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Shirazi SHUA, Rizvi F, Sherwani ZA, Siddiqui AR, Ul-Haq Z, Siddiqui H, Choudhary MI, Ahmad MS. Synthesis of isoniazid derivatives and evaluation of their α-chymotrypsin inhibitory effect through in silico guided in vitro studies. Biochem Biophys Res Commun 2024; 735:150805. [PMID: 39426135 DOI: 10.1016/j.bbrc.2024.150805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/08/2024] [Accepted: 10/08/2024] [Indexed: 10/21/2024]
Abstract
Alpha-chymotrypsin is a serine protease. Its overexpression is responsible for several ailments, such as chronic obstructive pulmonary disease, autoimmune diseases, pancreatitis, and colon cancers. Therefore, the discovery of potent α-chymotrypsin inhibitors is essential for the treatment of the aforementioned ailments. In this study, we identified new α-chymotrypsin inhibitors through a systematic approach, utilizing the in silico and in vivo studies to predict and confirm the inhibitory potential of isoniazid derivatives. During this study, six compounds 2, 3, 4, 7, 9, and 10 were shortlisted from ten isoniazid derivatives through in silico screening. After that, MD simulations were performed for these compounds. The shortlisted compounds were evaluated through an in vitro α-chymotrypsin inhibitory assay. Compounds 9 and 10 showed a potent inhibition against α-chymotrypsin. The identified compounds or their derivatives can be further investigated as drug leads against the ailments caused by α-chymotrypsin and related serine proteases.
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Affiliation(s)
- Syeda Hoor-Ul-Ain Shirazi
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Fazila Rizvi
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Zaid Anis Sherwani
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Ali Raza Siddiqui
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Zaheer Ul-Haq
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Hina Siddiqui
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - M Iqbal Choudhary
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Malik Shoaib Ahmad
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
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Liu S, Wang X, Hu QZ, Geng Y, Dong H. Paper-based flow sensor for detection of chymotrypsin and its inhibitors via viscosity change of gelatin. J Food Compost Anal 2022. [DOI: 10.1016/j.jfca.2022.105064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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3
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Esmat MA, Osman A, Hassan RE, Hagag SA, El-Maghraby TK. Hepatoprotective effect of ferulic acid and/or low doses of γ-irradiation against cisplatin-induced liver injury in rats. Hum Exp Toxicol 2022; 41:9603271221136205. [PMID: 36270770 DOI: 10.1177/09603271221136205] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2023]
Abstract
The therapeutic efficacy of cisplatin (CIS) is limited owing to its hepatotoxic side effects. The current study aimed to investigate the protective impact of ferulic acid (FA) and low-doses of γ-irradiation (LDR) against CIS-prompted hepatotoxicity in rats. Adult male Swiss albino rats were divided into eight groups: untreated group; FA, LDR, and CIS treated groups; and combinations of one or more of the above treatments. Post-treatment analyses included measuring redox markers like SOD and CAT activity, NO free radical content, and lipid peroxidation in liver tissue. Serum aminotransferase activities were also determined. Additionally, gene transcript levels of liver NF-ҡB-P65, caspase-1, COX-2, and IL-1β were quantified. Moreover, immunohistochemistry for caspase-3 and histopathological examinations were estimated in liver tissue. Our findings revealed increased levels of oxidative stress along with a significant reduction in anti-oxidative responses and a significant increase in serum aminotransferase activities in the CIS-intoxicated group. A similar increase was also observed in COX-2 and IL-1β transcript levels and caspase-3 enzyme activity, besides a decrease in transcript levels of NF-ҡB-p65 and caspase-1, indicating an overall inflammatory trend and an increase in the apoptotic shift. The co-administration of FA and/or treatment with LDR has ameliorated the hepatotoxic effect induced by CIS. The histopathological investigation of liver tissues confirmed this ameliorating action of these adjuvant therapies against CIS toxicity. In conclusion, it is plausible to suggest that the hepatoprotective effects of co-administration of FA and/or LDR against CIS-induced hepatotoxicity are attributed to the possession of anti-oxidative, anti-inflammatory, and anti-apoptotic capabilities.
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Affiliation(s)
- Marwa A Esmat
- Department of Radiation Biology, 110168National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Ahmed Osman
- Faculty of Science, Department of Biochemistry, 247928Ain Shams University, Cairo, Egypt
- Egypt-Japan University of Science and Technology (E-JUST), Alexandria, Egypt
| | - Rasha E Hassan
- Faculty of Science, Department of Biochemistry, 247928Ain Shams University, Cairo, Egypt
| | - Sanaa A Hagag
- Department of Radiation Biology, 110168National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt
| | - Tarek K El-Maghraby
- Department of Radiation Biology, 110168National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority, Cairo, Egypt
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Mahmoud GS, Hosny G, Sayed SA. Hepatoprotective effect of trypsin/chymotrypsin against olanzapine-induced non-alcoholic steatohepatitis in rats. Can J Physiol Pharmacol 2021; 99:1088-1096. [PMID: 34473596 DOI: 10.1139/cjpp-2021-0075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Metabolic side effects of atypical antipsychotics are an important cause of deterioration of cognitive function and failure of drug adherence. The antifatty effect trypsin/chymotrypsin (T/C) and their mechanisms of action remain unclear. To investigate possible therapeutic effect of T/C in rat model of chronic olanzapine (OLZ) - induced hepatic steatosis. Twenty rats were divided into two groups: control (C), given distilled water, and O, given 1 mg/kg of OLZ orally daily for 7 weeks. Then, both groups were given T/C 3 enzyme activity unit (EAU)/kg orally as an add-on treatment daily for the next 5 weeks and were named T/C or T/C+O groups. Rat performance in radial arm water maze was tested twice before and after T/C treatment. We measured liver enzymes, alpha-1 antitrypsin, albumin, total protein, direct and total bilirubin, inflammatory cytokines, and lipoprotein serum levels. Liver samples were collected for histopathology and Ki67 expression. The T/C add-on caused significant reduction in OLZ-induced elevation of alanine transaminase (ALT; P < 0.01), aspartate transaminase (AST; P < 0.001), alkaline phosphatase (ALP; P < 0.05), total cholesterol (Tc; P < 0.01), low-density lipoproteins (LDL-c; P < 0.05), steatosis score (P < 0.001), hepatocyte necrosis (P < 0.01), and significantly increased Ki67 expression (P < 0.01). The T/C add-on to OLZ provided protection against hepatic steatosis, elevated enzymes, and disturbed lipid profile and increased Ki67 without disturbing memory function.
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Affiliation(s)
- Ghada S Mahmoud
- Departments of Medical Physiology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ghada Hosny
- Department of Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Sally A Sayed
- Departments of Medical Physiology, Faculty of Medicine, Assiut University, Assiut, Egypt
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5
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Xu M, Liang H, Meng SS, Gu ZY. Enhancing the enzymatic inhibition performance of Cu-based metal-organic frameworks by shortening the organic ligands. Analyst 2021; 146:4235-4241. [PMID: 34096937 DOI: 10.1039/d1an00531f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Creating more exposed active sites on the metal-organic framework (MOF) surface is crucial for enhancing the recognition ability of MOF artificial receptors. Here, a copper-based MOF Cu(im)2 (im = imidazole) was utilized to act as an artificial receptor, inhibiting the activity of α-chymotrypsin. The shortest diazole ligand reduced the distance between regenerative copper sites, creating as many active sites as possible on the MOF unit surface. The amount of copper(ii) centers on the Cu(im)2 surface was calculated to be 4.96 × 106μm-2. Thus, Cu(im)2 showed exceedingly higher inhibition performance than other copper-based MOFs. The ChT activity was almost inhibited (88.8%) after the incubation with only 20 μg mL-1 Cu(im)2 for 10 min. The binding between ChT and Cu(im)2 was very fast with high affinity. Further results proved that Cu(im)2 inhibited the activity of ChT through electrostatic interactions and coordination interactions via the mixed inhibition mode. This strategy to use short ligands to create more active sites on the MOF surface provides a new direction to enhance the inhibition efficiency.
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Affiliation(s)
- Ming Xu
- Jiangsu Key Laboratory of Biofunctional Materials, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China.
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Griffiths JS, Camilli G, Kotowicz NK, Ho J, Richardson JP, Naglik JR. Role for IL-1 Family Cytokines in Fungal Infections. Front Microbiol 2021; 12:633047. [PMID: 33643264 PMCID: PMC7902786 DOI: 10.3389/fmicb.2021.633047] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/15/2021] [Indexed: 12/15/2022] Open
Abstract
Fungal pathogens kill approximately 1.5 million individuals per year and represent a severe disease burden worldwide. It is estimated over 150 million people have serious fungal disease such as recurrent mucosal infections or life-threatening systemic infections. Disease can ensue from commensal fungi or new infection and involves different fungal morphologies and the expression of virulence factors. Therefore, anti-fungal immunity is complex and requires coordination between multiple facets of the immune system. IL-1 family cytokines are associated with acute and chronic inflammation and are essential for the innate response to infection. Recent research indicates IL-1 cytokines play a key role mediating immunity against different fungal infections. During mucosal disease, IL-1R and IL-36R are required for neutrophil recruitment and protective Th17 responses, but function through different mechanisms. During systemic disease, IL-18 drives protective Th1 responses, while IL-33 promotes Th2 and suppresses Th1 immunity. The IL-1 family represents an attractive anti-fungal immunotherapy target. There is a need for novel anti-fungal therapeutics, as current therapies are ineffective, toxic and encounter resistance, and no anti-fungal vaccine exists. Furthering our understanding of the IL-1 family cytokines and their complex role during fungal infection may aid the development of novel therapies. As such, this review will discuss the role for IL-1 family cytokines in fungal infections.
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Affiliation(s)
- James S Griffiths
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - Giorgio Camilli
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - Natalia K Kotowicz
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - Jemima Ho
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - Jonathan P Richardson
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
| | - Julian R Naglik
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, United Kingdom
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Xu M, Meng SS, Liang H, Gu ZY. A metal–organic framework with tunable exposed facets as a high-affinity artificial receptor for enzyme inhibition. Inorg Chem Front 2020. [DOI: 10.1039/d0qi00827c] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Copper-based metal-organic framework HKUST-1 was utilized as artificial receptor to recognize positive-charged α-chymotrypsin with high affinity. The affinity between them could be tuned through comprehensive synthetic design of exposed facets.
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Affiliation(s)
- Ming Xu
- Jiangsu Key Laboratory of Biofunctional Materials
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials
- College of Chemistry and Materials Science
- Nanjing Normal University
- Nanjing
| | - Sha-Sha Meng
- Jiangsu Key Laboratory of Biofunctional Materials
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials
- College of Chemistry and Materials Science
- Nanjing Normal University
- Nanjing
| | - Hong Liang
- Jiangsu Key Laboratory of Biofunctional Materials
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials
- College of Chemistry and Materials Science
- Nanjing Normal University
- Nanjing
| | - Zhi-Yuan Gu
- Jiangsu Key Laboratory of Biofunctional Materials
- Jiangsu Collaborative Innovation Center of Biomedical Functional Materials
- College of Chemistry and Materials Science
- Nanjing Normal University
- Nanjing
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8
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Exploring the Involvement of NLRP3 and IL-1 β in Osteoarthritis of the Hand: Results from a Pilot Study. Mediators Inflamm 2019; 2019:2363460. [PMID: 30983879 PMCID: PMC6431515 DOI: 10.1155/2019/2363460] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 12/04/2018] [Accepted: 12/19/2018] [Indexed: 12/27/2022] Open
Abstract
Hand osteoarthritis (HOA) includes different subsets; a particular and uncommon form is erosive HOA (EHOA). Interleukin- (IL-) 1β plays a crucial role in the pathogenesis of osteoarthritis (OA); it is synthesized as an inactive precursor which requires the intervention of a cytosolic multiprotein complex, named inflammasome, for its activation. The aim of this study was to investigate the involvement of IL-1β and the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome in patients with EHOA and nonerosive HOA (NEHOA) compared to healthy controls. In particular, we evaluated the gene expression of IL-1β and NLRP3, the serum levels of IL-1β, IL-6, IL-17, and tumor necrosis factor- (TNF-) α, and the protein levels of IL-1β and NLRP3. We also assessed the relationships between IL-1β and NLRP3 and clinical, laboratory, and radiological findings. Fifty-four patients with HOA (25 EHOA and 29 NEHOA) and 20 healthy subjects were included in the study. Peripheral blood mononuclear cell (PBMC) gene and protein expressions of IL-1β and NLRP3 were quantified by quantitative real-time PCR and western blot. IL-1β, IL-6, IL-17, and TNF-α serum levels were determined by ELISA. IL-1β gene expression was significantly reduced (p = 0.0208) in EHOA compared to healthy controls. NLRP3 protein levels were significantly increased in the NEHOA group versus the control (p = 0.0063) and EHOA groups (p = 0.0038). IL-1β serum levels were not significantly different across the groups; IL-6, IL-17, and TNF-α were not detectable in any sample. IL-1β concentrations were negatively correlated with the Kellgren-Lawrence score in the whole population (r = −0.446; p = 0.0008) and in NEHOA (r = −0.608; p = 0.004), while IL-1β gene expression was positively correlated with the number of joint swellings in the EHOA group (r = 0.512; p = 0.011). Taken together, our results, showing poorly detectable IL-1β concentrations and minimal inflammasome activity in the PBMCs of HOA patients, suggest a low grade of systemic inflammation in HOA. This evidence does not preclude a possible involvement of these factors at the local level.
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Esnault S, Kelly EA, Johnson SH, DeLain LP, Haedt MJ, Noll AL, Sandbo N, Jarjour NN. Matrix Metalloproteinase-9-Dependent Release of IL-1 β by Human Eosinophils. Mediators Inflamm 2019; 2019:7479107. [PMID: 30906226 PMCID: PMC6398033 DOI: 10.1155/2019/7479107] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 11/22/2018] [Indexed: 12/14/2022] Open
Abstract
Asthma is often associated with airway eosinophilia, and therapies targeting eosinophils are now available to treat severe eosinophilic asthma. Eosinophilic asthma is often due to a type-2 immune response and production of IL-5, which leads to eosinophilopiesis and recruitment of mature eosinophils in the airways. A concomitant type-2 and type-17 response has been reported in some individuals. IL-17 may be enhanced by IL-1β production and can lead to neutrophilic inflammation. In fact, both eosinophilic and neutrophilic (mixed granulocytic) inflammation are simultaneously present in a large population of patients with asthma. In monocyte/macrophage cell populations, release of mature IL-1β occurs via toll-like receptor ligand-induced activation of the inflammasome. Within the inflammasome, a cascade of events leads to the activation of caspase-1, which cleaves pro-IL-1β protein into a mature, releasable, and active form. We have demonstrated that eosinophils can release IL-1β in a Toll-like receptor ligand-independent fashion. The objective of this study was to determine the mechanisms underlying the production and maturation of IL-1β in cytokine-activated eosinophils. Using eosinophils from circulating blood and from bronchoalveolar lavage fluid after an airway allergen challenge, the present study demonstrates that cytokine-activated eosinophils express and release a bioactive form of IL-1β with an apparent size less than the typical 17 kDa mature form produced by macrophages. Using a zymography approach and pharmacological inhibitors, we identified matrix metalloproteinase-9 (MMP-9) as a protease that cleaves pro-IL-1β into a ~15 kDa form and allows the release of IL-1β from cytokine-activated eosinophils. Therefore, we conclude that activated eosinophils produce MMP-9, which causes the release of IL-1β in an inflammasome/caspase-1-independent manner. The production of IL-1β by eosinophils may be a link between the eosinophilic/type-2 immune response and the neutrophilic/type-17 immune response that is often associated with a more severe and treatment-refractory type of asthma.
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Affiliation(s)
- Stephane Esnault
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA
| | - Elizabeth A. Kelly
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA
| | - Sean H. Johnson
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA
| | - Larissa P. DeLain
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA
| | - Madeline J. Haedt
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA
| | - Andrea L. Noll
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA
| | - Nathan Sandbo
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA
| | - Nizar N. Jarjour
- University of Wisconsin-Madison School of Medicine and Public Health, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Madison, WI, USA
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Fang H, Huang PC, Wu FY. A novel jointly colorimetric and fluorescent sensor for Cu 2+ recognition and its complex for sensing S 2- by a Cu 2+ displacement approach in aqueous media. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2018; 204:568-575. [PMID: 29975918 DOI: 10.1016/j.saa.2018.06.068] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 06/18/2018] [Indexed: 05/06/2023]
Abstract
In this work, a simple and easily synthesized Schiff-based derivative colorimetric and fluorescent sensor (1), 4-dimethylamino-benzoic acid (2-imidazole formaldehyde)-hydrazide, was obtained for the detection of Cu2+ and S2-. The compound 1 exhibited dual spectral responses to Cu2+, that is, vivid color change and fluorescence enhancement in the presence of Cu2+. The detection limits were valued as 0.46 μM and 15 nM according to absorption and fluorescent response, respectively. Both of them are below the World Health Organization (WHO) guidelines for drinking water (31.5 μM). In addition, the ensemble (1-Cu2+) selectively and sensitively detected a low concentration of S2-. As the addition of S2- instantly removed Cu2+ from the ensemble (1-Cu2+) resulting in a color change from yellow to colorless and a "turn-off" fluorescent response. The detection limit for S2- was estimated as 0.12 μM (from fluorescent method) and 0.68 μM (from absorption method), respectively, each of which was also lower than the maximum allowable level of S2- (15 μM) in drinking water defined by the WHO. The binding process was confirmed via UV-vis absorption, fluorescence measurements, 1H NMR, mass spectroscopy and density functional theory calculation. What's more, successful practical application of test paper is used to inspect the S2- which means the convenient and rapid assay in real samples can be achieved.
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Affiliation(s)
- Hao Fang
- College of Chemistry, Nanchang University, Nanchang 330031, China
| | - Peng-Cheng Huang
- College of Chemistry, Nanchang University, Nanchang 330031, China
| | - Fang-Ying Wu
- College of Chemistry, Nanchang University, Nanchang 330031, China.
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Crisford H, Sapey E, Stockley RA. Proteinase 3; a potential target in chronic obstructive pulmonary disease and other chronic inflammatory diseases. Respir Res 2018; 19:180. [PMID: 30236095 PMCID: PMC6149181 DOI: 10.1186/s12931-018-0883-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 09/06/2018] [Indexed: 12/15/2022] Open
Abstract
Chronic Obstructive Pulmonary Disease (COPD) is a common, multifactorial lung disease which results in significant impairment of patients' health and a large impact on society and health care burden. It is believed to be the result of prolonged, destructive neutrophilic inflammation which results in progressive damage to lung structures. During this process, large quantities of neutrophil serine proteinases (NSPs) are released which initiate the damage and contribute towards driving a persistent inflammatory state.Neutrophil elastase has long been considered the key NSP involved in the pathophysiology of COPD. However, in recent years, a significant role for Proteinase 3 (PR3) in disease development has emerged, both in COPD and other chronic inflammatory conditions. Therefore, there is a need to investigate the importance of PR3 in disease development and hence its potential as a therapeutic target. Research into PR3 has largely been confined to its role as an autoantigen, but PR3 is involved in triggering inflammatory pathways, disrupting cellular signalling, degrading key structural proteins, and pathogen response.This review summarises what is presently known about PR3, explores its involvement particularly in the development of COPD, and indicates areas requiring further investigation.
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Affiliation(s)
- Helena Crisford
- Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, B15 2GW, UK.
- Institute of Inflammation and Ageing, College of Medical and Dental Sciences, Centre for Translational Inflammation Research, University of Birmingham Research Laboratories, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham, B15 2WB, UK.
| | - Elizabeth Sapey
- Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham, B15 2GW, UK
| | - Robert A Stockley
- University Hospital Birmingham NHS Foundation Trust, Edgbaston, Birmingham, B15 2GW, UK
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Sarkar K, Dastidar P. Exfoliated Nanosheets of a Cu II Coordination Polymer Modulate Enzyme Activity of α-Chymotrypsin. Chemistry 2018; 24:11297-11302. [PMID: 29888818 DOI: 10.1002/chem.201802376] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 06/06/2018] [Indexed: 12/20/2022]
Abstract
A 2D coordination polymer derived from 5-azidoisophthalic acid (AIA) and Cu(NO3 )2 was designed with the aim of modulating the activity of a digestive enzyme α-chymotrypsin (ChT). The coordination polymer namely {[Cu0.5 (μ-AIA)0.5 (H2 O)]⋅2 H2 O}α (CP1) was successfully synthesized and fully characterized by single-crystal X-ray diffraction (SXRD). An exfoliated nanosheet (ENS) of CP1 was readily produced by overnight stirring of hand-ground CP1 crystals dispersed in DMSO. ENS(CP1) was demonstrated to be acting as an inhibitor of ChT; as much as ≈97 % inhibition of ChT was achieved with 100 μm of ENS(CP1) using N-succinyl-l-phenylalanine-p-nitroanilide (SPNA) as substrate. Enzyme kinetics data revealed that the inhibition of ChT followed a competitive pathway. An enzyme assay under varying ionic strength and varying concentration of free histidine revealed that the active site His-57 participated in coordination with the CuII metal center of ENS(CP1) thereby preventing the substrate (SPNA) from binding with the enzyme resulting in efficient inhibition.
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Affiliation(s)
- Koushik Sarkar
- Department of Organic Chemistry, Indian Association for the Cultivation of Science (IACS), 2A and 2B, Raja S. C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India
| | - Parthasarathi Dastidar
- Department of Organic Chemistry, Indian Association for the Cultivation of Science (IACS), 2A and 2B, Raja S. C. Mullick Road, Jadavpur, Kolkata, 700032, West Bengal, India
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Xu M, Yang S, Gu Z. Two‐Dimensional Metal‐Organic Framework Nanosheets: A Rapidly Growing Class of Versatile Nanomaterials for Gas Separation, MALDI‐TOF Matrix and Biomimetic Applications. Chemistry 2018; 24:15131-15142. [DOI: 10.1002/chem.201800556] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Indexed: 01/17/2023]
Affiliation(s)
- Ming Xu
- Jiangsu Key Laboratory of Biofunctional Materials, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials ScienceNanjing Normal University 210023 Nanjing China
| | - Shi‐Shu Yang
- Jiangsu Key Laboratory of Biofunctional Materials, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials ScienceNanjing Normal University 210023 Nanjing China
| | - Zhi‐Yuan Gu
- Jiangsu Key Laboratory of Biofunctional Materials, Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, College of Chemistry and Materials ScienceNanjing Normal University 210023 Nanjing China
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14
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Nam JS, Jagga S, Sharma AR, Lee JH, Park JB, Jung JS, Lee SS. Anti-inflammatory effects of traditional mixed extract of medicinal herbs (MEMH) on monosodium urate crystal-induced gouty arthritis. Chin J Nat Med 2018; 15:561-575. [PMID: 28939019 DOI: 10.1016/s1875-5364(17)30084-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Indexed: 02/07/2023]
Abstract
Korean oriental medicine prescription is widely used for the treatment of gouty diseases. In the present study, we investigated anti-inflammatory effects of modified Korean herbal formulation, mixed extract of medicinal herbs (MEMH), and its modulatory effects on inflammatory mediators associated with gouty arthritis. Both in vitro and in vivo studies were carried out to assess the anti-inflammatory efficacy of MEMH on monosodium urate (MSU) crystals-induced gouty inflammation. MSU crystals stimulated human chondrosarcoma cell line, SW1353, and human primary chondrocytes were treated with MEMH in vitro. The expression levels of pro-inflammatory mediators and metalloproteases were analyzed. The effect of MEMH on NFκB signaling pathway in SW1353 cells was examined. Effect of MEMH on the mRNA expression level of pro-inflammatory mediators and chemotactic factor from human monocytic cell line, THP-1, was also analyzed. The probable role of MEMH in the differentiation process of osteoblast like cells, SaOS-2, after MSU treatment was also observed. To investigate the effects of MEMH in vivo, MSU crystals-induced ankle arthritic model was established. Histopathological changes in affected joints and plasma levels of pro-inflammatory mediators (IL-1β and TNFα) were recorded. MEMH inhibited NFκB signaling pathway and COX-2 protein expression in chondrocytes. MSU-induced mRNA expressions of pro-inflammatory mediators and chemotactic cytokines were suppressed by MEMH. In MSU crystals-induced ankle arthritic mouse model, administration of MEMH relieved inflammatory symptoms and decreased the plasma levels of IL-1β and TNFα. The results indicated that MEMH can effectively inhibit the expression of inflammatory mediators in gouty arthritis, demonstrating its potential for treating gouty arthritis.
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Affiliation(s)
- Ju-Suk Nam
- Institute For Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Supriya Jagga
- Institute For Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Ashish Ranjan Sharma
- Institute For Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Joon-Hee Lee
- Hana Oriental Clinic, Chucnheon, Gangwon-do 24433, Republic of Korea
| | - Jong Bong Park
- Institute For Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-do 24252, Republic of Korea
| | - Jun-Sub Jung
- Institute of Natural Medicine, College of Medicine, Hallym University, Chucheon, Gangwon-do 24252, Republic of Korea
| | - Sang-Soo Lee
- Institute For Skeletal Aging & Orthopedic Surgery, Hallym University-Chuncheon Sacred Heart Hospital, Chuncheon, Gangwon-do 24252, Republic of Korea.
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15
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Bonnekoh H, Scheffel J, Kambe N, Krause K. The role of mast cells in autoinflammation. Immunol Rev 2018; 282:265-275. [DOI: 10.1111/imr.12633] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Hanna Bonnekoh
- Department of Dermatology and Allergy; Allergie-Centrum-Charité; Charité - Universitätsmedizin Berlin; Berlin Germany
- Autoinflammation Reference Center Charité (ARC2); Charité - Universitätsmedizin Berlin; Berlin Germany
| | - Jörg Scheffel
- Department of Dermatology and Allergy; Allergie-Centrum-Charité; Charité - Universitätsmedizin Berlin; Berlin Germany
- Autoinflammation Reference Center Charité (ARC2); Charité - Universitätsmedizin Berlin; Berlin Germany
| | - Naotomo Kambe
- Department of Dermatology; Kansai Medical University; Hirakata Japan
- Allergy Center; Kansai Medical University; Hirakata Japan
| | - Karoline Krause
- Department of Dermatology and Allergy; Allergie-Centrum-Charité; Charité - Universitätsmedizin Berlin; Berlin Germany
- Autoinflammation Reference Center Charité (ARC2); Charité - Universitätsmedizin Berlin; Berlin Germany
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16
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Inflammatory Joint Disorders and Neutrophilic Dermatoses: a Comprehensive Review. Clin Rev Allergy Immunol 2017; 54:269-281. [DOI: 10.1007/s12016-017-8629-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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17
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Orlowski GM, Sharma S, Colbert JD, Bogyo M, Robertson SA, Kataoka H, Chan FK, Rock KL. Frontline Science: Multiple cathepsins promote inflammasome-independent, particle-induced cell death during NLRP3-dependent IL-1β activation. J Leukoc Biol 2017; 102:7-17. [PMID: 28087651 PMCID: PMC6608057 DOI: 10.1189/jlb.3hi0316-152r] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Revised: 11/28/2016] [Accepted: 12/05/2016] [Indexed: 12/21/2022] Open
Abstract
Sterile particles cause several chronic, inflammatory diseases, characterized by repeating cycles of particle phagocytosis and inflammatory cell death. Recent studies have proposed that these processes are driven by the NLRP3 inflammasome, a platform activated by phagocytosed particles, which controls both caspase-1-dependent cell death (pyroptosis) and mature IL-1β secretion. After phagocytosis, particles can disrupt lysosomes, and inhibitor studies have suggested that the resulting release of a lysosomal protease-cathepsin B-into the cytosol somehow activates NLRP3. However, using primary murine macrophages, we found that particle-induced cell death occurs independent of NLRP3/caspase-1 and depends instead on multiple, redundant cathepsins. In contrast, nigericin, a soluble activator of NLRP3 inflammasomes, induced cell death that was dependent on the NLRP3. Interestingly, nigericin-induced cell death depended partly on a single cathepsin, cathepsin X. By inhibiting or silencing multiple cathepsins in macrophages, several key proinflammatory events induced by sterile particles are blocked, including cell death, pro-IL-1β production, and IL-1β secretion. These data suggest that cathepsins might be potential therapeutic targets in particulate-mediated inflammatory disease. In support of this concept, we find that a broad-spectrum cathepsin inhibitor can suppress particle-induced IL-1-dependent peritonitis.
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Affiliation(s)
- Gregory M Orlowski
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Shruti Sharma
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Jeff D Colbert
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Matthew Bogyo
- Department of Pathology, Stanford University School of Medicine, Stanford, California, USA
- Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA; and
| | - Stephanie A Robertson
- Sandler Center for Drug Discovery, University of California, San Francisco, California, USA
| | - Hiroshi Kataoka
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Francis K Chan
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
| | - Kenneth L Rock
- Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts, USA;
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18
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Xu M, Yuan S, Chen XY, Chang YJ, Day G, Gu ZY, Zhou HC. Two-Dimensional Metal–Organic Framework Nanosheets as an Enzyme Inhibitor: Modulation of the α-Chymotrypsin Activity. J Am Chem Soc 2017; 139:8312-8319. [DOI: 10.1021/jacs.7b03450] [Citation(s) in RCA: 140] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Ming Xu
- Jiangsu
Key Laboratory of Biofunctional Materials, Jiangsu Collaborative Innovation
Center of Biomedical Functional Materials, College of Chemistry and
Materials Science, Nanjing Normal University, Nanjing, 210023, China
| | - Shuai Yuan
- Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255, United States
| | - Xin-Yu Chen
- Jiangsu
Key Laboratory of Biofunctional Materials, Jiangsu Collaborative Innovation
Center of Biomedical Functional Materials, College of Chemistry and
Materials Science, Nanjing Normal University, Nanjing, 210023, China
| | - Yu-Jie Chang
- Jiangsu
Key Laboratory of Biofunctional Materials, Jiangsu Collaborative Innovation
Center of Biomedical Functional Materials, College of Chemistry and
Materials Science, Nanjing Normal University, Nanjing, 210023, China
| | - Gregory Day
- Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255, United States
| | - Zhi-Yuan Gu
- Jiangsu
Key Laboratory of Biofunctional Materials, Jiangsu Collaborative Innovation
Center of Biomedical Functional Materials, College of Chemistry and
Materials Science, Nanjing Normal University, Nanjing, 210023, China
| | - Hong-Cai Zhou
- Department of Chemistry, Texas A&M University, College Station, Texas 77843-3255, United States
- Department of Materials Science and Engineering, Texas A&M University, College Station, Texas 77842, United States
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Marasini BP, Rahim F, Perveen S, Karim A, Mohammed Khan K, Atta-ur-Rahman, Choudhary MI. Synthesis, structure-activity relationships studies of benzoxazinone derivatives as α -chymotrypsin inhibitors. Bioorg Chem 2017; 70:210-221. [DOI: 10.1016/j.bioorg.2017.01.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 12/20/2016] [Accepted: 01/03/2017] [Indexed: 01/29/2023]
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20
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Yu G, Bai Z, Chen Z, Chen H, Wang G, Wang G, Liu Z. The NLRP3 inflammasome is a potential target of ozone therapy aiming to ease chronic renal inflammation in chronic kidney disease. Int Immunopharmacol 2017; 43:203-209. [PMID: 28038382 DOI: 10.1016/j.intimp.2016.12.022] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 12/16/2016] [Accepted: 12/17/2016] [Indexed: 01/08/2023]
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21
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[Interleukin-1, inflammasome and autoinflammatory diseases]. Rev Med Interne 2016; 39:233-239. [PMID: 27639913 DOI: 10.1016/j.revmed.2016.07.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 07/29/2016] [Indexed: 01/26/2023]
Abstract
Interleukin-1 is a major cytokine of innate immunity and inflammation. It exerts various systemic effects during the inflammatory response, such as fever induction, thrombopoiesis and granulopoiesis, or leukocyte recruitment. Its involvement has been demonstrated in many inflammatory-mediated diseases, such as diabetes or gout. Moreover, interleukin-1 plays a pivotal role in some autoinflammatory diseases, such as cryopyrinopathies or familial Mediterranean fever. In these diseases, a constitutional defect of the inflammasome, a protein complex responsible for the activation of interleukin-1, explains the hypersecretion of interleukin-1. Other autoinflammatory diseases have a more complex pathophysiology involving deregulation of the interleukin-1 pathway, upstream or downstream of the inflammasome, or through more complex mechanisms. In this review, we are detailing the synthesis, the activation, the signalling, and the regulation of interleukin-1. We then describe the autoinflammatory diseases or related-diseases where the pathological role of interleukin-1 has been demonstrated.
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22
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Siddiqui H, Farooq R, Marasini BP, Malik R, Syed N, Moin ST, Atta-ur-Rahman, Choudhary MI. Synthesis and in vitro α-chymotrypsin inhibitory activity of 6-chlorobenzimidazole derivatives. Bioorg Med Chem 2016; 24:3387-95. [DOI: 10.1016/j.bmc.2016.05.018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 05/04/2016] [Accepted: 05/12/2016] [Indexed: 01/05/2023]
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23
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An Essential Role for SHARPIN in the Regulation of Caspase 1 Activity in Sepsis. THE AMERICAN JOURNAL OF PATHOLOGY 2016; 186:1206-20. [PMID: 26968342 DOI: 10.1016/j.ajpath.2015.12.026] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2015] [Revised: 12/06/2015] [Accepted: 12/16/2015] [Indexed: 12/22/2022]
Abstract
Sepsis is burdened by high mortality due to uncontrolled inflammatory response to pathogens. Increased caspase 1 activation causing maturation of IL1β/18 remains a therapeutic challenge in sepsis. SHARPIN (shank-associated regulator of G-protein signaling homology domain-interacting protein), a component of the LUBAC (linear ubiquitin chain-assembly complex), regulates inflammation, with unknown effects on caspase 1 activation. Mice lacking Casp1, Casp11, or both in a Sharpin-deficient background were generated, exposed to lipopolysaccharide-induced endotoxemia, and injected with caspase 1 inhibitor. We monitored survival, Il1β/18, and caspase 1/11 levels in plasma and organs and deciphered mechanisms of SHARPIN-dependent caspase 1 inhibition. A correlation between LUBAC and active caspase 1 was found in blood mononuclear cells from septic patients. SHARPIN bound caspase 1 and disrupted p20/p10 dimer formation, the last step of caspase 1 processing, thereby inhibiting enzyme activation and maturation of IL1β/18 in a LUBAC-independent manner. In septic patients, LUBAC-independent decline in SHARPIN correlated with enhancement of active caspase 1 in circulating mononuclear cells. Septic Sharpin-deficient mice displayed enrichment in mature Il1β/18 and active caspase 1, and shortened survival. Inhibition of caspase 1 reduced levels of Il1β/18 and splenic cell death, and prolonged survival in septic Sharpin-deficient mice. Our findings identify SHARPIN as a potent in vivo caspase 1 inhibitor and propose the caspase 1-SHARPIN interaction as a target in sepsis.
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24
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Interleukin-1 Family Cytokines in Liver Diseases. Mediators Inflamm 2015; 2015:630265. [PMID: 26549942 PMCID: PMC4624893 DOI: 10.1155/2015/630265] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 09/27/2015] [Indexed: 02/06/2023] Open
Abstract
The gene encoding IL-1 was sequenced more than 30 years ago, and many related cytokines, such as IL-18, IL-33, IL-36, IL-37, IL-38, IL-1 receptor antagonist (IL-1Ra), and IL-36Ra, have since been identified. IL-1 is a potent proinflammatory cytokine and is involved in various inflammatory diseases. Other IL-1 family ligands are critical for the development of diverse diseases, including inflammatory and allergic diseases. Only IL-1Ra possesses the leader peptide required for secretion from cells, and many ligands require posttranslational processing for activation. Some require inflammasome-mediated processing for activation and release, whereas others serve as alarmins and are released following cell membrane rupture, for example, by pyroptosis or necroptosis. Thus, each ligand has the proper molecular process to exert its own biological functions. In this review, we will give a brief introduction to the IL-1 family cytokines and discuss their pivotal roles in the development of various liver diseases in association with immune responses. For example, an excess of IL-33 causes liver fibrosis in mice via activation and expansion of group 2 innate lymphoid cells to produce type 2 cytokines, resulting in cell conversion into pro-fibrotic M2 macrophages. Finally, we will discuss the importance of IL-1 family cytokine-mediated molecular and cellular networks in the development of acute and chronic liver diseases.
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25
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Antonopoulos C, Russo HM, El Sanadi C, Martin BN, Li X, Kaiser WJ, Mocarski ES, Dubyak GR. Caspase-8 as an Effector and Regulator of NLRP3 Inflammasome Signaling. J Biol Chem 2015; 290:20167-84. [PMID: 26100631 PMCID: PMC4536427 DOI: 10.1074/jbc.m115.652321] [Citation(s) in RCA: 174] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 06/12/2015] [Indexed: 12/20/2022] Open
Abstract
We recently described the induction of noncanonical IL-1β processing via caspase-8 recruited to ripoptosome signaling platforms in myeloid leukocytes. Here, we demonstrate that activated NLRP3·ASC inflammasomes recruit caspase-8 to drive IL-1β processing in murine bone marrow-derived dendritic cells (BMDC) independent of caspase-1 and -11. Sustained stimulation (>2 h) of LPS-primed caspase-1-deficient (Casp1/11(-/-)) BMDC with the canonical NLRP3 inflammasome agonist nigericin results in release of bioactive IL-1β in conjunction with robust caspase-8 activation. This IL-1β processing and caspase-8 activation do not proceed in Nlrp3(-/-) or Asc(-/-) BMDC and are suppressed by pharmacological inhibition of caspase-8, indicating that caspase-8 can act as a direct IL-1β-converting enzyme during NLRP3 inflammasome activation. In contrast to the rapid caspase-1-mediated death of wild type (WT) BMDC via NLRP3-dependent pyroptosis, nigericin-stimulated Casp1/11(-/-) BMDC exhibit markedly delayed cell death via NLRP3-dependent apoptosis. Biochemical analyses of WT and Casp1/11(-/-) BMDC indicated that caspase-8 is proteolytically processed within detergent-insoluble ASC-enriched protein complexes prior to extracellular export during nigericin treatment. Although nigericin-stimulated caspase-1 activation and activity are only modestly attenuated in caspase-8-deficient (Casp8(-/-)Rip3(-/-)) BMDC, these cells do not exhibit the rapid loss of viability of WT cells. These results support a contribution of caspase-8 to both IL-1β production and regulated death signaling via NLRP3 inflammasomes. In the absence of caspase-1, NLRP3 inflammasomes directly utilize caspase-8 as both a pro-apoptotic initiator and major IL-1β-converting protease. In the presence of caspase-1, caspase-8 acts as a positive modulator of the NLRP3-dependent caspase-1 signaling cascades that drive both IL-1β production and pyroptotic death.
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Affiliation(s)
| | - Hana M Russo
- Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | | | - Bradley N Martin
- Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, the Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, and
| | - Xiaoxia Li
- the Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, and
| | - William J Kaiser
- the Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Edward S Mocarski
- the Department of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, Atlanta, Georgia 30322
| | - George R Dubyak
- Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, From the Departments of Physiology and Biophysics and
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Inflammasome-induced IL-1β secretion in microglia is characterized by delayed kinetics and is only partially dependent on inflammatory caspases. J Neurosci 2015; 35:678-87. [PMID: 25589762 DOI: 10.1523/jneurosci.2510-14.2015] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Inflammasomes are multiprotein complexes that link pathogen recognition and cellular stress to the processing of the proinflammatory cytokine interleukin-1β (IL-1β). Whereas inflammasome-mediated activation is heavily studied in hematopoietic macrophages and dendritic cells, much less is known about microglia, resident tissue macrophages of the brain that originate from a distinct progenitor. To directly compare inflammasome-mediated activation in different types of macrophages, we isolated primary microglia and hematopoietic macrophages from adult, healthy rhesus macaques. We analyzed the expression profile of NOD (nucleotide-binding oligomerization domain)-like receptors, adaptor proteins, and caspases and characterized inflammasome activation and regulation in detail. We here demonstrate that primary microglia can respond to the same innate stimuli as hematopoietic macrophages. However, microglial responses are more persistent due to lack of negative regulation on pro-IL-1β expression. In addition, we show that while caspase 1, 4, and 5 activation is pivotal for inflammasome-induced IL-1β secretion by hematopoietic macrophages, microglial secretion of IL-1β is only partially dependent on these inflammatory caspases. These results identify key cell type-specific differences that may aid the development of strategies to modulate innate immune responses in the brain.
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27
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Chao WC, Yen CL, Wu YH, Chen SY, Hsieh CY, Chang TC, Ou HY, Shieh CC. Increased resistin may suppress reactive oxygen species production and inflammasome activation in type 2 diabetic patients with pulmonary tuberculosis infection. Microbes Infect 2015; 17:195-204. [DOI: 10.1016/j.micinf.2014.11.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 11/22/2014] [Accepted: 11/27/2014] [Indexed: 12/17/2022]
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28
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Zhu X, Song Y, Huo R, Zhang J, Sun S, He Y, Gao H, Zhang M, Sun X, Zhai T, Li H, Sun Y, Zhou Z, Shen B, Xiao L, Li N. Cyr61 participates in the pathogenesis of rheumatoid arthritis by promoting proIL-1β production by fibroblast-like synoviocytes through an AKT-dependent NF-κB signaling pathway. Clin Immunol 2015; 157:187-97. [PMID: 25728492 DOI: 10.1016/j.clim.2015.02.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Revised: 11/24/2014] [Accepted: 02/17/2015] [Indexed: 12/11/2022]
Abstract
IL-1β plays a major role in the development of rheumatoid arthritis (RA). We previously showed that Cyr61 participates in RA pathogenesis as a proinflammatory factor. Here, we found that the levels of IL-1β and Cyr61 were higher in RA SF than in osteoarthritis (OA) SF. IL-1β mRNA and proIL-1β protein levels were remarkably increased in Cyr61-stimulated FLS; however, IL-1β was hardly detectable in the supernatant. We also found that the level of adenosine triphosphate (ATP) in SF and ST was significantly increased in RA patients and that the level of IL-1β in supernatants from Cyr61-activated FLS increased significantly when we added exogenous ATP to the culture. Mechanistically, Cyr61 induced proIL-1β production in FLS via the AKT-dependent NF-κB signaling pathway, and ATP caused Cyr61-induced proIL-1β to generate IL-1β in a caspase-1-dependent manner. Our results reveal a novel role of Cyr61 in RA that involves the promotion of proIL-1β production in FLS.
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Affiliation(s)
- Xianjin Zhu
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China; Affiliated Union Hospital of Fujian Medical University, Fuzhou, PR China
| | - Yanfang Song
- Affiliated Renmin Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, PR China
| | - Rongfen Huo
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Jie Zhang
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Songtao Sun
- Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, PR China
| | - Yong He
- Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, PR China
| | - Huali Gao
- Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, PR China
| | - Miaojia Zhang
- Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | - Xiaoxuan Sun
- Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, PR China
| | - Tianhang Zhai
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Huidan Li
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Yue Sun
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Zhou Zhou
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Baihua Shen
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Lianbo Xiao
- Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Shanghai, PR China.
| | - Ningli Li
- Shanghai Institute of Immunology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China.
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Yakut E, Jakobs C, Peric A, Michel G, Baal N, Bein G, Brüne B, Hornung V, Hackstein H. Extracorporeal photopheresis promotes IL-1β production. THE JOURNAL OF IMMUNOLOGY 2015; 194:2569-77. [PMID: 25681340 DOI: 10.4049/jimmunol.1400694] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Extracorporeal photopheresis (ECP) is a widely used clinical cell-based therapy exhibiting efficacy in heterogenous immune-mediated diseases such as cutaneous T cell lymphoma, graft-versus-host disease, and organ allograft rejection. Despite its documented efficacy in cancer immunotherapy, little is known regarding the induction of immunostimulatory mediators by ECP. In this article, we show that ECP promotes marked release of the prototypic immunostimulatory cytokine IL-1β. ECP primes IL-1β production and activates IL-1β maturation and release in the context of caspase-1 activation in monocytes and myeloid dendritic cells. Of interest, IL-1β maturation by ECP was fully intact in murine cells deficient in caspase-1, suggesting the predominance of an inflammasome-independent pathway for ECP-dependent IL-1β maturation. Clinically, patient analysis revealed significantly increased IL-1β production in stimulated leukapheresis concentrates and peripheral blood samples after ECP. Collectively, these results provide evidence for promotion of IL-1β production by ECP and offer new insight into the immunostimulatory capacity of ECP.
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Affiliation(s)
- Erhan Yakut
- Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, D-35390 Giessen, Germany
| | - Christopher Jakobs
- Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany; and
| | - Adriana Peric
- Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, D-35390 Giessen, Germany
| | - Gabriela Michel
- Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, D-35390 Giessen, Germany
| | - Nelli Baal
- Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, D-35390 Giessen, Germany
| | - Gregor Bein
- Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, D-35390 Giessen, Germany
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany
| | - Veit Hornung
- Institute of Molecular Medicine, University Hospital, University of Bonn, 53127 Bonn, Germany; and
| | - Holger Hackstein
- Institute for Clinical Immunology and Transfusion Medicine, Justus-Liebig-University Giessen, D-35390 Giessen, Germany;
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30
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Gillespie RMC, Brown SJ. From the outside-in: Epidermal targeting as a paradigm for atopic disease therapy. World J Dermatol 2015; 4:16-32. [DOI: 10.5314/wjd.v4.i1.16] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Revised: 11/29/2014] [Accepted: 12/17/2014] [Indexed: 02/06/2023] Open
Abstract
Atopic dermatitis (AD) is a chronic inflammatory skin disorder which can precede asthma and allergic rhinitis in a disease trajectory known as the atopic march. The pathophysiology of AD includes cutaneous inflammation, disrupted epidermal barrier function, xerosis and propensity to secondary infections. AD had previously been thought to arise from the systemic atopic immune response and therapies are therefore directed towards ameliorating Th2-mediated inflammation. However in recent years the focus has shifted towards primary defects in the skin barrier as an initiating event in AD. Links between loss-of-function variants in the gene encoding filaggrin and disrupted activity of epidermal serine proteases and AD have been reported. Based on these observations, a mechanism has been described by which epidermal barrier dysfunction may lead to inflammation and allergic sensitization. Exogenous and endogenous stressors can further exacerbate inherited barrier abnormalities to promote disease activity. Pathways underlying progression of the atopic march remain unclear, but recent findings implicate thymic stromal lymphopoietin as a factor linking AD to subsequent airway inflammation in asthma. This new appreciation of the epidermis in the development of AD should lead to deployment of more specific strategies to restore barrier function in atopic patients and potentially halt the atopic march.
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Karmakar M, Katsnelson M, Malak HA, Greene NG, Howell SJ, Hise AG, Camilli A, Kadioglu A, Dubyak GR, Pearlman E. Neutrophil IL-1β processing induced by pneumolysin is mediated by the NLRP3/ASC inflammasome and caspase-1 activation and is dependent on K+ efflux. THE JOURNAL OF IMMUNOLOGY 2015; 194:1763-75. [PMID: 25609842 DOI: 10.4049/jimmunol.1401624] [Citation(s) in RCA: 190] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Although neutrophils are the most abundant cells in acute infection and inflammation, relatively little attention has been paid to their role in inflammasome formation and IL-1β processing. In the present study, we investigated the mechanism by which neutrophils process IL-1β in response to Streptococcus pneumoniae. Using a murine model of S. pneumoniae corneal infection, we demonstrated a requirement for IL-1β in bacterial clearance, and we showed that Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), and caspase-1 are essential for IL-1β production and bacterial killing in the cornea. Neutrophils in infected corneas had multiple specks with enzymatically active caspase-1 (YVAD-FLICA 660), and bone marrow neutrophils stimulated with heat-killed S. pneumoniae (signal 1) and pneumolysin (signal 2) exhibited multiple specks when stained for NLRP3, ASC, or Caspase-1. High-molecular mass ASC complexes were also detected, consistent with oligomer formation. Pneumolysin induced K(+) efflux in neutrophils, and blocking K(+) efflux inhibited caspase-1 activation and IL-1β processing; however, neutrophils did not undergo pyroptosis, indicating that K(+) efflux and IL-1β processing is not a consequence of cell death. There was also no role for lysosomal destabilization or neutrophil elastase in pneumolysin-mediated IL-1β processing in neutrophils. Taken together, these findings demonstrate an essential role for neutrophil-derived IL-1β in S. pneumoniae infection, and they elucidate the role of the NLRP3 inflammasome in cleavage and secretion of IL-1β in neutrophils. Given the ubiquitous presence of neutrophils in acute bacterial and fungal infections, these findings will have implications for other microbial diseases.
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Affiliation(s)
- Mausita Karmakar
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106
| | - Michael Katsnelson
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106
| | - Hesham A Malak
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, United Kingdom
| | - Neil G Greene
- Graduate Program in Molecular Microbiology, Department of Molecular Biology and Microbiology and Howard Hughes Medical Institute, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111; and
| | - Scott J Howell
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106
| | - Amy G Hise
- Department of Medicine, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH 44106
| | - Andrew Camilli
- Graduate Program in Molecular Microbiology, Department of Molecular Biology and Microbiology and Howard Hughes Medical Institute, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111; and
| | - Aras Kadioglu
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, United Kingdom
| | - George R Dubyak
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106
| | - Eric Pearlman
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106;
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Lin YC, Huang DY, Wang JS, Lin YL, Hsieh SL, Huang KC, Lin WW. Syk is involved in NLRP3 inflammasome-mediated caspase-1 activation through adaptor ASC phosphorylation and enhanced oligomerization. J Leukoc Biol 2015; 97:825-835. [PMID: 25605870 DOI: 10.1189/jlb.3hi0814-371rr] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 11/03/2014] [Accepted: 11/30/2014] [Indexed: 12/27/2022] Open
Abstract
NLRP3 is the most crucial member of the NLR family, as it detects the existence of pathogen invasion and self-derived molecules associated with cellular damage. Several studies have reported that excessive NLRP3 inflammasome-mediated caspase-1 activation is a key factor in the development of diseases. Recent studies have reported that Syk is involved in pathogen-induced NLRP3 inflammasome activation; however, the detailed mechanism linking Syk to NLRP3 inflammasome remains unclear. In this study, we showed that Syk mediates NLRP3 stimuli-induced processing of procaspase-1 and the consequent activation of caspase-1. Moreover, the kinase activity of Syk is required to potentiate caspase-1 activation in a reconstituted NLRP3 inflammasome system in HEK293T cells. The adaptor protein ASC bridges NLRP3 with the effector protein caspase-1. Herein, we find that Syk can associate directly with ASC and NLRP3 by its kinase domain but interact indirectly with procaspase-1. Syk can phosphorylate ASC at Y146 and Y187 residues, and the phosphorylation of both residues is critical to enhance ASC oligomerization and the recruitment of procaspase-1. Together, our results reveal a new molecular pathway through which Syk promotes NLRP3 inflammasome formation, resulting from the phosphorylation of ASC. Thus, the control of Syk activity might be effective to modulate NLRP3 inflammasome activation and treat NLRP3-related immune diseases.
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Affiliation(s)
- Ying-Cing Lin
- *Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences and Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; Institute of Biomedical Sciences and Genomics Research Center, Academia Sinica, Taipei, Taiwan; and Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Duen-Yi Huang
- *Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences and Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; Institute of Biomedical Sciences and Genomics Research Center, Academia Sinica, Taipei, Taiwan; and Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jang-Shiun Wang
- *Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences and Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; Institute of Biomedical Sciences and Genomics Research Center, Academia Sinica, Taipei, Taiwan; and Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Yi-Ling Lin
- *Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences and Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; Institute of Biomedical Sciences and Genomics Research Center, Academia Sinica, Taipei, Taiwan; and Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shie-Liang Hsieh
- *Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences and Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; Institute of Biomedical Sciences and Genomics Research Center, Academia Sinica, Taipei, Taiwan; and Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Kuo-Chin Huang
- *Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences and Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; Institute of Biomedical Sciences and Genomics Research Center, Academia Sinica, Taipei, Taiwan; and Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Wan-Wan Lin
- *Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Medical Sciences and Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan; Institute of Biomedical Sciences and Genomics Research Center, Academia Sinica, Taipei, Taiwan; and Department of Family Medicine, National Taiwan University Hospital, Taipei, Taiwan
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Henriksbo BD, Lau TC, Cavallari JF, Denou E, Chi W, Lally JS, Crane JD, Duggan BM, Foley KP, Fullerton MD, Tarnopolsky MA, Steinberg GR, Schertzer JD. Fluvastatin causes NLRP3 inflammasome-mediated adipose insulin resistance. Diabetes 2014; 63:3742-7. [PMID: 24917577 DOI: 10.2337/db13-1398] [Citation(s) in RCA: 111] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Statins reduce lipid levels and are widely prescribed. Statins have been associated with an increased incidence of type 2 diabetes, but the mechanisms are unclear. Activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3)/caspase-1 inflammasome, promotes insulin resistance, a precursor of type 2 diabetes. We showed that four different statins increased interleukin-1β (IL-1β) secretion from macrophages, which is characteristic of NLRP3 inflammasome activation. This effect was dose dependent, absent in NLRP3(-/-) mice, and prevented by caspase-1 inhibition or the diabetes drug glyburide. Long-term fluvastatin treatment of obese mice impaired insulin-stimulated glucose uptake in adipose tissue. Fluvastatin-induced activation of the NLRP3/caspase-1 pathway was required for the development of insulin resistance in adipose tissue explants, an effect also prevented by glyburide. Fluvastatin impaired insulin signaling in lipopolysaccharide-primed 3T3-L1 adipocytes, an effect associated with increased caspase-1 activity, but not IL-1β secretion. Our results define an NLRP3/caspase-1-mediated mechanism of statin-induced insulin resistance in adipose tissue and adipocytes, which may be a contributing factor to statin-induced development of type 2 diabetes. These results warrant scrutiny of insulin sensitivity during statin use and suggest that combination therapies with glyburide, or other inhibitors of the NLRP3 inflammasome, may be effective in preventing the adverse effects of statins.
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Affiliation(s)
- Brandyn D Henriksbo
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Trevor C Lau
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Joseph F Cavallari
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Emmanuel Denou
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Wendy Chi
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - James S Lally
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Justin D Crane
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Brittany M Duggan
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Kevin P Foley
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Morgan D Fullerton
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Mark A Tarnopolsky
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
| | - Gregory R Steinberg
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Jonathan D Schertzer
- Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
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Je IG, Kim HH, Park PH, Kwon TK, Seo SY, Shin TY, Kim SH. SG-HQ2 inhibits mast cell-mediated allergic inflammation through suppression of histamine release and pro-inflammatory cytokines. Exp Biol Med (Maywood) 2014; 240:631-8. [PMID: 25349218 DOI: 10.1177/1535370214555663] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2014] [Accepted: 07/18/2014] [Indexed: 11/17/2022] Open
Abstract
In this study, we investigated the effect of 3,4,5-trihydroxy-N-(8-hydroxyquinolin-2-yl)benzamide) (SG-HQ2), a synthetic analogue of gallic acid (3,4,5-trihydroxybenzoic acid), on the mast cell-mediated allergic inflammation and the possible mechanism of action. Mast cells play major roles in immunoglobulin E-mediated allergic responses by the release of histamine, lipid-derived mediators, and pro-inflammatory cytokines. We previously reported the potential effects of gallic acid using allergic inflammation models. For incremental research, we synthesized the SG-HQ2 by the modification of functional groups from gallic acid. SG-HQ2 attenuated histamine release by the reduction of intracellular calcium in human mast cells and primary peritoneal mast cells. The inhibitory efficacy of SG-HQ2 was similar with gallic acid. Enhanced expression of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β, interleukin-4, and interleukin-6 in activated mast cells was significantly diminished by SG-HQ2 100 times lower concentration of gallic acid. This inhibitory effect was mediated by the reduction of nuclear factor-κB. In animal models, SG-HQ2 inhibited compound 48/80-induced serum histamine release and immunoglobulin E-mediated local allergic reaction, passive cutaneous anaphylaxis. Our results indicate that SG-HQ2, an analogue of gallic acid, might be a possible therapeutic candidate for mast cell-mediated allergic inflammatory diseases through suppression of histamine release and pro-inflammatory cytokines.
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Affiliation(s)
- In-Gyu Je
- CMRI, BK21 Plus KNU Biomedical Convergence Program, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea
| | - Hui-Hun Kim
- CMRI, BK21 Plus KNU Biomedical Convergence Program, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea
| | - Pil-Hoon Park
- College of Pharmacy, Yeungnam University, Gyeongbuk 712-749, Republic of Korea
| | - Taeg Kyu Kwon
- Department of Immunology, Keimyung University, Daegu 704-701, Republic of Korea
| | - Seung-Yong Seo
- College of Pharmacy, Gachon University, Incheon 406-840, Republic of Korea
| | - Tae-Yong Shin
- College of Pharmacy, Woosuk University, Jeonju 565-701, Republic of Korea
| | - Sang-Hyun Kim
- CMRI, BK21 Plus KNU Biomedical Convergence Program, Department of Pharmacology, School of Medicine, Kyungpook National University, Daegu 700-422, Republic of Korea
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35
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Davaro F, Forde SD, Garfield M, Jiang Z, Halmen K, Tamburro ND, Kurt-Jones E, Fitzgerald KA, Golenbock DT, Wang D. 3-Hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin)-induced 28-kDa interleukin-1β interferes with mature IL-1β signaling. J Biol Chem 2014; 289:16214-22. [PMID: 24790079 DOI: 10.1074/jbc.m114.571505] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Multiple clinical trials have shown that the 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known as statins have anti-inflammatory effects. However, the underlying molecular mechanism remains unclear. The proinflammatory cytokine interleukin-1β (IL-1β) is synthesized as a non-active precursor. The 31-kDa pro-IL-1β is processed into the 17-kDa active form by caspase-1-activating inflammasomes. Here, we report a novel signaling pathway induced by statins, which leads to processing of pro-IL-1β into an intermediate 28-kDa form. This statin-induced IL-1β processing is independent of caspase-1- activating inflammasomes. The 28-kDa form of IL-1β cannot activate interleukin-1 receptor-1 (IL1R1) to signal inflammatory responses. Instead, it interferes with mature IL-1β signaling through IL-1R1 and therefore may dampen inflammatory responses initiated by mature IL-1β. These results may provide new clues to explain the anti-inflammatory effects of statins.
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Affiliation(s)
- Facundo Davaro
- From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and
| | - Sorcha D Forde
- From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and
| | - Mark Garfield
- NIAID, National Institutes of Health, Rockville, Maryland 20852
| | - Zhaozhao Jiang
- From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and
| | - Kristen Halmen
- From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and
| | - Nelsy Depaula Tamburro
- From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and
| | - Evelyn Kurt-Jones
- From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and
| | - Katherine A Fitzgerald
- From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and
| | - Douglas T Golenbock
- From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and
| | - Donghai Wang
- From the Division of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605 and
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de Veer SJ, Furio L, Harris JM, Hovnanian A. Proteases: common culprits in human skin disorders. Trends Mol Med 2014; 20:166-78. [DOI: 10.1016/j.molmed.2013.11.005] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/24/2013] [Accepted: 11/25/2013] [Indexed: 12/17/2022]
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Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice. Proc Natl Acad Sci U S A 2014; 111:1072-7. [PMID: 24395802 DOI: 10.1073/pnas.1318685111] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Chronic recurrent multifocal osteomyelitis (CRMO) is a human autoinflammatory disorder that primarily affects bone. Missense mutation (L98P) of proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) in mice leads to a disease that is phenotypically similar to CRMO called chronic multifocal osteomyelitis (cmo). Here we show that deficiency of IL-1RI in cmo mice resulted in a significant reduction in the time to onset of disease as well as the degree of bone pathology. Additionally, the proinflammatory cytokine IL-1β, but not IL-1α, played a critical role in the pathology observed in cmo mice. In contrast, disease in cmo mice was found to be independent of the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome as well as caspase-1. Neutrophils, but not bone marrow-derived macrophages, from cmo mice secreted increased IL-1β in response to ATP, silica, and Pseudomonas aeruginosa compared with neutrophils from WT mice. This aberrant neutrophil response was sensitive to inhibition by serine protease inhibitors. These results demonstrate an inflammasome-independent role for IL-1β in disease progression of cmo and implicate neutrophils and neutrophil serine proteases in disease pathogenesis. These data provide a rationale for directly targeting IL-1RI or IL-1β as a therapeutic strategy in CRMO.
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Edye ME, Lopez-Castejon G, Allan SM, Brough D. Acidosis drives damage-associated molecular pattern (DAMP)-induced interleukin-1 secretion via a caspase-1-independent pathway. J Biol Chem 2013; 288:30485-30494. [PMID: 24022484 PMCID: PMC3798512 DOI: 10.1074/jbc.m113.478941] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The proinflammatory cytokine IL-1β is a key mediator of inflammatory responses that contribute to and exacerbate brain injury. IL-1β is synthesized by microglia in the brain as an inactive precursor (pro-IL-1β). Cleavage of pro-IL-1β to a mature form is stimulated by damage-associated molecular patterns (DAMPs). These DAMPs are sensed by a pattern recognition receptor called NLRP3, which forms an inflammasome, resulting in the activation of caspase-1 and cleavage of pro-IL-1β. To date, regulation of the inflammasome in culture has been studied under normal culture conditions, and it is not known how DAMPs signal under disease relevant conditions such as acidosis. Given the presence of acidosis in pathological states, our objective was to test the hypothesis that acidic conditions modify DAMP-induced IL-1β release from cultured primary mouse glial cells. When LPS-primed glial cells were stimulated with DAMPs under acidic conditions (pH 6.2), the predominant IL-1β form secreted was the 20-kDa rather than the 17-kDa caspase-1-dependent species. Lactic acidosis, induced by the addition of 25 mm lactic acid, also induced the release of 20-kDa IL-1β. This 20-kDa product was produced independently of NLRP3 and caspase-1 but was inhibited by the cathepsin D inhibitor pepstatin A. These data suggest that under disease relevant acidosis, DAMPs and lactic acid induce the secretion of IL-1β independently of the inflammasome. Therapeutic strategies directed to the inhibition of IL-1β processing should therefore consider alternative processing of IL-1β in addition to caspase-1-dependent processing.
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Affiliation(s)
- Michelle E Edye
- From the Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
| | - Gloria Lopez-Castejon
- From the Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
| | - Stuart M Allan
- From the Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom.
| | - David Brough
- From the Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, United Kingdom
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Gabelloni ML, Sabbione F, Jancic C, Fuxman Bass J, Keitelman I, Iula L, Oleastro M, Geffner JR, Trevani AS. NADPH oxidase derived reactive oxygen species are involved in human neutrophil IL-1β secretion but not in inflammasome activation. Eur J Immunol 2013; 43:3324-35. [PMID: 23963575 DOI: 10.1002/eji.201243089] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2012] [Revised: 08/01/2013] [Accepted: 08/15/2013] [Indexed: 11/11/2022]
Abstract
Neutrophils are essential players in acute inflammatory responses. Upon stimulation, neutrophils activate NADPH oxidase, generating an array of reactive oxygen species (ROS). Interleukin-1 beta (IL-1β) is a major proinflammatory cytokine synthesized as a precursor that has to be proteolytically processed to become biologically active. The role of ROS in IL-1β processing is still controversial and has not been previously studied in neutrophils. We report here that IL-1β processing in human neutrophils is dependent on caspase-1 and on the serine proteases elastase and/or proteinase 3. NADPH oxidase deficient neutrophils activated caspase-1 and did not exhibit differences in NALP3 expression, indicating that ROS are neither required for inflammasome activation nor for its priming, as has been reported for macrophages. Strikingly, ROS exerted opposite effects on the processing and secretion of IL-1β; whereas ROS negatively controlled caspase-1 activity, as reported in mononuclear phagocytes, ROS were found to be necessary for the exportation of mature IL-1β out of the cell, a role never previously described. The complex ROS-mediated regulation of neutrophil IL-1β secretion might constitute a physiological mechanism to control IL-1β-dependent inflammatory processes where neutrophils play a crucial role.
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Affiliation(s)
- María Laura Gabelloni
- Departamento de Inmunología, Instituto de Medicina Experimental (IMEX)-CONICET, Academia Nacional de Medicina, Buenos Aires, Argentina
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Shenderov K, Barber DL, Mayer-Barber KD, Gurcha SS, Jankovic D, Feng CG, Oland S, Hieny S, Caspar P, Yamasaki S, Lin X, Ting JPY, Trinchieri G, Besra GS, Cerundolo V, Sher A. Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome. THE JOURNAL OF IMMUNOLOGY 2013; 190:5722-30. [PMID: 23630357 DOI: 10.4049/jimmunol.1203343] [Citation(s) in RCA: 96] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Although adjuvants are critical vaccine components, their modes of action are poorly understood. In this study, we investigated the mechanisms by which the heat-killed mycobacteria in CFA promote Th17 CD4(+) T cell responses. We found that IL-17 secretion by CD4(+) T cells following CFA immunization requires MyD88 and IL-1β/IL-1R signaling. Through measurement of Ag-specific responses after adoptive transfer of OTII cells, we confirmed that MyD88-dependent signaling controls Th17 differentiation rather than simply production of IL-17. Additional experiments showed that CFA-induced Th17 differentiation involves IL-1β processing by the inflammasome, as mice lacking caspase-1, ASC, or NLRP3 exhibit partially defective responses after immunization. Biochemical fractionation studies further revealed that peptidoglycan is the major component of heat-killed mycobacteria responsible for inflammasome activation. By assaying Il1b transcripts in the injection site skin of CFA-immunized mice, we found that signaling through the adaptor molecule caspase activation and recruitment domain 9 (CARD9) plays a major role in triggering pro-IL-1β expression. Moreover, we demonstrated that recognition of the mycobacterial glycolipid trehalose dimycolate (cord factor) by the C-type lectin receptor mincle partially explains this CARD9 requirement. Importantly, purified peptidoglycan and cord factor administered in mineral oil synergized to recapitulate the Th17-promoting activity of CFA, and, as expected, this response was diminished in caspase-1- and CARD9-deficient mice. Taken together, these findings suggest a general strategy for the rational design of Th17-skewing adjuvants by combining agonists of the CARD9 pathway with inflammasome activators.
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Affiliation(s)
- Kevin Shenderov
- Immunobiology Section, Laboratory of Parasitic Diseases, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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Zimmerling S, Waibler Z, Resch T, Sutter G, Schwantes A. Interleukin-1β receptor expressed by modified vaccinia virus Ankara interferes with interleukin-1β activity produced in various virus-infected antigen-presenting cells. Virol J 2013; 10:34. [PMID: 23356675 PMCID: PMC3616829 DOI: 10.1186/1743-422x-10-34] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2012] [Accepted: 01/23/2013] [Indexed: 02/01/2023] Open
Abstract
Background Modified vaccinia virus Ankara (MVA) is a highly attenuated virus and a promising vaccine vector with potent immune stimulating properties. Deletion of the gene encoding the viral interleukin-1beta receptor (vIL-1βR) in MVA (MVAΔIL-1βR) was previously shown to enhance memory T cell function. Here, we investigated the influence of vIL-1βR on blocking interleukin-1beta (IL-1β) upon MVA infection in various antigen presenting cells of murine and human origin, and analyzed whether inflammasome function contributes to IL-1β production in different cell types. Findings Extending previous studies, immunizing mice with low doses of MVAΔIL-1βR still showed enhanced memory CD8+ T cell activation compared to MVA wild-type (MVAwt) immunization. In vitro, murine myeloid dendritic cells, and activated, but not naive primary macrophages were identified as potent producers of IL-1β upon infection with MVA. Importantly, free IL-1β was only detected in the absence of vIL-1βR. Moreover, MVAΔIL-1βR increased amounts of bioactive IL-1β compared to MVAwt after infection of human THP-1 cells, as detected using a reporter system that only responds to active and free IL-1β. The MVA-mediated induction of IL-1β was confirmed to depend on inflammasome function in human and murine cells, however in murine cells this apparently involves caspase-1-independent pathways. Conclusions MVA lacking IL-1β blocking activity leads to increased concentrations of free IL-1β upon infection of murine and human antigen presenting cells; this is likely responsible for enhanced memory T cell activation upon MVAΔIL-1βR immunization of mice. Moreover, our results suggest that MVA-mediated IL-1β induction is a multifactorial process.
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Bougault C, Gosset M, Houard X, Salvat C, Godmann L, Pap T, Jacques C, Berenbaum F. Stress-induced cartilage degradation does not depend on the NLRP3 inflammasome in human osteoarthritis and mouse models. ACTA ACUST UNITED AC 2012; 64:3972-81. [PMID: 22933232 DOI: 10.1002/art.34678] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 08/14/2012] [Indexed: 01/15/2023]
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What is behind the non-antibiotic properties of minocycline? Pharmacol Res 2012; 67:18-30. [PMID: 23085382 DOI: 10.1016/j.phrs.2012.10.006] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2012] [Revised: 09/13/2012] [Accepted: 10/09/2012] [Indexed: 11/24/2022]
Abstract
Minocycline is a second-generation, semi-synthetic tetracycline that has been in use in therapy for over 30 years for its antibiotic properties against both Gram-positive and Gram-negative bacteria. It displays antibiotic activity due to its ability to bind to the 30S ribosomal subunit of bacteria and thus inhibit protein synthesis. More recently, it has been described to exert a variety of biological actions beyond its antimicrobial activity, including anti-inflammatory and anti-apoptotic activities, inhibition of proteolysis, as well as suppression of angiogenesis and tumor metastasis, which have been confirmed in different experimental models of non-infectious diseases. There are also many studies that have focused on the mechanisms involved in these non-antibiotic properties of minocycline, including anti-oxidant activity, inhibition of several enzyme activities, inhibition of apoptosis and regulation of immune cell activation and proliferation. This review summarizes the current findings in this topic, mainly focusing on the mechanisms underlying the immunomodulatory and anti-inflammatory activities of minocycline.
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Karmakar M, Sun Y, Hise AG, Rietsch A, Pearlman E. Cutting edge: IL-1β processing during Pseudomonas aeruginosa infection is mediated by neutrophil serine proteases and is independent of NLRC4 and caspase-1. THE JOURNAL OF IMMUNOLOGY 2012; 189:4231-5. [PMID: 23024281 DOI: 10.4049/jimmunol.1201447] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
To examine the role of caspase-1 and the NLRC4 inflammasome during bacterial infection, C57BL/6, IL-1β(-/-), caspase-1(-/-), and NLRC4(-/-) mouse corneas were infected with ExoS/T- or ExoU-expressing Pseudomonas aeruginosa. We found that IL-1β was essential for neutrophil recruitment and bacterial clearance and was produced by myeloid cells rather than resident cells. In addition, neutrophils were found to be the primary source of mature IL-1β during infection, and there was no significant difference in IL-1β processing between C57BL/6 and caspase-1(-/-) or NLRC4(-/-) infected corneas. IL-1β cleavage by human and mouse neutrophils was blocked by serine protease inhibitors and was impaired in infected neutrophil elastase (NE)(-/-) corneas. NE(-/-) mice also had an impaired ability to clear the infection. Together, these results demonstrate that during P. aeruginosa infection, neutrophils are the primary source of mature IL-1β and that IL-1β processing is dependent on serine proteases and not NLRC4 or caspase-1.
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Affiliation(s)
- Mausita Karmakar
- Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
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Thorpe M, Yu J, Boinapally V, Ahooghalandari P, Kervinen J, Garavilla LD, Hellman L. Extended cleavage specificity of the mast cell chymase from the crab-eating macaque (Macaca fascicularis): an interesting animal model for the analysis of the function of the human mast cell chymase. Int Immunol 2012; 24:771-82. [PMID: 22949566 DOI: 10.1093/intimm/dxs081] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Serine proteases are the major protein constituents within mast cell secretory granules. These proteases are subdivided into chymases and tryptases depending on their primary cleavage specificity. Here, we present the extended cleavage specificity of the macaque mast cell chymase and compare the specificity with human chymase (HC) and dog chymase (DC) that were produced in the same insect cell expression host. The macaque chymase (MC) shows almost identical characteristics as the HC, including both primary and extended cleavage specificities as well as sensitivity to protease inhibitors, whereas the DC differs in several of these characteristics. Although previous studies have shown that mouse mast cell protease-4 (mMCP-4) is similar in its hydrolytic specificity to the HC, mouse mast cells contain several related enzymes. Thus mice may not be the most appropriate model organism for studying HC activity and inhibition. Importantly, macaques express only one chymase and, as primates, are closely related to human general physiology. In addition, the human and macaque enzymes both cleave angiotensin I (Ang I) in the same way, generating primarily angiotensin II (Ang II) and they do not further degrade the peptide like most rodent enzymes do. Both enzymes also cleave two additional potential in vivo substrates, fibronectin and secretory leukocyte protease inhibitor (SLPI) in a similar way. Given the fact that both HC and MC are encoded by a single gene with high sequence homology and that many physiological processes are similar between these species, the macaque may be a very interesting model to study the physiological role of the chymase and to determine the potency and potential side-effects of various chymase inhibitors designed for therapeutic human use.
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Affiliation(s)
- Michael Thorpe
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Biomedical Center, Box 596, SE-751 24 Uppsala, Sweden
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Salminen A, Ojala J, Kaarniranta K, Kauppinen A. Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases. Cell Mol Life Sci 2012; 69:2999-3013. [PMID: 22446749 PMCID: PMC11114788 DOI: 10.1007/s00018-012-0962-0] [Citation(s) in RCA: 204] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2011] [Revised: 02/23/2012] [Accepted: 03/12/2012] [Indexed: 12/20/2022]
Abstract
Oxidative stress and low-grade inflammation are the hallmarks of the aging process and are even more enhanced in many age-related degenerative diseases. Mitochondrial dysfunction and oxidative stress can provoke and potentiate inflammatory responses, but the mechanism has remained elusive. Recent studies indicate that oxidative stress can induce the assembly of multiprotein inflammatory complexes called the inflammasomes. Nod-like receptor protein 3 (NLRP3) is the major immune sensor for cellular stress signals, e.g., reactive oxygen species, ceramides, and cathepsin B. NLRP3 activation triggers the caspase-1-mediated maturation of the precursors of IL-1β and IL-18 cytokines. During aging, the autophagic clearance of mitochondria declines and dysfunctional mitochondria provoke chronic oxidative stress, which disturbs the cellular redox balance. Moreover, increased NF-κB signaling observed during aging could potentiate the expression of NLRP3 and cytokine proforms enhancing the priming of NLRP3 inflammasomes. Recent studies have demonstrated that NLRP3 activation is associated with several age-related diseases, e.g., the metabolic syndrome. We will review here the emerging field of inflammasomes in the appearance of the proinflammatory phenotype during the aging process and in age-related diseases.
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Affiliation(s)
- Antero Salminen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, FIN-70211, Kuopio, Finland.
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Abstract
Despite the acknowledged contributions of a defective epidermal permeability barrier, dryness of the skin, and the propensity to develop secondary infections to the etiology and pathophysiology of atopic dermatitis (AD), these epidermal changes have, until recently, been assumed to reflect downstream consequences that are secondary phenomena of the primary immunologic abnormality--the historical "inside-outside" view that AD is basically an intrinsic inflammatory disease. In this review, we focused on the role of the epidermal barrier function in the pathophysiology of AD. Specifically, we presented data in support of a barrier-initiated pathogenesis of AD, ie, the "outside-inside" concept. First, we reviewed the evidence on the existence of inherited barrier abnormalities in AD. Reported studies on the possible association of mutations in the filaggrin gene (FLG) and data on human tissue kallikreins (KLKs) and AD have been addressed. We then dealt with the question of the causal link between impaired epidermal barrier and inflammation. Finally, the association between innate immune defense system and the increased avidity of Staphylococcus aureus for atopic skin was examined. Despite very convincing evidence to support the barrier-initiated pathogenesis of AD, the view that AD reflects the downstream consequences of a primary immunologic abnormality cannot be dismissed out of hand. Almost every line of evidence in support of the role of the epidermal barrier as the "driver" of the disease activity can be challenged and at least partially contradicted by opposing evidence. Until more data are available and until all the dust settles around this issue, we should take advantage of what we already know and use our knowledge for practical purposes. Deployment of specific strategies to restore the barrier function in AD means the use of moisturizers as first-line therapy.
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Affiliation(s)
- Ronni Wolf
- Dermatology Unit, Kaplan Medical Center, Rehovot 76100, Israel.
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Abstract
Caspase-1, formerly known as interleukin (IL)-1-converting enzyme is best established as the protease responsible for the processing of the key pro-inflammatory cytokine IL-1β from an inactive precursor to an active, secreted molecule. Thus, caspase-1 is regarded as a key mediator of inflammatory processes, and has become synonymous with inflammation. In addition to the processing of IL-1β, caspase-1 also executes a rapid programme of cell death, termed pyroptosis, in macrophages in response to intracellular bacteria. Pyroptosis is also regarded as a host response to remove the niche of the bacteria and to hasten their demise. These processes are generally accepted as the main roles of caspase-1. However, there is also a wealth of literature supporting a direct role for caspase-1 in non-infectious cell death processes. This is true in mammals, but also in non-mammalian vertebrates where caspase-1-dependent processing of IL-1β is absent because of the lack of appropriate caspase-1 cleavage sites. This literature is most prevalent in the brain where caspase-1 may directly regulate neuronal cell death in response to diverse insults. We attempt here to summarise the evidence for caspase-1 as a cell death enzyme and propose that, in addition to the processing of IL-1β, caspase-1 has an important and a conserved role as a cell death protease.
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Abstract
The immune system plays an essential role in protecting the host against infections and to accomplish this task has evolved mechanisms to recognize microbes and destroy them. In addition, it monitors the health of cells and responds to ones that have been injured and killed, even if this occurs under sterile conditions. This process is initiated when dying cells expose intracellular molecules that can be recognized by cells of the innate immune system. As a consequence of this recognition, dendritic cells are activated in ways that help to promote T-cell responses to antigens associated with the dying cells. In addition, macrophages are stimulated to produce the cytokine interleukin-1 that then acts on radioresistant parenchymal cells in the host in ways that drive a robust inflammatory response. In addition to dead cells, a number of other sterile particles and altered physiological states can similarly stimulate an inflammatory response and do so through common pathways involving the inflammasome and interleukin-1. These pathways underlie the pathogenesis of a number of diseases.
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Affiliation(s)
- Kenneth L Rock
- Department of Pathology, UMass Medical School, Worcester, MA 01655, USA.
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