeting NLRP3 (Nucleotide-Binding Domain, Leucine-Rich–Containing Family, Pyrin Domain–Containing-3) Inflammasome in Cardiovascular Disorders. Arterioscler Thromb Vasc Biol 2018; 38:2765-2779. [PMID: 30571177 DOI: 10.1161/atvbaha.118.311916] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/07/2023]
Abstract
Inflammation is an important innate immune response to infection or tissue damage. Inflammasomes are involved in the onset and development of inflammation. The NLRP3 (nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3) inflammasome is the best-characterized inflammasome. Recent evidence has indicated the importance of the NLRP3 inflammasome in the pathophysiology of cardiovascular disorders. To further understand the roles of the NLRP3 inflammasome in the cardiovascular system, we provide a comprehensive overview and discuss the remaining questions. First, a summary of NLRP3 inflammasome in the cardiovascular system is introduced. Then, the associations between NLRP3 inflammasome and cardiovascular disorders are presented. Finally, we discuss existing problems and potential directions with this issue. The information compiled here summarizes recent progress, thus potentially aiding in the understanding of the NLRP3 inflammasome in cardiovascular disorders, designing experimental and clinical research about the NLRP3 inflammasome, and promoting therapeutics for cardiovascular disorders.
Collapse
Affiliation(s)
- Zheng Wang
- From the Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Taibai, Xi’an, China (Z.W., C.L., Y.Y.)
- Department of Cardiothoracic Surgery, Wuhan General Hospital of The People’s Liberation Army, China (Z.W.)
| | - Wei Hu
- Department of Immunology (W.H.), The Fourth Military Medical University, Xi’an, China
| | - Chenxi Lu
- From the Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Taibai, Xi’an, China (Z.W., C.L., Y.Y.)
| | - Zhiqiang Ma
- Department of Thoracic Surgery, Tangdu Hospital (Z.M.), The Fourth Military Medical University, Xi’an, China
| | - Shuai Jiang
- Department of Aerospace Medicine (S.J.), The Fourth Military Medical University, Xi’an, China
| | - Chunhu Gu
- Department of Cardiovascular Surgery, Xijing Hospital (C.G.), The Fourth Military Medical University, Xi’an, China
| | - Darío Acuña-Castroviejo
- Biomedical Research Center, Health Sciences Technology Park, University of Granada, Spain (D.A.-C.)
| | - Yang Yang
- From the Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Taibai, Xi’an, China (Z.W., C.L., Y.Y.)
| |
Collapse
|
37
|
Zha LH, Zhou J, Li TZ, Luo H, He JN, Zhao L, Yu ZX. NLRC3: A Novel Noninvasive Biomarker for Pulmonary Hypertension Diagnosis. Aging Dis 2018; 9:843-851. [PMID: 30271661 PMCID: PMC6147585 DOI: 10.14336/ad.2017.1102] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/07/2017] [Accepted: 11/02/2017] [Indexed: 11/25/2022] Open
Abstract
The nucleotide-oligomerization domain (NOD)-like receptor subfamily C3 (NLRC3) is a newly discovered and incompletely characterized member of the NLR family which negatively regulates inflammatory responses. Inflammation is considered a critical pathogenesis in pulmonary hypertension (PH). This is the first study to hypothesize that NLRC3 is closely correlated with PH. Total of 43 PH patients who were diagnosed by right heart catheterization (RHC) and 20 age-matched healthy control subjects were included. Echocardiographic variables and blood biochemical parameters were tested. Results of World Health Organization functional class (WHOFC), Borg dyspnea score and 6-minute walk tests (6MWT) were recorded. Mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance (PVR) were measured from RHC. Serum NLRC3 concentrations were detected by ELISA. ROC curve analysis was used to evaluate the diagnostic value of NLRC3 concentrations in PH. We found that serum NLRC3 concentration was significantly decreased in PH compared to the healthy control group. Serum NLRC3 concentration correlated negatively with mPAP and PVR. In addition, a negative correlation between serum NLRC3 concentration and WHOFC were detected. We proposed a cut-off value of 2.897ng/mL for serum NLRC3 concentration which was able to predict PH with 88% sensitivity and 85% specificity. In conclusion, NLRC3 concentrations in PH were significantly decreased, suggesting that NLRC3 may potentially be a diagnosis index and represent a prognostic factor for PH patients.
Collapse
Affiliation(s)
- Li-Huang Zha
- 1Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan, China.,3Department of Cardiology, Zhuzhou Central Hospital, Zhuzhou, Hunan, China
| | - Jun Zhou
- 2Medical Science Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Tang-Zhiming Li
- 1Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Hui Luo
- 1Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jing-Ni He
- 1Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lin Zhao
- 1Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zai-Xin Yu
- 1Department of Cardiology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| |
Collapse
|
38
|
Interleukin 1-β, interleukin-1 receptor antagonist and vitamin D levels in children with atopic dermatitis. Cent Eur J Immunol 2018; 43:180-185. [PMID: 30135631 PMCID: PMC6102616 DOI: 10.5114/ceji.2018.77388] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/03/2016] [Accepted: 01/16/2017] [Indexed: 11/28/2022] Open
Abstract
Introduction Among the broad spectrum of cytokines, interleukin 1-β (IL-1β) has been implicated in induction and subsequent aggravation of skin lesions in atopic dermatitis (AD). A considerable body of evidence suggests that vitamin D status also influences the risk and/or severity of AD. Material and methods Fifty-seven children suffering from mild to severe AD were enrolled in the study. The control group consisted of 33 matched healthy children. In all the children serum concentrations of IL-1β/IL-1F2 and the interleukin-1 receptor antagonist IL-Ra/1F3 were measured. Serum 25(OH)D concentration was obtained for 49 patients with AD and all healthy children. Results In children with AD 59.2% of children had insufficiency, 24.5% had deficiency and 16.3% had a sufficient serum 25(OH)D level. In the control group 26.5%, 52.9% and 20% of participants had insufficiency/deficiency/sufficiency of 25(OH)D, respectively. The severity of AD was positively correlated with total IgE level, percentage and absolute count of eosinophils and IL-1Ra. IL-1β correlated with IL-1Ra. Conclusions In children with AD the serum vitamin D level was lower than in healthy children. The correlation between severity of AD and IL-1Ra may prove that inflammasome-dependent IL-1β is involved in immunopathogenesis of the disease. Further studies are needed on a larger population of children to confirm the role of this cytokine in development of AD.
Collapse
|
39
|
Ulke-Lemée A, Lau A, Nelson MC, James MT, Muruve DA, MacDonald JA. Quantification of Inflammasome Adaptor Protein ASC in Biological Samples by Multiple-Reaction Monitoring Mass Spectrometry. Inflammation 2018; 41:1396-1408. [DOI: 10.1007/s10753-018-0787-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/15/2022]
|
40
|
Wan J, Zhang J, Chen D, Yu B, Huang Z, Mao X, Zheng P, Yu J, He J. Alginate oligosaccharide enhances intestinal integrity of weaned pigs through altering intestinal inflammatory responses and antioxidant status. RSC Adv 2018; 8:13482-13492. [PMID: 35542522 PMCID: PMC9079839 DOI: 10.1039/c8ra01943f] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/05/2018] [Accepted: 04/02/2018] [Indexed: 01/13/2023] Open
Abstract
Alginate oligosaccharide (AOS), prepared from depolymerised alginate, a natural polysaccharide occurring in the cell walls of brown algae, provides beneficial effects for intestinal health. However, the underlying mechanisms by which AOS supplementation maintains the intestinal integrity of weaned pigs remain obscure. Here, we aimed to determine how AOS modulates the intestinal integrity of weaned pigs. Twenty-four weaned pigs were assigned to two treatments: a control group (basal diet) and an AOS group (the basal diet supplemented with 100 mg kg-1 AOS). On day 15, eight pigs per treatment were randomly selected and sacrificed for serum and intestinal samples. We observed that AOS supplementation enhanced the intestinal integrity, as evidenced by the increased (P < 0.05) intestinal occludin protein abundance. Compared to the control group, AOS ingestion both elevated (P < 0.05) the jejunal and ileal catalase activity and decreased (P < 0.05) the duodenal and jejunal tumour necrosis factor-α concentration and mast cell tryptase expression. Furthermore, AOS down-regulated (P < 0.05) the duodenal toll-like receptor 4 (TLR4) and its down-stream signals, myeloid differentiation factor 88 (MyD88), interleukin-1 receptor-associated kinase 1 (IRAK1) and tumour necrosis factor receptor-associated factor 6 (TRAF6) mRNA levels, as well as jejunal nucleotide-binding oligomerisation domain protein 1 (NOD1) and its adaptor molecule, receptor-interacting serine/threonine-protein kinase 2 (RIPK2), mRNA levels. Additionally, phospho-nuclear factor-κB (p-NF-κB) p65 protein abundance in the duodenum and jejunum was down-regulated (P < 0.05) following AOS supplementation. According to the above results, the enhanced intestinal integrity in AOS-supplemented pigs appears to be associated with the elevated antioxidant capacity and the reduced mast cell degranulation, as well as the inhibited pro-inflammatory cytokines production via inhibiting the TLR4/NF-κB and NOD1/NF-κB signalling pathways.
Collapse
Affiliation(s)
- Jin Wan
- Institute of Animal Nutrition, Sichuan Agricultural University Chengdu 611130 Sichuan People's Republic of China +86-28-86290920 +86-13-419354223
| | - Jiao Zhang
- Institute of Animal Nutrition, Sichuan Agricultural University Chengdu 611130 Sichuan People's Republic of China +86-28-86290920 +86-13-419354223
| | - Daiwen Chen
- Institute of Animal Nutrition, Sichuan Agricultural University Chengdu 611130 Sichuan People's Republic of China +86-28-86290920 +86-13-419354223
| | - Bing Yu
- Institute of Animal Nutrition, Sichuan Agricultural University Chengdu 611130 Sichuan People's Republic of China +86-28-86290920 +86-13-419354223
| | - Zhiqing Huang
- Institute of Animal Nutrition, Sichuan Agricultural University Chengdu 611130 Sichuan People's Republic of China +86-28-86290920 +86-13-419354223
| | - Xiangbing Mao
- Institute of Animal Nutrition, Sichuan Agricultural University Chengdu 611130 Sichuan People's Republic of China +86-28-86290920 +86-13-419354223
| | - Ping Zheng
- Institute of Animal Nutrition, Sichuan Agricultural University Chengdu 611130 Sichuan People's Republic of China +86-28-86290920 +86-13-419354223
| | - Jie Yu
- Institute of Animal Nutrition, Sichuan Agricultural University Chengdu 611130 Sichuan People's Republic of China +86-28-86290920 +86-13-419354223
| | - Jun He
- Institute of Animal Nutrition, Sichuan Agricultural University Chengdu 611130 Sichuan People's Republic of China +86-28-86290920 +86-13-419354223
| |
Collapse
|
41
|
Turunen JA, Wedenoja J, Repo P, Järvinen RS, Jäntti JE, Mörtenhumer S, Riikonen AS, Lehesjoki AE, Majander A, Kivelä TT. Keratoendotheliitis Fugax Hereditaria: A Novel Cryopyrin-Associated Periodic Syndrome Caused by a Mutation in the Nucleotide-Binding Domain, Leucine-Rich Repeat Family, Pyrin Domain-Containing 3 (NLRP3) Gene. Am J Ophthalmol 2018; 188:41-50. [PMID: 29366613 DOI: 10.1016/j.ajo.2018.01.017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/24/2017] [Revised: 12/22/2017] [Accepted: 01/12/2018] [Indexed: 01/25/2023]
Abstract
PURPOSE To describe the phenotype and the genetic defect in keratoendotheliitis fugax hereditaria, an autosomal dominant keratitis that periodically affects the corneal endothelium and stroma, leading in some patients to opacities and decreased visual acuity. DESIGN Cross-sectional, hospital-based study. METHODS Patient Population: Thirty affected and 7 unaffected subjects from 7 families, and 4 sporadic patients from Finland. OBSERVATION PROCEDURES Ophthalmic examination and photography, corneal topography, specular microscopy, and optical coherence tomography in 34 patients, whole exome sequencing in 10 patients, and Sanger sequencing in 34 patients. MAIN OUTCOME MEASURES Clinical phenotype, disease-causing genetic variants. RESULTS Unilateral attacks of keratoendotheliitis typically occurred 1-6 times a year (median, 2.5), starting at a median age of 11 years (range, 5-28 years), and lasted for 1-2 days. The attacks were characterized by cornea pseudoguttata and haze in the posterior corneal stroma, sometimes with a mild anterior chamber reaction, and got milder and less frequent in middle age. Seventeen (50%) patients had bilateral stromal opacities. The disease was inherited as an autosomal dominant trait. A likely pathogenic variant c.61G>C in the NLRP3 gene, encoding cryopyrin, was detected in all 34 tested patients and segregated with the disease. This variant is present in both Finnish and non-Finnish European populations at a frequency of about 0.02% and 0.01%, respectively. CONCLUSION Keratoendotheliitis fugax hereditaria is an autoinflammatory cryopyrin-associated periodic syndrome caused by a missense mutation c.61G>C in exon 1 of NLRP3 in Finnish patients. It is additionally expected to occur in other populations of European descent.
Collapse
|
42
|
Involvement of Innate Immune System in Late Stages of Inherited Photoreceptor Degeneration. Sci Rep 2017; 7:17897. [PMID: 29263354 PMCID: PMC5738376 DOI: 10.1038/s41598-017-18236-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/26/2017] [Accepted: 12/05/2017] [Indexed: 01/10/2023] Open
Abstract
Retinitis pigmentosa (RP) is a group of inherited retinal degenerations that lead to progressive vision loss. Many mutations in 60 different genes have been shown to cause RP. Given the diversity of genes and mutations that cause RP, corrective gene therapy approaches currently in development may prove both time-consuming and cost-prohibitive for treatment of all forms of RP. An alternative approach is to find common biological pathways that cause retinal degeneration in various forms of RP, and identify new molecular targets. With this goal, we analyzed the retinal transcriptome of two non-allelic forms of RP in dogs, rcd1 and xlpra2, at clinically relevant advanced stages of the two diseases. Both diseases showed very similar trends in changes in gene expression compared to control normal dogs. Pathway analysis revealed upregulation of various components of the innate immune system in both diseases, including inflammasome and complement pathways. Our results show that the retinal transcriptome at advanced stages of RP is very similar to that of other retinal degenerative diseases such as age-related macular degeneration and diabetic retinopathy. Thus, drugs and therapeutics already in development for targeting these retinopathies may also prove useful for the treatment of many forms of RP.
Collapse
|
43
|
Silva AL, Peres C, Conniot J, Matos AI, Moura L, Carreira B, Sainz V, Scomparin A, Satchi-Fainaro R, Préat V, Florindo HF. Nanoparticle impact on innate immune cell pattern-recognition receptors and inflammasomes activation. Semin Immunol 2017; 34:3-24. [PMID: 28941640 DOI: 10.1016/j.smim.2017.09.003] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/03/2017] [Revised: 09/10/2017] [Accepted: 09/11/2017] [Indexed: 12/19/2022]
Abstract
Nanotechnology-based strategies can dramatically impact the treatment, prevention and diagnosis of a wide range of diseases. Despite the unprecedented success achieved with the use of nanomaterials to address unmet biomedical needs and their particular suitability for the effective application of a personalized medicine, the clinical translation of those nanoparticulate systems has still been impaired by the limited understanding on their interaction with complex biological systems. As a result, unexpected effects due to unpredicted interactions at biomaterial and biological interfaces have been underlying the biosafety concerns raised by the use of nanomaterials. This review explores the current knowledge on how nanoparticle (NP) physicochemical and surface properties determine their interactions with innate immune cells, with particular attention on the activation of pattern-recognition receptors and inflammasome. A critical perspective will additionally address the impact of biological systems on the effect of NP on immune cell activity at the molecular level. We will discuss how the understanding of the NP-innate immune cell interactions can significantly add into the clinical translation by guiding the design of nanomedicines with particular effect on targeted cells, thus improving their clinical efficacy while minimizing undesired but predictable toxicological effects.
Collapse
Affiliation(s)
- Ana Luísa Silva
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
| | - Carina Peres
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal; Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium
| | - João Conniot
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
| | - Ana I Matos
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
| | - Liane Moura
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
| | - Bárbara Carreira
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
| | - Vanessa Sainz
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
| | - Anna Scomparin
- Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel and dSagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Ronit Satchi-Fainaro
- Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel and dSagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Véronique Préat
- Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, 1200 Brussels, Belgium.
| | - Helena F Florindo
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
| |
Collapse
|
44
|
Lei Y, Chen CJ, Yan XX, Li Z, Deng XH. Early-life lipopolysaccharide exposure potentiates forebrain expression of NLRP3 inflammasome proteins and anxiety-like behavior in adolescent rats. Brain Res 2017; 1671:43-54. [DOI: 10.1016/j.brainres.2017.06.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/19/2016] [Revised: 06/08/2017] [Accepted: 06/12/2017] [Indexed: 12/14/2022]
|
45
|
Palmitic acid elicits hepatic stellate cell activation through inflammasomes and hedgehog signaling. Life Sci 2017; 176:42-53. [PMID: 28322865 DOI: 10.1016/j.lfs.2017.03.012] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/16/2017] [Revised: 03/15/2017] [Accepted: 03/16/2017] [Indexed: 02/07/2023]
|
46
|
Immune and Neuroendocrine Mechanisms of Stress Vulnerability and Resilience. Neuropsychopharmacology 2017; 42:62-80. [PMID: 27291462 PMCID: PMC5143517 DOI: 10.1038/npp.2016.90] [Citation(s) in RCA: 238] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 03/05/2016] [Revised: 05/17/2016] [Accepted: 05/18/2016] [Indexed: 12/15/2022]
Abstract
Diagnostic criteria for mood disorders including major depressive disorder (MDD) largely ignore biological factors in favor of behavioral symptoms. Compounding this paucity of psychiatric biomarkers is a need for therapeutics to adequately treat the 30-50% of MDD patients who are unresponsive to traditional antidepressant medications. Interestingly, MDD is highly prevalent in patients suffering from chronic inflammatory conditions, and MDD patients exhibit higher levels of circulating pro-inflammatory cytokines. Together, these clinical findings suggest a role for the immune system in vulnerability to stress-related psychiatric illness. A growing body of literature also implicates the immune system in stress resilience and coping. In this review, we discuss the mechanisms by which peripheral and central immune cells act on the brain to affect stress-related neurobiological and neuroendocrine responses. We specifically focus on the roles of pro-inflammatory cytokine signaling, peripheral monocyte infiltration, microglial activation, and hypothalamic-pituitary-adrenal axis hyperactivity in stress vulnerability. We also highlight recent evidence suggesting that adaptive immune responses and treatment with immune modulators (exogenous glucocorticoids, humanized antibodies against cytokines) may decrease depressive symptoms and thus represent an attractive alternative to the current antidepressant treatments.
Collapse
|
47
|
Xie Q, Wei T, Huang C, Liu P, Sun M, Shen W, Gao P. Nebivolol Ameliorates Cardiac NLRP3 Inflammasome Activation in a Juvenile-Adolescent Animal Model of Diet-Induced Obesity. Sci Rep 2016; 6:34326. [PMID: 27686325 PMCID: PMC5043271 DOI: 10.1038/srep34326] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/13/2016] [Accepted: 09/12/2016] [Indexed: 01/02/2023] Open
Abstract
NLRP3 is involved in obesity-induced cardiac remodeling and dysfunction. In this study, we evaluated whether the cardiac protective effects of nebivolol relied on attenuating NLRP3 activation in a juvenile-adolescent animal model of diet-induced obesity. Weaning male Sprague-Dawley rats were fed with either a standard chow diet (ND) or a high-fat diet (HFD) for 8 weeks. The obese rats were subsequently subdivided into three groups: 1) HFD control group; 2) HFD with low-dose nebivolol (5 mg/kg/d); 3) HFD with high-dose nebivolol (10 mg/kg/d). Treatment with nebivolol prevented HFD-induced obesity associated excess cardiac lipid accumulation as well as myocardial mitochondrial dysfunction. Nebivolol attenuated pro-inflammatory cytokines secretion and NLRP3 inflammasome activation in myocardium of obese rats. In parallel, nebivolol treatment of obese animals increased cardiac β3-AR expression, reversing the reduction of endothelial nitric oxide synthase (eNOS). In vitro, nebivolol treatment of palmitate-incubated H9C2 cells suppressed autophagy, restored mitochondrial biogenesis, leading to decreased mitochondrial reactive oxygen species (mtROS) generation, and suppressed NLRP3 inflammasome activation. Meanwhile the presence of shRNA against β3-AR or against eNOS deteriorated the protective effects of nebivolol. These data suggest the beneficial effect of nebivolol on myocardial lipotoxicity contributing to inhibiting NLRP3 inflammasome activation possibly via improved mitochondrial dysfunction.
Collapse
Affiliation(s)
- Qihai Xie
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.,Department of Cardiology, Shanghai Jiading District Central Hospital, Shanghai, China
| | - Tong Wei
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Chenglin Huang
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Penghao Liu
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Mengwei Sun
- Key Laboratory of State General Administration of Sport, Shanghai Research Institute of Sports Science, Shanghai, China
| | - Weili Shen
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Pingjin Gao
- State Key Laboratory of Medical Genomics, Shanghai Key Laboratory of Hypertension, Department of Hypertension Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| |
Collapse
|
48
|
3,4-Methylenedioxy-β-Nitrostyrene Ameliorates Experimental Burn Wound Progression by Inhibiting the NLRP3 Inflammasome Activation. Plast Reconstr Surg 2016; 137:566e-575e. [PMID: 26910701 DOI: 10.1097/01.prs.0000479972.06934.83] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Burn wound progression remains a challenging problem in the clinic. Secondary tissue damage caused by unlimited inflammatory response is considered to be one of the key factors contributing to this clinical problem. Nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome has recently been found to play important roles in immune activation and the inflammatory response after burn/trauma. This experimental study aims (1) to observe the expression and distribution of NLRP3 inflammasome in burn wounds of a rat burn model and (2) to study whether inhibiting the NLRP3 inflammasome activation would ameliorate burn wound progression. METHODS A deep second-degree burn was inflicted on the backs of Wistar rats. The expression of NLRP3 inflammasome components and interleukin-1β were determined by Western blot and coimmunoprecipitation. The distribution of NLRP3 inflammasome was assessed by immunohistochemical staining and double-labeling immunofluorescence. Neutrophil infiltration, wound perfusion, burn depth, and wound healing time were assessed. RESULTS Burn induced remarkable NLRP3 inflammasome activation and cleavage of interleukin-1β. The NLRP3 inflammasome was observed mainly in macrophages of the zone of stasis. 3,4-Methylenedioxy-β-nitrostyrene significantly inhibited NLRP3 inflammasome activation and inflammatory cytokine production in burn wounds. Consequently, neutrophil infiltration was reduced, wound perfusion was restored, burn wound progression was ameliorated, and wound healing was accelerated. CONCLUSIONS In this study, the authors demonstrated that burn induced NLRP3 inflammasome activation and inflammatory response in wounds, which may be associated with burn wound progression. Treatment with 3,4-methylenedioxy-β-nitrostyrene inhibited NLRP3 inflammasome activation, ameliorated burn wound progression, and promoted wound healing.
Collapse
|
49
|
Ballbach M, Hall T, Brand A, Neri D, Singh A, Schaefer I, Herrmann E, Hansmann S, Handgretinger R, Kuemmerle-Deschner J, Hartl D, Rieber N. Induction of Myeloid-Derived Suppressor Cells in Cryopyrin-Associated Periodic Syndromes. J Innate Immun 2016; 8:493-506. [PMID: 27351923 DOI: 10.1159/000446615] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/14/2015] [Accepted: 05/05/2016] [Indexed: 12/23/2022] Open
Abstract
Cryopyrin-associated periodic syndromes (CAPS) are caused by mutations in the NLRP3 gene leading to overproduction of IL-1β and other NLRP3 inflammasome products. Myeloid-derived suppressor cells (MDSCs) represent a novel innate immune cell subset capable of suppressing T-cell responses. As inflammasome products were previously found to induce MDSCs, we hypothesized that NLRP3 inflammasome-dependent factors induce the generation of MDSCs in CAPS. We studied neutrophilic MDSCs, their clinical relevance, and MDSC-inducing factors in a unique cohort of CAPS patients under anti-IL-1 therapy. Despite anti-IL-1 therapy and low clinical disease activity, CAPS patients showed significantly elevated MDSCs compared to healthy controls. MDSCs were functionally competent, as they suppressed polyclonal T-cell proliferation, as well as Th1 and Th17 responses. In addition, MDSCs decreased monocytic IL-1β secretion. Multiplex assays revealed a distinct pattern of MDSC-inducing cytokines, chemokines, and growth factors. Experimental analyses demonstrated that IL-1 cytokine family members and autoinflammation-associated alarmins differentially induced human MDSCs. Increased MDSCs might represent a novel autologous anti-inflammatory mechanism in autoinflammatory conditions and may serve as a future therapeutic target.
Collapse
Affiliation(s)
- Marlene Ballbach
- Department of Pediatrics I, University of Tübingen, Tübingen, Germany
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
50
|
Guerrero CA, Acosta O. Inflammatory and oxidative stress in rotavirus infection. World J Virol 2016; 5:38-62. [PMID: 27175349 PMCID: PMC4861870 DOI: 10.5501/wjv.v5.i2.38] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 08/12/2015] [Revised: 10/23/2015] [Accepted: 01/29/2016] [Indexed: 02/05/2023] Open
Abstract
Rotaviruses are the single leading cause of life-threatening diarrhea affecting children under 5 years of age. Rotavirus entry into the host cell seems to occur by sequential interactions between virion proteins and various cell surface molecules. The entry mechanisms seem to involve the contribution of cellular molecules having binding, chaperoning and oxido-reducing activities. It appears to be that the receptor usage and tropism of rotaviruses is determined by the species, cell line and rotavirus strain. Rotaviruses have evolved functions which can antagonize the host innate immune response, whereas are able to induce endoplasmic reticulum (ER) stress, oxidative stress and inflammatory signaling. A networking between ER stress, inflammation and oxidative stress is suggested, in which release of calcium from the ER increases the generation of mitochondrial reactive oxygen species (ROS) leading to toxic accumulation of ROS within ER and mitochondria. Sustained ER stress potentially stimulates inflammatory response through unfolded protein response pathways. However, the detailed characterization of the molecular mechanisms underpinning these rotavirus-induced stressful conditions is still lacking. The signaling events triggered by host recognition of virus-associated molecular patterns offers an opportunity for the development of novel therapeutic strategies aimed at interfering with rotavirus infection. The use of N-acetylcysteine, non-steroidal anti-inflammatory drugs and PPARγ agonists to inhibit rotavirus infection opens a new way for treating the rotavirus-induced diarrhea and complementing vaccines.
Collapse
|