|
1
|
Marques-da-Silva C, Schmidt-Silva C, Bowers C, Charles-Chess NAE, Samuel C, Shiau JC, Park ES, Yuan Z, Kim BH, Kyle DE, Harty JT, MacMicking JD, Kurup SP. Type I interferons induce guanylate-binding proteins and lysosomal defense in hepatocytes to control malaria. Cell Host Microbe 2025; 33:529-544.e9. [PMID: 40168996 DOI: 10.1016/j.chom.2025.03.008] [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: 09/03/2024] [Revised: 01/09/2025] [Accepted: 03/10/2025] [Indexed: 04/03/2025]
Abstract
Plasmodium parasites undergo development and replication within hepatocytes before infecting erythrocytes and initiating clinical malaria. Although type I interferons (IFNs) are known to hinder Plasmodium infection within the liver, the underlying mechanisms remain unclear. Here, we describe two IFN-I-driven hepatocyte antimicrobial programs controlling liver-stage malaria. First, oxidative defense by NADPH oxidases 2 and 4 triggers a pathway of lysosomal fusion with the parasitophorous vacuole (PV) to help clear Plasmodium. Second, guanylate-binding protein (GBP) 1-mediated disruption of the PV activates the caspase-1 inflammasome, inducing pyroptosis to remove infected host cells. Remarkably, both human and mouse hepatocytes enlist these cell-autonomous immune programs to eliminate Plasmodium, with their pharmacologic or genetic inhibition leading to profound malarial susceptibility in vivo. In addition to identifying IFN-I-mediated cell-autonomous immune circuits controlling Plasmodium infection in the hepatocytes, our study also extends the understanding of how non-immune cells are integral to protective immunity against malaria.
Collapse
Affiliation(s)
- Camila Marques-da-Silva
- Department of Cellular Biology, University of Georgia, Athens, GA, USA; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA
| | - Clyde Schmidt-Silva
- Department of Cellular Biology, University of Georgia, Athens, GA, USA; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA
| | - Carson Bowers
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA
| | - Nana Appiah Essel Charles-Chess
- Department of Cellular Biology, University of Georgia, Athens, GA, USA; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA
| | - Cristina Samuel
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA
| | - Justine C Shiau
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA; Department of Infectious Diseases, University of Georgia, Athens, GA, USA
| | - Eui-Soon Park
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA; Yale Systems Biology Institute, West Haven, CT, USA; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Zhongyu Yuan
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA; Yale Systems Biology Institute, West Haven, CT, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Bae-Hoon Kim
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA; Yale Systems Biology Institute, West Haven, CT, USA; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Dennis E Kyle
- Department of Cellular Biology, University of Georgia, Athens, GA, USA; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA; Department of Infectious Diseases, University of Georgia, Athens, GA, USA
| | - John T Harty
- Department of Pathology, University of Iowa, Iowa City, IA, USA; Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA, USA
| | - John D MacMicking
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT, USA; Yale Systems Biology Institute, West Haven, CT, USA; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Samarchith P Kurup
- Department of Cellular Biology, University of Georgia, Athens, GA, USA; Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA.
| |
Collapse
|
|
2
|
Abrams ED, Basu A, Zavorka Thomas ME, Henrickson SE, Abraham RS. Expanding the diagnostic toolbox for complex genetic immune disorders. J Allergy Clin Immunol 2025; 155:255-274. [PMID: 39581295 DOI: 10.1016/j.jaci.2024.11.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 10/29/2024] [Accepted: 11/12/2024] [Indexed: 11/26/2024]
Abstract
Laboratory-based immunology evaluation is essential to the diagnostic workup of patients with complex immune disorders, and is as essential, if not more so, depending on the context, as genetic testing, because it enables identification of aberrant pathways amenable to therapeutic intervention and clarifies variants of uncertain significance. There have been considerable advances in techniques and instrumentation in the clinical laboratory in the past 2 decades, although there are still "miles to go." One of the goals of the clinical laboratory is to ensure advanced diagnostic testing is widely accessible to physicians and thus patients, through reference laboratories, particularly in the context of academic medical centers. This ensures a greater likelihood of translating research discoveries into the diagnostic laboratory, on the basis of patient care needs rather than a sole emphasis on commercial utility. However, these advances are under threat from burdensome regulatory oversight that can compromise, at best, and curtail, at worst, the ability to rapidly diagnose rare immune disorders and ensure delivery of precision medicine. This review discusses the clinical utility of diagnostic immunology tools, beyond cellular immunophenotyping of lymphocyte subsets, which can be used in conjunction with clinical and other laboratory data for diagnosis as well as monitoring of therapeutic response in patients with genetic immunologic diseases.
Collapse
Affiliation(s)
- Eric D Abrams
- Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pa
| | - Amrita Basu
- Diagnostic Immunology Laboratory, Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio
| | - Megan E Zavorka Thomas
- Diagnostic Immunology Laboratory, Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio
| | - Sarah E Henrickson
- Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pa; Institute for Immunology and Immune Health, University of Pennsylvania, Philadelphia, Pa; Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
| | - Roshini S Abraham
- Diagnostic Immunology Laboratory, Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio.
| |
Collapse
|
|
3
|
Svadlakova T, Kolackova M, Kulich P, Kotoucek J, Rosecka M, Krejsek J, Fiala Z, Andrýs C. Human Primary Monocytes as a Model for in vitro Immunotoxicity Testing: Evaluation of the Regulatory Properties of TiO 2 Nanoparticles. Int J Nanomedicine 2025; 20:1171-1189. [PMID: 39902067 PMCID: PMC11789775 DOI: 10.2147/ijn.s498690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 01/07/2025] [Indexed: 02/05/2025] Open
Abstract
Introduction A critical step preceding the potential biomedical application of nanoparticles is the evaluation of their immunomodulatory effects. Such nanoparticles are expected to enter the bloodstream where they can be recognized and processed by circulating monocytes. Despite the required biocompatibility, this interaction can affect intracellular homeostasis and modulate physiological functions, particularly inflammation. This study focuses on titanium dioxide (TiO2) as an example of relatively low cytotoxic nanoparticles with potential biomedical use and aims to evaluate their possible modulatory effects on the inflammasome-based response in human primary monocytes. Methods Monocyte viability, phenotypic changes, and cytokine production were determined after exposure to TiO2 (diameter, 25 nm; P25) alone. In the case of the modulatory effects, we focused on NLRP3 activation. The production of IL-1β and IL-10 was evaluated after (a) simultaneous activation of monocytes with bacterial stimuli muramyl dipeptide (MDP), or lipopolysaccharide (LPS), and TiO2 (co-exposure model), (b) prior activation with TiO2 alone and subsequent exposure to bacterial stimuli MDP or LPS. The differentiation of TiO2-treated monocytes into macrophages and their polarization were also assessed. Results The selected TiO2 concentration range (30-120 µg/mL) did not induce any significant cytotoxic effects. The highest dose of TiO2 promoted monocyte survival and differentiation into macrophages, with the M2 subset being the most prevalent. Nanoparticles alone did not induce substantial production of inflammatory cytokines IL-1β, IL-6, or TNF-α. The immunomodulatory effect on NLRP3 depended on the type of costimulant used. While co-exposure of monocytes to MDP and TiO2 boosted NLRP3 activity, co-exposure to LPS and TiO2 inhibited NLRP3 by enhancing IL-10 release. The inhibitory effect of TiO2 on NLRP3 based on the promotion of IL-10 was confirmed in a post-exposure model for both costimulants. Conclusion This study confirmed a non-negligible modulatory effect on primary monocytes in their inflammasome-based response and differentiation ability.
Collapse
Affiliation(s)
- Tereza Svadlakova
- Department of Clinical Immunology and Allergology, University Hospital Hradec Kralove and Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
- Department of Preventive Medicine, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Martina Kolackova
- Department of Clinical Immunology and Allergology, University Hospital Hradec Kralove and Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Pavel Kulich
- Department of Pharmacology and Toxicology, Veterinary Research Institute, Brno, Czech Republic
| | - Jan Kotoucek
- Department of Pharmacology and Toxicology, Veterinary Research Institute, Brno, Czech Republic
- Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic
| | - Michaela Rosecka
- Department of Clinical Immunology and Allergology, University Hospital Hradec Kralove and Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Jan Krejsek
- Department of Clinical Immunology and Allergology, University Hospital Hradec Kralove and Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Zdeněk Fiala
- Department of Preventive Medicine, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| | - Ctirad Andrýs
- Department of Clinical Immunology and Allergology, University Hospital Hradec Kralove and Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic
| |
Collapse
|
|
4
|
Tiwari AK, Mohanty B. Neurotensin via Type I Receptor Modulates the Endotoxemia Induced Oxido-Inflammatory Stress on the Sympathetic Adrenomedullary System of Mice Regulating NF-κβ/Nor-Epinephrine Pathway. Cell Biochem Biophys 2025:10.1007/s12013-025-01679-5. [PMID: 39881060 DOI: 10.1007/s12013-025-01679-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2025] [Indexed: 01/31/2025]
Abstract
The present study investigated the role of the neurotensin/NTS in the modulation of the lipopolysaccharide/LPS induced dysfunction of the sympatho-adrenal-medullary system/SAM using both the NTS receptor 1/NTSR1 agonist PD149163/PD and antagonist SR48692 /SR. Forty eight mice were maintained in eight groups; Group I/control, Groups II, III, IV, and VII received LPS for 5 days further Group III/IV/VII received PD low dose/PDL, PD high dose /PDH and SR for 28 days respectively. Group V/VI received similar only PDL and PDH dose respectively whereas Group VIII was exposed to only SR for 28 days. Adrenal tissues histopathology examined through hematoxylin-eosin staining. The plasma levels of pro-inflammatory mediators (NF-kβ, TNF-α, IL-6), IL-10, corticosterone/CORT, nor-epinephrine/NE and NTS were assessed through ELISA. Biochemical detection was adopted to check the level of oxidative stress, assessed by measuring the thiobarbituric acid reactive substance/TBARS, superoxide dismutase/SOD and catalase/CAT in adrenal tissue to determine the therapeutic effect of NTS receptor 1 analogs. Compared with LPS group, PD ameliorated the adrenal medulla histopathology by significantly decreasing pro-inflammatory mediators, CORT and NE as well as enhancing IL-10, normalizing NTS level via down-regulating NF-κβ level. PD inhibited the oxidative stress in SAM system of adrenal by reducing TBARS, while enhancing SOD and CAT activity via regulating the CORT and NE levels. Conversely, SR administration could not normalize the deleterious effect caused by the LPS due to up-regulation of NF-κβ level. Therefore, PD ameliorates the inflammation and oxidative stress of SAM system by inhibiting NF-kβ/NE signaling pathway. Thus, PD could be used as a biological tool in SAM dysfunction for therapeutic evaluation of chronic inflammatory diseases.
Collapse
Affiliation(s)
- Asheesh Kumar Tiwari
- Department of Zoology, University of Allahabad, Prayagraj, Uttar Pradesh, 211002, India
| | - Banalata Mohanty
- Department of Zoology, University of Allahabad, Prayagraj, Uttar Pradesh, 211002, India.
| |
Collapse
|
|
5
|
Luo J, Li X, Zhang L, Deng M, Zhao J, Zhang J, Tang W, Guo Q, Wang L. 5-deoxy-rutaecarpine protects against LPS-induced acute lung injury via inhibiting NLRP3 inflammasome-related inflammation. Front Pharmacol 2025; 16:1522146. [PMID: 39981175 PMCID: PMC11841402 DOI: 10.3389/fphar.2025.1522146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 01/10/2025] [Indexed: 02/22/2025] Open
Abstract
Introduction Acute lung injury (ALI) induced by lipopolysaccharide (LPS) is a significant medical condition characterized by severe pulmonary inflammation and tissue damage. NLRP3 inflammasome-driven inflammation is essential in ALI pathogenesis, inspiring novel therapeutic strategies that focus on NLRP3 and inflammation. In this study, we investigated the therapeutic potential of 5-deoxy-rutaecarpine (5-DR), a rutaecarpine derivative, in attenuating LPS-induced ALI. Methods In this study, we evaluated the effects of 5-DR treatment in mice exposed to LPS, lung tissues, bronchoalveolar lavage fluid, and serum were collected for analysis. LPS-stimulated J774A.1 mouse macrophages were used to further investigate the anti-inflammatory effects of 5-DR in vitro. Various techniques including histopathology, Western blotting, and luciferase reporter assay were employed. Results 5-DR treatment significantly reduced lung edema, inflammatory cell infiltration in mice with LPS burden, and reduced the levels of inflammatory mediators like interleukin-1β in the mice and in LPS-stimulated J774A.1 mouse macrophages. Further western blotting analysis showed 5-DR decreased the levels of NLRP3, cleaved caspase-1, and mature IL-1β in mice and J774A.1 cells exposed to LPS. Additionally, NF-κB pathway activation significantly diminished the inhibition of the NLRP3 inflammasome by 5-DR. Discussion Our findings highlight the therapeutic potential of 5-DR as a promising candidate for treating LPS-induced ALI, offering insights into its underlying mechanism that targets NLRP3 inflammasome-mediated inflammation.
Collapse
Affiliation(s)
- Jinque Luo
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, “The 14th Five-Year Plan” Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
- Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
| | - Xin Li
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, “The 14th Five-Year Plan” Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
- Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
| | - Li Zhang
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, “The 14th Five-Year Plan” Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
- Hunan Provincial University Key Laboratory of the Fundamental and Clinical Research on Functional Nucleic Acid, College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
| | - Meijing Deng
- The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, Hunan, China
| | - Jieyang Zhao
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, “The 14th Five-Year Plan” Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
| | - Jinghuan Zhang
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, “The 14th Five-Year Plan” Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
| | - Wenyu Tang
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, “The 14th Five-Year Plan” Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
| | - Qinghua Guo
- Department of Emergency, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China
| | - Ling Wang
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, “The 14th Five-Year Plan” Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
| |
Collapse
|
|
6
|
Geisler L, Detjen K, Hellberg T, Kohlhepp M, Grötzinger C, Knorr J, Eichhorn I, Mohr R, Holtmann T, Wiedenmann B, Tacke F, Roderburg C, Wree A. miR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine Neoplasms. Cells 2025; 14:111. [PMID: 39851539 PMCID: PMC11763622 DOI: 10.3390/cells14020111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 01/08/2025] [Accepted: 01/08/2025] [Indexed: 01/26/2025] Open
Abstract
Neuroendocrine neoplasms (NENs) are a diverse group originating from endocrine cells/their precursors in pancreas, small intestine, or lung. The key serum marker is chromogranin A (CgA). While commonly elevated in patients with NEN, its prognostic value is still under discussion. Secretion/posttranslational proteolytic cleavage of CgA results in multiple bioactive fragments, which are essential regulators of the cardiovascular and immune system. miR-223, regulator of Nrlp3 inflammasome and neutrophil activation, was recently found to have decreased in patients with NEN. We performed flow cytometry of circulating neutrophils in a patient cohort (n = 10) with NEN, microdissection and histology of tumor tissue. Subsequently, in vitro transfections using the well-established human pancreatic NEN cell line (BON), and co-culture experiments with primary macrophages and neutrophils were performed. Serum miR-223 in patients correlated with the expression of the neutrophil activation marker CD15 in circulating cells. Neutrophilic CD62L/CD63 showed good discrimination compared to healthy controls. Immune cell-derived miR-155, miR-193 and miR-223 colocalize with neutrophil in the extra-tumoral tissue alongside Nlrp3-associated caspase-1 activation. miR-223 knockdown in BON decreased the CgA intracellularly, increased in cellular granularity and caspase-1 activation. Plasmin inhibitor a2-aP reverted those effects. Western Blot showed fragmented CgA following miR-223 knockdown, which altered the inflammatory potential of neutrophils. Our data hence provide initial insights into an immunoregulatory mechanism via miR-223 and CgA in NEN cells, as regulation of miR-223 in NEN may affect tumor-associated inflammation.
Collapse
Affiliation(s)
- Lukas Geisler
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
- Department of Biology, Humboldt University of Berlin, 10099 Berlin, Germany
| | - Katharina Detjen
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Teresa Hellberg
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Marlene Kohlhepp
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Carsten Grötzinger
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Jana Knorr
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Ines Eichhorn
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Raphael Mohr
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Theresa Holtmann
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Bertram Wiedenmann
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| | - Christoph Roderburg
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, 40225 Düsseldorf, Germany
| | - Alexander Wree
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, 13353 Berlin, Germany
| |
Collapse
|
|
7
|
Schulz LN, Varghese A, Michenkova M, Wedemeyer M, Pindrik JA, Leonard JR, Garcia-Bonilla M, McAllister JP, Cassady K, Wilson RK, Mardis ER, Limbrick DD, Isaacs AM. Neuroinflammatory pathways and potential therapeutic targets in neonatal post-hemorrhagic hydrocephalus. Pediatr Res 2024:10.1038/s41390-024-03733-z. [PMID: 39725707 DOI: 10.1038/s41390-024-03733-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 10/28/2024] [Accepted: 11/04/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Post-hemorrhagic hydrocephalus (PHH) is a severe complication in premature infants following intraventricular hemorrhage (IVH). It is characterized by abnormal cerebrospinal fluid (CSF) accumulation, disrupted CSF dynamics, and elevated intracranial pressure (ICP), leading to significant neurological impairments. OBJECTIVE This review provides an overview of recent molecular insights into the pathophysiology of PHH and evaluates emerging therapeutic approaches aimed at addressing its underlying mechanisms. METHODS Recent studies were reviewed, focusing on molecular and cellular mechanisms implicated in PHH, including neuroinflammatory pathways, immune mediators, and regulatory genes. The potential of advanced technologies such as whole genome/exome sequencing, proteomics, epigenetics, and single-cell transcriptomics to identify key molecular targets was also analyzed. RESULTS PHH has been strongly linked to neuroinflammatory processes triggered by the degradation of blood byproducts. These processes involve cytokines, chemokines, the complement system, and other immune mediators, as well as regulatory genes and epigenetic mechanisms. Current treatments, primarily surgical CSF diversion, do not address the underlying molecular pathology. Emerging therapies, such as mesenchymal stem cell-based interventions, show promise in modulating immune responses and mitigating neurological damage. However, concerns about the safety of these novel approaches in neonatal populations and their potential effects on brain development remain unresolved. CONCLUSIONS Advanced molecular tools and emerging therapies have the potential to transform the treatment of PHH by targeting its underlying pathophysiology. Further research is needed to validate these approaches, enhance their safety profiles, and improve outcomes for infants with PHH. IMPACT STATEMENT 1. This review elucidates the molecular complexities of post-hemorrhagic hydrocephalus (PHH) by examining specific immune pathways and their impact on disease pathogenesis and progression. 2. It outlines the application of genomic, epigenomic, and proteomic technologies to identify critical molecular targets in PHH, setting the stage for innovative, targeted therapeutic approaches that could improve the outcomes of neonates affected by PHH. 3. It discusses the potential of gene and stem cell therapies in treating PHH, offering non-surgical alternatives and focusing on the underlying neuroinflammatory mechanisms.
Collapse
Affiliation(s)
- Lauren N Schulz
- Department of Neurological Surgery, Ohio State University Medical Center, Columbus, OH, USA
| | - Aaron Varghese
- Department of Undergraduate Studies, Miami University, Oxford, OH, USA
| | - Marie Michenkova
- Medical Scientist Training Program, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Michelle Wedemeyer
- Department of Neurological Surgery, Ohio State University Medical Center, Columbus, OH, USA
- Division of Neurological Surgery, Nationwide Children's Hospital, Columbus, OH, USA
- Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
| | - Jonathan A Pindrik
- Department of Neurological Surgery, Ohio State University Medical Center, Columbus, OH, USA
- Division of Neurological Surgery, Nationwide Children's Hospital, Columbus, OH, USA
| | - Jeffrey R Leonard
- Department of Neurological Surgery, Ohio State University Medical Center, Columbus, OH, USA
- Division of Neurological Surgery, Nationwide Children's Hospital, Columbus, OH, USA
| | - Maria Garcia-Bonilla
- Department of Neurosurgery, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - James Pat McAllister
- Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Kevin Cassady
- Division of Infectious Disease, Nationwide Children's Hospital, Columbus, OH, USA
- Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
| | - Richard K Wilson
- Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
| | - Elaine R Mardis
- Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA
| | - David D Limbrick
- Medical Scientist Training Program, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
- Department of Neurosurgery, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Albert M Isaacs
- Department of Neurological Surgery, Ohio State University Medical Center, Columbus, OH, USA.
- Division of Neurological Surgery, Nationwide Children's Hospital, Columbus, OH, USA.
- Steve and Cindy Rasmussen Institute for Genomic Medicine, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH, USA.
| |
Collapse
|
|
8
|
Lamantia V, Bissonnette S, Beaudry M, Cyr Y, Rosiers CD, Baass A, Faraj M. EPA and DHA inhibit LDL-induced upregulation of human adipose tissue NLRP3 inflammasome/IL-1β pathway and its association with diabetes risk factors. Sci Rep 2024; 14:27146. [PMID: 39511203 PMCID: PMC11543682 DOI: 10.1038/s41598-024-73672-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 09/19/2024] [Indexed: 11/15/2024] Open
Abstract
Elevated numbers of atherogenic lipoproteins (apoB) predict the incidence of type 2 diabetes (T2D). We reported that this may be mediated via the activation of the NLRP3 inflammasome, as low-density lipoproteins (LDL) induce interleukin-1 beta (IL-1β) secretion from human white adipose tissue (WAT) and macrophages. However, mitigating nutritional approaches remained unknown. We tested whether omega-3 eicosapentaenoic and docosahexaenoic acids (EPA and DHA) treat LDL-induced upregulation of WAT IL-1β-secretion and its relation to T2D risk factors. Twelve-week intervention with EPA and DHA (2.7 g/day, Webber Naturals) abolished baseline group-differences in WAT IL-1β-secretion between subjects with high-apoB (N = 17) and low-apoB (N = 16) separated around median plasma apoB. Post-intervention LDL failed to trigger IL-1β-secretion and inhibited it in lipopolysaccharide-stimulated WAT. Omega-3 supplementation also improved β-cell function and postprandial fat metabolism in association with higher blood EPA and mostly DHA. It also blunted the association of WAT NLRP3 and IL1B expression and IL-1β-secretion with multiple cardiometabolic risk factors including adiposity. Ex vivo, EPA and DHA inhibited WAT IL-1β-secretion in a dose-dependent manner. In conclusion, EPA and DHA treat LDL-induced upregulation of WAT NLRP3 inflammasome/IL-1β pathway and related T2D risk factors. This may aid in the prevention of T2D and related morbidities in subjects with high-apoB.Clinical Trail Registration ClinicalTrials.gov (NCT04496154): Omega-3 to Reduce Diabetes Risk in Subjects with High Number of Particles That Carry "Bad Cholesterol" in the Blood - Full Text View - ClinicalTrials.gov.
Collapse
Affiliation(s)
- Valérie Lamantia
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), 110, Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Montréal Diabetes Research Center (MDRC), Montréal, QC, Canada
| | - Simon Bissonnette
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), 110, Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Montréal Diabetes Research Center (MDRC), Montréal, QC, Canada
| | - Myriam Beaudry
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), 110, Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
| | - Yannick Cyr
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), 110, Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Montréal Diabetes Research Center (MDRC), Montréal, QC, Canada
| | - Christine Des Rosiers
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Montréal Heart Institute, Montréal, QC, Canada
| | - Alexis Baass
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), 110, Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Faculty of Medicine, McGill University, Montreal, QC, Canada
| | - May Faraj
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
- Institut de Recherches Cliniques de Montréal (IRCM), 110, Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada.
- Montréal Diabetes Research Center (MDRC), Montréal, QC, Canada.
- Faculty of Medicine, McGill University, Montreal, QC, Canada.
| |
Collapse
|
|
9
|
Marques-da-Silva C, Schmidt-Silva C, Bowers C, Charles-Chess E, Shiau JC, Park ES, Yuan Z, Kim BH, Kyle DE, Harty JT, MacMicking JD, Kurup SP. Type-I IFNs induce GBPs and lysosomal defense in hepatocytes to control malaria. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.22.619707. [PMID: 39484443 PMCID: PMC11526971 DOI: 10.1101/2024.10.22.619707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Plasmodium parasites undergo development and replication within the hepatocytes before infecting the erythrocytes and initiating clinical malaria. Although type-I interferons (IFNs) are known to hinder Plasmodium infection within the liver, the underlying mechanisms remain unclear. Here, we describe two IFN-I-driven hepatocyte antimicrobial programs controlling liver-stage malaria. First, oxidative defense by NADPH oxidases 2 and 4 triggers a pathway of lysosomal fusion with the parasitophorous vacuole (PV) to help clear Plasmodium . Second, guanylate-binding protein (GBP) 1 disruption of the PV activates caspase-1 inflammasome, inducing pyroptosis to remove the infected host cells. Remarkably, both human and mouse hepatocytes enlist these cell-autonomous immune programs to eliminate Plasmodium ; their pharmacologic or genetic inhibition led to profound malarial susceptibility, and are essential in vivo . In addition to identifying the IFN-I-mediated cell-autonomous immune circuits controlling Plasmodium infection in the hepatocytes, this study extends our understanding of how non-immune cells are integral to protective immunity against malaria.
Collapse
|
|
10
|
Wang W, Dernst A, Martin B, Lorenzi L, Cadefau-Fabregat M, Phulphagar K, Wagener A, Budden C, Stair N, Wagner T, Färber H, Jaensch A, Stahl R, Duthie F, Schmidt SV, Coll RC, Meissner F, Cuartero S, Latz E, Mangan MSJ. Butyrate and propionate are microbial danger signals that activate the NLRP3 inflammasome in human macrophages upon TLR stimulation. Cell Rep 2024; 43:114736. [PMID: 39277863 DOI: 10.1016/j.celrep.2024.114736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 03/06/2024] [Accepted: 08/23/2024] [Indexed: 09/17/2024] Open
Abstract
Short-chain fatty acids (SCFAs) are immunomodulatory compounds produced by the microbiome through dietary fiber fermentation. Although generally considered beneficial for gut health, patients suffering from inflammatory bowel disease (IBD) display poor tolerance to fiber-rich diets, suggesting that SCFAs may have contrary effects under inflammatory conditions. To investigate this, we examined the effect of SCFAs on human macrophages in the presence of Toll-like receptor (TLR) agonists. In contrast to anti-inflammatory effects under steady-state conditions, we found that butyrate and propionate activated the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the presence of TLR agonists. Mechanistically, these SCFAs prevented transcription of FLICE-like inhibitory protein (cFLIP) and interleukin-10 (IL-10) through histone deacetylase (HDAC) inhibition, triggering caspase-8-dependent NLRP3 inflammasome activation. SCFA-driven NLRP3 activation was potassium efflux independent and did not result in cell death but rather triggered hyperactivation and IL-1β release. Our findings demonstrate that butyrate and propionate are bacterially derived danger signals that regulate NLRP3 inflammasome activation through epigenetic modulation of the inflammatory response.
Collapse
Affiliation(s)
- Wei Wang
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, UK
| | - Alesja Dernst
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Bianca Martin
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Lucia Lorenzi
- Josep Carreras Leukemia Research Institute (IJC), 08916 Badalona, Barcelona, Spain
| | | | - Kshiti Phulphagar
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Antonia Wagener
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Christina Budden
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Neil Stair
- Institute for Genetics, CECAD Research Center, University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany
| | - Theresa Wagner
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Harald Färber
- Institute for Hygiene and Public Health, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Andreas Jaensch
- Institute for Hygiene and Public Health, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Rainer Stahl
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Fraser Duthie
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Susanne V Schmidt
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Rebecca C Coll
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast BT9 7BL, UK
| | - Felix Meissner
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany
| | - Sergi Cuartero
- Josep Carreras Leukemia Research Institute (IJC), 08916 Badalona, Barcelona, Spain
| | - Eicke Latz
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases, 53127 Bonn, Germany; Department of Infectious Diseases & Immunology, UMass Medical School, Worcester, MA 01605, USA; Deutsches Rheuma Forschungszentrum Berlin (DRFZ), 10117 Berlin, Germany.
| | - Matthew S J Mangan
- Institute of Innate Immunity, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany; German Center for Neurodegenerative Diseases, 53127 Bonn, Germany.
| |
Collapse
|
|
11
|
Hodge K, Buck DJ, Das S, Davis RL. The effects of chronic, continuous β-funaltrexamine pre-treatment on lipopolysaccharide-induced inflammation and behavioral deficits in C57BL/6J mice. J Inflamm (Lond) 2024; 21:33. [PMID: 39223594 PMCID: PMC11367784 DOI: 10.1186/s12950-024-00407-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 08/27/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Inflammation and neuroinflammation are integral to the progression and severity of many diseases and are strongly associated with cardiovascular disease, cancer, autoimmune disorders, neurodegenerative disease, and neuropsychiatric disorders. These diseases can be difficult to treat without addressing the underlying inflammation, and, as such, a growing need has arisen for pharmaceutical treatments that target inflammatory mediators and signaling pathways. Our lab has investigated the therapeutic potential of the irreversible µ-opioid antagonist β-funaltrexamine (β-FNA) and discovered that acute treatment ameliorates inflammation in astrocytes in vitro and inhibits central and peripheral inflammation and reduces anxiety- and sickness-like behavior in male C57BL/6J mice. Now, our investigation has expanded to investigate the chronic pre-treatment effects of β-FNA on lipopolysaccharide (LPS)-induced inflammation and behavior in male C57BL/6J mice. RESULTS Micro-osmotic drug pumps were surgically inserted into the subcutaneous intrascapular space of male C57BL/6J mice. β-FNA or saline vehicle was continuously administered for seven days. On the sixth day, mice were given intraperitoneal injections of LPS or saline. An elevated plus maze test, followed by a forced swim test, were administered 24 h post-injection to measure sickness-, anxiety- and depressive-like behavior. Immediately after testing, frontal cortex, hippocampus, spleen, and plasma were collected. Levels of inflammatory chemokines C-C motif chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 10 (CXCL10) were measured in tissues by enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to assess expression of the enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) and the NLR family pyrin domain-containing protein 3 (NRLP3) inflammasome in frontal cortex and spleen tissues. Chronic pre-treatment robustly decreased inflammation in the hippocampus, frontal cortex, and spleen and reduced or abolished anxiety- and sickness-like behavior (e.g., increased time spent motionless, increased time spent in a contracted position, and reduced distance moved). However, treatment with β-FNA alone increased both inflammation in the frontal cortex and anxiety-like behavior. CONCLUSION These findings provide novel insights into the anti-inflammatory and behavior-modifying effects of chronic β-FNA pre-treatment and continue to support the therapeutic potential of β-FNA under inflammatory conditions.
Collapse
Affiliation(s)
- Karissa Hodge
- Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK, 74107, USA
| | - Daniel J Buck
- Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK, 74107, USA
| | - Subhas Das
- Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK, 74107, USA
| | - Randall L Davis
- Oklahoma State University Center for Health Sciences, 1111 West 17th Street, Tulsa, OK, 74107, USA.
| |
Collapse
|
|
12
|
Brint A, Greene S, Fennig-Victor AR, Wang S. Multiple sclerosis: the NLRP3 inflammasome, gasdermin D, and therapeutics. ANNALS OF TRANSLATIONAL MEDICINE 2024; 12:62. [PMID: 39118955 PMCID: PMC11304424 DOI: 10.21037/atm-23-1960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 04/26/2024] [Indexed: 08/10/2024]
Abstract
Multiple sclerosis (MS) stands as a chronic inflammatory disease characterized by its neurodegenerative impacts on the central nervous system. The complexity of MS and the significant challenges it poses to patients have made the exploration of effective treatments a crucial area of research. Among the various mechanisms under investigation, the role of inflammation in MS progression is of particular interest. Inflammatory responses within the body are regulated by various cellular mechanisms, one of which involves the nucleotide-binding oligomerization domain (NOD)-, leucine-rich repeat (LRR)-, and pyrin domains (PYD)-containing protein 3 (NLRP3). NLRP3 acts as a sensor within cells, playing a pivotal role in controlling the inflammatory response. Its activation is a critical step leading to the assembly of the NLRP3 inflammasome complex, a process that has profound implications for inflammatory diseases like MS. The NLRP3 inflammasome's activation is intricately linked to the subsequent activation of caspase 1 and gasdermin D (GsdmD), signaling pathways that are central to the inflammatory process. GsdmD, a prominent member of the Gasdermin protein family, is particularly noteworthy for its role in pyroptotic cell death, a form of programmed cell death that is distinct from apoptosis and is characterized by its inflammatory nature. This pathway's activation contributes significantly to the pathology of MS by exacerbating inflammatory responses within the nervous system. Given the detrimental effects of unregulated inflammation in MS, therapeutics targeting these inflammatory processes offer a promising avenue for alleviating the symptoms experienced by patients. This review delves into the intricacies of the pyroptotic pathways, highlighting how the formation of the NLRP3 inflammasome induces such pathways and the potential intervention points for therapeutic agents. By inhibiting key steps within these pathways, it is possible to mitigate the inflammatory response, thereby offering relief to those suffering from MS. Understanding these mechanisms not only sheds light on the pathophysiology of MS but also paves the way for the development of novel therapeutic strategies aimed at controlling the disease's progression through the modulation of the body's inflammatory response.
Collapse
Affiliation(s)
- Amie Brint
- Chemistry Department, University of Arkansas at Little Rock, Little Rock, AR, USA
- College of Medicine and Graduate School, University of Arkansas for Medical Sciences, Little Rock, AR, USA
| | - Seth Greene
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, USA
| | - Alyssa R. Fennig-Victor
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, USA
| | - Shanzhi Wang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, USA
| |
Collapse
|
|
13
|
Mitroshina EV, Vedunova MV. The Role of Oxygen Homeostasis and the HIF-1 Factor in the Development of Neurodegeneration. Int J Mol Sci 2024; 25:4581. [PMID: 38731800 PMCID: PMC11083463 DOI: 10.3390/ijms25094581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/04/2024] [Accepted: 04/05/2024] [Indexed: 05/13/2024] Open
Abstract
Understanding the molecular underpinnings of neurodegeneration processes is a pressing challenge for medicine and neurobiology. Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent forms of neurodegeneration. To date, a substantial body of experimental evidence has strongly implicated hypoxia in the pathogenesis of numerous neurological disorders, including AD, PD, and other age-related neurodegenerative conditions. Hypoxia-inducible factor (HIF) is a transcription factor that triggers a cell survival program in conditions of oxygen deprivation. The involvement of HIF-1α in neurodegenerative processes presents a complex and sometimes contradictory picture. This review aims to elucidate the current understanding of the interplay between hypoxia and the development of AD and PD, assess the involvement of HIF-1 in their pathogenesis, and summarize promising therapeutic approaches centered on modulating the activity of the HIF-1 complex.
Collapse
Affiliation(s)
- Elena V. Mitroshina
- Institute of Biology and Biomedicine, Lobachevsky State University of Nizhny Novgorod, 23 Gagarin Avenue, 603022 Nizhny Novgorod, Russia;
| | | |
Collapse
|
|
14
|
Tsukalov I, Sánchez-Cerrillo I, Rajas O, Avalos E, Iturricastillo G, Esparcia L, Buzón MJ, Genescà M, Scagnetti C, Popova O, Martin-Cófreces N, Calvet-Mirabent M, Marcos-Jimenez A, Martínez-Fleta P, Delgado-Arévalo C, de Los Santos I, Muñoz-Calleja C, Calzada MJ, González Álvaro I, Palacios-Calvo J, Alfranca A, Ancochea J, Sánchez-Madrid F, Martin-Gayo E. NFκB and NLRP3/NLRC4 inflammasomes regulate differentiation, activation and functional properties of monocytes in response to distinct SARS-CoV-2 proteins. Nat Commun 2024; 15:2100. [PMID: 38453949 PMCID: PMC10920883 DOI: 10.1038/s41467-024-46322-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 02/22/2024] [Indexed: 03/09/2024] Open
Abstract
Increased recruitment of transitional and non-classical monocytes in the lung during SARS-CoV-2 infection is associated with COVID-19 severity. However, whether specific innate sensors mediate the activation or differentiation of monocytes in response to different SARS-CoV-2 proteins remain poorly characterized. Here, we show that SARS-CoV-2 Spike 1 but not nucleoprotein induce differentiation of monocytes into transitional or non-classical subsets from both peripheral blood and COVID-19 bronchoalveolar lavage samples in a NFκB-dependent manner, but this process does not require inflammasome activation. However, NLRP3 and NLRC4 differentially regulated CD86 expression in monocytes in response to Spike 1 and Nucleoprotein, respectively. Moreover, monocytes exposed to Spike 1 induce significantly higher proportions of Th1 and Th17 CD4 + T cells. In contrast, monocytes exposed to Nucleoprotein reduce the degranulation of CD8 + T cells from severe COVID-19 patients. Our study provides insights in the differential impact of innate sensors in regulating monocytes in response to different SARS-CoV-2 proteins, which might be useful to better understand COVID-19 immunopathology and identify therapeutic targets.
Collapse
Affiliation(s)
- Ilya Tsukalov
- Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain
| | - Ildefonso Sánchez-Cerrillo
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
- CIBER Infectious Diseases (CIBERINFECC), Instituto de Salud Carlos III, Madrid, Spain
| | - Olga Rajas
- Pneumology Unit from Hospital Universitario La Princesa, Madrid, Spain
| | - Elena Avalos
- Pneumology Unit from Hospital Universitario La Princesa, Madrid, Spain
| | | | - Laura Esparcia
- Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - María José Buzón
- Infectious Diseases Department, Institut de Recerca Hospital Univesritari Vall d'Hebrón (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Meritxell Genescà
- Infectious Diseases Department, Institut de Recerca Hospital Univesritari Vall d'Hebrón (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Camila Scagnetti
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Olga Popova
- Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain
| | - Noa Martin-Cófreces
- Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Marta Calvet-Mirabent
- Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Ana Marcos-Jimenez
- Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Pedro Martínez-Fleta
- Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Cristina Delgado-Arévalo
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Ignacio de Los Santos
- CIBER Infectious Diseases (CIBERINFECC), Instituto de Salud Carlos III, Madrid, Spain
- Infectious Diseases Unit from Hospital Universitario La Princesa, Madrid, Spain
| | - Cecilia Muñoz-Calleja
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
- CIBER Infectious Diseases (CIBERINFECC), Instituto de Salud Carlos III, Madrid, Spain
| | - María José Calzada
- Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
| | - Isidoro González Álvaro
- Rheumatology Department from Hospital Universitario La Princesa. Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - José Palacios-Calvo
- Department of Pathology, Hospital Universitario Ramón y Cajal. Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Universidad de Alcalá. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Arantzazu Alfranca
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
- CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
| | - Julio Ancochea
- Pneumology Unit from Hospital Universitario La Princesa, Madrid, Spain
| | - Francisco Sánchez-Madrid
- Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
- CIBER Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
| | - Enrique Martin-Gayo
- Medicine Faculty, Universidad Autónoma de Madrid, Madrid, Spain.
- Immunology Unit from Hospital Universitario La Princesa, Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.
- CIBER Infectious Diseases (CIBERINFECC), Instituto de Salud Carlos III, Madrid, Spain.
| |
Collapse
|
|
15
|
Marques-da-Silva C, Schmidt-Silva C, Baptista RP, Kurup SP. Inherently Reduced Expression of ASC Restricts Caspase-1 Processing in Hepatocytes and Promotes Plasmodium Infection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:596-606. [PMID: 38149914 PMCID: PMC10872340 DOI: 10.4049/jimmunol.2300440] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 12/06/2023] [Indexed: 12/28/2023]
Abstract
Inflammasome-mediated caspase-1 activation facilitates innate immune control of Plasmodium in the liver, thereby limiting the incidence and severity of clinical malaria. However, caspase-1 processing occurs incompletely in both mouse and human hepatocytes and precludes the generation of mature IL-1β or IL-18, unlike in other cells. Why this is so or how it impacts Plasmodium control in the liver has remained unknown. We show that an inherently reduced expression of the inflammasome adaptor molecule apoptosis-associated specklike protein containing CARD (ASC) is responsible for the incomplete proteolytic processing of caspase-1 in murine hepatocytes. Transgenically enhancing ASC expression in hepatocytes enabled complete caspase-1 processing, enhanced pyroptotic cell death, maturation of the proinflammatory cytokines IL-1β and IL-18 that was otherwise absent, and better overall control of Plasmodium infection in the liver of mice. This, however, impeded the protection offered by live attenuated antimalarial vaccination. Tempering ASC expression in mouse macrophages, on the other hand, resulted in incomplete processing of caspase-1. Our work shows how caspase-1 activation and function in host cells are fundamentally defined by ASC expression and offers a potential new pathway to create better disease and vaccination outcomes by modifying the latter.
Collapse
Affiliation(s)
- Camila Marques-da-Silva
- Department of Cellular Biology, University of Georgia, Athens, GA
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA
| | - Clyde Schmidt-Silva
- Department of Cellular Biology, University of Georgia, Athens, GA
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA
| | - Rodrigo P Baptista
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA
| | - Samarchith P Kurup
- Department of Cellular Biology, University of Georgia, Athens, GA
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA
| |
Collapse
|
|
16
|
Kouroumalis E, Tsomidis I, Voumvouraki A. Viral Liver Disease and Intestinal Gut–Liver Axis. GASTROINTESTINAL DISORDERS 2024; 6:64-93. [DOI: 10.3390/gidisord6010005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
The intestinal microbiota is closely related to liver diseases via the intestinal barrier and bile secretion to the gut. Impairment of the barrier can translocate microbes or their components to the liver where they can contribute to liver damage and fibrosis. The components of the barrier are discussed in this review along with the other elements of the so-called gut–liver axis. This bidirectional relation has been widely studied in alcoholic and non-alcoholic liver disease. However, the involvement of microbiota in the pathogenesis and treatment of viral liver diseases have not been extensively studied, and controversial data have been published. Therefore, we reviewed data regarding the integrity and function of the intestinal barrier and the changes of the intestinal microbioma that contribute to progression of Hepatitis B (HBV) and Hepatitis C (HCV) infection. Their consequences, such as cirrhosis and hepatic encephalopathy, were also discussed in connection with therapeutic interventions such as the effects of antiviral eradication and the use of probiotics that may influence the outcome of liver disease. Profound alterations of the microbioma with significant reduction in microbial diversity and changes in the abundance of both beneficial and pathogenic bacteria were found.
Collapse
Affiliation(s)
- Elias Kouroumalis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Ioannis Tsomidis
- Department of Gastroenterology, Medical School, University of Crete, 71500 Heraklion, Greece
| | - Argyro Voumvouraki
- 1st Department of Internal Medicine, AHEPA University Hospital, 54621 Thessaloniki, Greece
| |
Collapse
|
|
17
|
Khanna K, Yan H, Mehra M, Rohatgi N, Mbalaviele G, Mellins ED, Faccio R. Tmem178 Negatively Regulates IL-1β Production Through Inhibition of the NLRP3 Inflammasome. Arthritis Rheumatol 2024; 76:107-118. [PMID: 37534578 PMCID: PMC11421209 DOI: 10.1002/art.42666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 06/30/2023] [Accepted: 07/13/2023] [Indexed: 08/04/2023]
Abstract
OBJECTIVE Inflammasomes modulate the release of bioactive interleukin (IL)-1β. Excessive IL-1β levels are detected in patients with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS) with mutated and unmutated inflammasome components, raising questions on the mechanisms of IL-1β regulation in these disorders. METHODS To investigate how the NLRP3 inflammasome is modulated in sJIA, we focused on Transmembrane protein 178 (Tmem178), a negative regulator of calcium levels in macrophages, and measured IL-1β and caspase-1 activation in wild-type (WT) and Tmem178-/- macrophages after calcium chelators, silencing of Stim1, a component of store-operated calcium entry (SOCE), or by expressing a Tmem178 mutant lacking the Stromal Interaction Molecule 1 (Stim1) binding site. Mitochondrial function in both genotypes was assessed by measuring oxidative respiration, mitochondrial reactive oxygen species (mtROS), and mitochondrial damage. CSS development was analyzed in Perforin-/- /Tmem178-/- mice infected with lymphocytic choriomeningitis virus (LCMV) in which inflammasome or IL-1β signaling was pharmacologically inhibited. Human TMEM178 and IL1B transcripts were analyzed in data sets of whole blood and peripheral blood monocytes from healthy controls and patients with active sJIA. RESULTS TMEM178 levels are reduced in whole blood and monocytes from patients with sJIA while IL1B levels are increased. Accordingly, Tmem178-/- macrophages produce elevated IL-1β compared with WT cells. The elevated intracellular calcium levels after SOCE activation in Tmem178-/- macrophages induce mitochondrial damage, release mtROS, and ultimately promote NLRP3 inflammasome activation. In vivo, inhibition of inflammasome or IL-1β neutralization prolongs Tmem178-/- mouse survival in LCMV-induced CSS. CONCLUSION Down-regulation of TMEM178 levels may represent a marker of disease activity and help identify patients who could benefit from inflammasome targeting.
Collapse
Affiliation(s)
- Kunjan Khanna
- Department of Orthopedics, Washington University in St Louis, MO, USA
- These authors contributed equally
| | - Hui Yan
- Department of Orthopedics, Washington University in St Louis, MO, USA
- Current address: Key Laboratory for Animal Disease-Resistance Nutrition of China Ministry of Education, Ministry of Agriculture and Rural Affairs and Sichuan Province, Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, China
- These authors contributed equally
| | - Muneshwar Mehra
- Department of Neuroscience, Washington University in St Louis, MO, USA
| | - Nidhi Rohatgi
- Department of Pathology and Immunology, Washington University in St Louis, MO, USA
| | | | | | - Roberta Faccio
- Department of Orthopedics, Washington University in St Louis, MO, USA
- Shriners Hospital for Children, St Louis, MO, USA
| |
Collapse
|
|
18
|
Ghait M, Duduskar SN, Rooney M, Häfner N, Reng L, Göhrig B, Reuken PA, Bloos F, Bauer M, Sponholz C, Bruns T, Rubio I. The non-canonical inflammasome activators Caspase-4 and Caspase-5 are differentially regulated during immunosuppression-associated organ damage. Front Immunol 2023; 14:1239474. [PMID: 38106412 PMCID: PMC10722270 DOI: 10.3389/fimmu.2023.1239474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 11/16/2023] [Indexed: 12/19/2023] Open
Abstract
The non-canonical inflammasome, which includes caspase-11 in mice and caspase-4 and caspase-5 in humans, is upregulated during inflammatory processes and activated in response to bacterial infections to carry out pyroptosis. Inadequate activity of the inflammasome has been associated with states of immunosuppression and immunopathological organ damage. However, the regulation of the receptors caspase-4 and caspase-5 during severe states of immunosuppression is largely not understood. We report that CASP4 and CASP5 are differentially regulated during acute-on-chronic liver failure and sepsis-associated immunosuppression, suggesting non-redundant functions in the inflammasome response to infection. While CASP5 remained upregulated and cleaved p20-GSDMD could be detected in sera from critically ill patients, CASP4 was downregulated in critically ill patients who exhibited features of immunosuppression and organ failure. Mechanistically, downregulation of CASP4 correlated with decreased gasdermin D levels and impaired interferon signaling, as reflected by decreased activity of the CASP4 transcriptional activators IRF1 and IRF2. Caspase-4 gene and protein expression inversely correlated with markers of organ dysfunction, including MELD and SOFA scores, and with GSDMD activity, illustrating the association of CASP4 levels with disease severity. Our results document the selective downregulation of the non-canonical inflammasome activator caspase-4 in the context of sepsis-associated immunosuppression and organ damage and provide new insights for the development of biomarkers or novel immunomodulatory therapies for the treatment of severe infections.
Collapse
Affiliation(s)
- Mohamed Ghait
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Shivalee N Duduskar
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Michael Rooney
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
| | - Norman Häfner
- Department of Gynecology, Jena University Hospital, Jena, Germany
| | - Laura Reng
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Bianca Göhrig
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
| | - Philipp A Reuken
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
| | - Frank Bloos
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Michael Bauer
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Christoph Sponholz
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
| | - Tony Bruns
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
- Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany
| | - Ignacio Rubio
- Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
- Department for Anesthesiology & Intensive Care Medicine, Jena University Hospital, Jena, Germany
| |
Collapse
|
|
19
|
Looi CK, Foong LC, Chung FFL, Khoo ASB, Loo EM, Leong CO, Mai CW. Targeting the crosstalk of epigenetic modifications and immune evasion in nasopharyngeal cancer. Cell Biol Toxicol 2023; 39:2501-2526. [PMID: 37755585 DOI: 10.1007/s10565-023-09830-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 09/11/2023] [Indexed: 09/28/2023]
Abstract
Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer that is highly associated with Epstein-Barr virus (EBV) infection. EBV acts as an epigenetic driver in NPC tumorigenesis, reprogramming the viral and host epigenomes to regulate viral latent gene expression, and creating an environment conducive to the malignant transformation of nasopharyngeal epithelial cells. Targeting epigenetic mechanisms in pre-clinical studies has been shown promise in eradicating tumours and overcoming immune resistance in some solid tumours. However, its efficacy in NPC remains inclusive due to the complex nature of this cancer. In this review, we provide an updated understanding of the roles of epigenetic factors in regulating EBV latent gene expression and promoting NPC progression. We also explore the crosstalk between epigenetic mechanisms and immune evasion in NPC. Particularly, we discuss the potential roles of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors in reversing immune suppression and augmenting antitumour immunity. Furthermore, we highlight the advantages of combining epigenetic therapy and immune checkpoint inhibitor to reverse immune resistance and improve clinical outcomes. Epigenetic drugs have the potential to modulate both epigenetic mediators and immune factors involved in NPC. However, further research is needed to fully comprehend the diverse range of epigenetic modifications in NPC. A deeper understanding of the crosstalk between epigenetic mechanisms and immune evasion during NPC progression is crucial for the development of more effective treatments for this challenging disease.
Collapse
Affiliation(s)
- Chin-King Looi
- School of Postgraduate Studies, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Lian-Chee Foong
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Pudong New District, Shanghai, 200127, China
| | - Felicia Fei-Lei Chung
- Department of Medical Sciences, School of Medical and Life Sciences, Sunway University, 47500, Subang Jaya, Selangor, Malaysia
| | - Alan Soo-Beng Khoo
- School of Postgraduate Studies, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
- Department of Medical Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Pennsylvania, PA, 19107, USA
| | - Ee-Mun Loo
- AGTC Genomics, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, UCSI University, No. 1, Jalan Menara Gading, UCSI Heights, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Chee-Onn Leong
- AGTC Genomics, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
- Center for Cancer and Stem Cell Research, Development, and Innovation (IRDI), Institute for Research, International Medical University, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Chun-Wai Mai
- State Key Laboratory of Systems Medicine for Cancer, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Pudong New District, Shanghai, 200127, China.
- Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, UCSI University, No. 1, Jalan Menara Gading, UCSI Heights, Cheras, 56000, Kuala Lumpur, Malaysia.
| |
Collapse
|
|
20
|
Doglio MG, Verboom L, Ruilova Sosoranga E, Frising UC, Asaoka T, Gansemans Y, Van Nieuwerburgh F, van Loo G, Wullaert A. Myeloid OTULIN deficiency couples RIPK3-dependent cell death to Nlrp3 inflammasome activation and IL-1β secretion. Sci Immunol 2023; 8:eadf4404. [PMID: 38000038 DOI: 10.1126/sciimmunol.adf4404] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Accepted: 09/25/2023] [Indexed: 11/26/2023]
Abstract
Loss-of-function mutations in the deubiquitinase OTULIN result in an inflammatory pathology termed "OTULIN-related autoinflammatory syndrome" (ORAS). Genetic mouse models revealed essential roles for OTULIN in inflammatory and cell death signaling, but the mechanisms by which OTULIN deficiency connects cell death to inflammation remain unclear. Here, we identify OTULIN deficiency as a cellular condition that licenses RIPK3-mediated cell death in murine macrophages, leading to Nlrp3 inflammasome activation and subsequent IL-1β secretion. OTULIN deficiency uncoupled Nlrp3 inflammasome activation from gasdermin D-mediated pyroptosis, instead allowing RIPK3-dependent cell death to act as an Nlrp3 inflammasome activator and mechanism for IL-1β release. Accordingly, elevated serum IL-1β levels in myeloid-specific OTULIN-deficient mice were diminished by deleting either Ripk3 or Nlrp3. These findings identify OTULIN as an inhibitor of RIPK3-mediated IL-1β release in mice.
Collapse
Affiliation(s)
- M Giulia Doglio
- Department of Internal Medicine and Paediatrics, Ghent University, 9052 Ghent, Belgium
- VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium
| | - Lien Verboom
- VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Emily Ruilova Sosoranga
- Department of Internal Medicine and Paediatrics, Ghent University, 9052 Ghent, Belgium
- VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium
| | - Ulrika C Frising
- Department of Internal Medicine and Paediatrics, Ghent University, 9052 Ghent, Belgium
- VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium
| | - Tomoko Asaoka
- Department of Internal Medicine and Paediatrics, Ghent University, 9052 Ghent, Belgium
- VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium
| | - Yannick Gansemans
- Laboratory of Pharmaceutical Biotechnology, Ghent University, 9000 Ghent, Belgium
| | | | - Geert van Loo
- VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium
| | - Andy Wullaert
- Department of Internal Medicine and Paediatrics, Ghent University, 9052 Ghent, Belgium
- VIB-UGent Center for Inflammation Research, VIB, 9052 Ghent, Belgium
- Laboratory of Proteinscience, Proteomics and Epigenetic Signalling (PPES), Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| |
Collapse
|
|
21
|
Bissonnette S, Lamantia V, Ouimet B, Cyr Y, Devaux M, Rabasa-Lhoret R, Chrétien M, Saleh M, Faraj M. Native low-density lipoproteins are priming signals of the NLRP3 inflammasome/interleukin-1β pathway in human adipose tissue and macrophages. Sci Rep 2023; 13:18848. [PMID: 37914804 PMCID: PMC10620147 DOI: 10.1038/s41598-023-45870-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 10/25/2023] [Indexed: 11/03/2023] Open
Abstract
Elevated plasma numbers of atherogenic apoB-lipoproteins (apoB), mostly as low-density lipoproteins (LDL), predict diabetes risk by unclear mechanisms. Upregulation of the NLRP3 inflammasome/interleukin-1 beta (IL-1β) system in white adipose tissue (WAT) is implicated in type 2 diabetes (T2D); however, metabolic signals that stimulate it remain unexplored. We hypothesized that (1) subjects with high-apoB have higher WAT IL-1β-secretion than subjects with low-apoB, (2) WAT IL-1β-secretion is associated with T2D risk factors, and (3) LDL prime and/or activate the WAT NLRP3 inflammasome. Forty non-diabetic subjects were assessed for T2D risk factors related to systemic and WAT glucose and fat metabolism. Regulation of the NLRP3 inflammasome was explored using LDL without/with the inflammasome's priming and activation controls (LPS and ATP). LDL induced IL1B-expression and IL-1β-secretion in the presence of ATP in WAT and macrophages. Subjects with high-apoB had higher WAT IL-1β-secretion independently of covariates. The direction of association of LDL-induced WAT IL-1β-secretion to T2D risk factors was consistently pathological in high-apoB subjects only. Adjustment for IL-1β-secretion eliminated the association of plasma apoB with T2D risk factors. In conclusion, subjects with high-apoB have higher WAT IL-1β-secretion that may explain their risk for T2D and may be related to LDL-induced priming of the NLRP3 inflammasome.ClinicalTrials.gov (NCT04496154): Omega-3 to Reduce Diabetes Risk in Subjects With High Number of Particles That Carry "Bad Cholesterol" in the Blood-Full Text View-ClinicalTrials.gov.
Collapse
Affiliation(s)
- Simon Bissonnette
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), Office 1770.2, 110, Avenue Des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Montréal Diabetes Research Center (MDRC), Montréal, QC, Canada
| | - Valérie Lamantia
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), Office 1770.2, 110, Avenue Des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Montréal Diabetes Research Center (MDRC), Montréal, QC, Canada
| | - Benjamin Ouimet
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), Office 1770.2, 110, Avenue Des Pins Ouest, Montréal, QC, H2W 1R7, Canada
| | - Yannick Cyr
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), Office 1770.2, 110, Avenue Des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Montréal Diabetes Research Center (MDRC), Montréal, QC, Canada
| | - Marie Devaux
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), Office 1770.2, 110, Avenue Des Pins Ouest, Montréal, QC, H2W 1R7, Canada
| | - Remi Rabasa-Lhoret
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), Office 1770.2, 110, Avenue Des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Montréal Diabetes Research Center (MDRC), Montréal, QC, Canada
| | - Michel Chrétien
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada
- Institut de Recherches Cliniques de Montréal (IRCM), Office 1770.2, 110, Avenue Des Pins Ouest, Montréal, QC, H2W 1R7, Canada
| | - Maya Saleh
- Faculty of Medicine, McGill University, Montréal, QC, Canada
- University of Bordeaux, Bordeaux, France
| | - May Faraj
- Faculty of Medicine, Université de Montréal, Montréal, QC, Canada.
- Institut de Recherches Cliniques de Montréal (IRCM), Office 1770.2, 110, Avenue Des Pins Ouest, Montréal, QC, H2W 1R7, Canada.
- Montréal Diabetes Research Center (MDRC), Montréal, QC, Canada.
- Faculty of Medicine, McGill University, Montréal, QC, Canada.
| |
Collapse
|
|
22
|
Viil J, Somelar-Duracz K, Jaako K, Anier K, Zharkovsky A. Characterization of IMG Microglial Cell Line as a Valuable In Vitro Tool for NLRP3 Inflammasome Studies. Cell Mol Neurobiol 2023; 43:2053-2069. [PMID: 36163404 PMCID: PMC11412188 DOI: 10.1007/s10571-022-01285-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2022] [Accepted: 09/14/2022] [Indexed: 11/03/2022]
Abstract
Microglial cells constantly surveil the cerebral microenvironment and become activated following injury and disease to mediate inflammatory responses. The nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasome, which is abundantly expressed in microglial cells, plays a key role in these responses as well as in the development of many neurological disorders. Microglial cell lines are a valuable tool to study the causes and possible treatments for neurological diseases which are linked to inflammation. Here, we investigated whether the mouse microglial cell line IMG is suitable to study NLRP3 inflammasome by incubating cells with different concentrations of NLRP3 inflammasome priming and activating agents lipopolysaccharide (LPS) and ATP, respectively, and applying short (4 h) or long (24 h) LPS incubation times. After short LPS incubation, the mRNA levels of most pro-inflammatory and NLRP3 inflammasome-associated genes were more upregulated than after long incubation. Moreover, the combination of higher LPS and ATP concentrations with short incubation time resulted in greater levels of active forms of caspase-1 and interleukin-1 beta (IL-1β) proteins than low LPS and ATP concentrations or long incubation time. We also demonstrated that treatment with NLRP3 inflammasome inhibitor glibenclamide suppressed NLRP3 inflammasome activation in IMG cells, as illustrated by the downregulation of gasdermin D N-fragment and mature caspase-1 and IL-1β protein levels. In addition, we conducted similar experiments with primary microglial cells and BV-2 cell line to determine the similarities and differences in their responses. Overall, our results indicate that IMG cell line could be a valuable tool for NLRP3 inflammasome studies. In IMG cells, 4-h incubation with lipopolysaccharide (LPS) induces a stronger upregulation of NLRP3 inflammasome-associated pro-inflammatory genes compared to 24-h incubation. NLRP3 inflammasome is robustly activated only after the addition of 3 mM of ATP following short LPS incubation time.
Collapse
Affiliation(s)
- Janeli Viil
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia.
| | - Kelli Somelar-Duracz
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia
| | - Külli Jaako
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia
| | - Kaili Anier
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia
| | - Alexander Zharkovsky
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia
| |
Collapse
|
|
23
|
Ghasemi M, Roshandel E, Mohammadian M, Farhadihosseinabadi B, Akbarzadehlaleh P, Shamsasenjan K. Mesenchymal stromal cell-derived secretome-based therapy for neurodegenerative diseases: overview of clinical trials. Stem Cell Res Ther 2023; 14:122. [PMID: 37143147 PMCID: PMC10161443 DOI: 10.1186/s13287-023-03264-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Accepted: 03/06/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Over the past few years, mesenchymal stromal cells (MSCs) have attracted a great deal of scientific attention owing to their promising results in the treatment of incurable diseases. However, there are several concerns about their possible side effects after direct cell transplantation, including host immune response, time-consuming cell culture procedures, and the dependence of cell quality on the donor, which limit the application of MSCs in clinical trials. On the other hand, it is well accepted that the beneficial effects of MSCs are mediated by secretome rather than cell replacement. MSC secretome refers to a variety of bioactive molecules involved in different biological processes, specifically neuro-regeneration. MAIN BODY Due to the limited ability of the central nervous system to compensate for neuronal loss and relieve disease progress, mesenchymal stem cell products may be used as a potential cure for central nervous system disorders. In the present study, the therapeutic effects of MSC secretome were reviewed and discussed the possible mechanisms in the three most prevalent central nervous system disorders, namely Alzheimer's disease, multiple sclerosis, and Parkinson's disease. The current work aimed to help discover new medicine for the mentioned complications. CONCLUSION The use of MSC-derived secretomes in the treatment of the mentioned diseases has encouraging results, so it can be considered as a treatment option for which no treatment has been introduced so far.
Collapse
Affiliation(s)
- Maryam Ghasemi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Roshandel
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mozhdeh Mohammadian
- Department of Hematology, School of Medicine, Tarbiat Modares University (TMU), Tehran, Iran
| | | | - Parvin Akbarzadehlaleh
- Pharmaceutical Biotechnology Department, Pharmacy Faculty, Tabriz University of Medical Science, Tabriz, Iran
| | - Karim Shamsasenjan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
24
|
Pan J, Peng J, Li X, Wang H, Rong X, Peng Y. Transmission of NLRP3-IL-1β Signals in Cerebral Ischemia and Reperfusion Injury: from Microglia to Adjacent Neuron and Endothelial Cells via IL-1β/IL-1R1/TRAF6. Mol Neurobiol 2023; 60:2749-2766. [PMID: 36717480 DOI: 10.1007/s12035-023-03232-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 01/12/2023] [Indexed: 02/01/2023]
Abstract
The pyrin domain-containing protein 3 (NLRP3) inflammasome drives the profound cerebral ischemia and reperfusion injury (I/R) and mediates the secretion of IL-1β (interleukin-1β), which exerts a subsequent cascade of inflammatory injury. The NLRP3-activated-microglial manipulation in adjacent neuronal and endothelial NLRP3 activation has been confirmed in our previous studies. In the present study, we extended the cognition of how microglia mediated neuronal and endothelial NLRP3-IL-1β signaling during cerebral ischemia and reperfusion injury. In vitro, Neuro-2a and bEND3 cells were cultured alone or co-cultured with BV2 cells and oxygen-glucose deprivation/reoxygenation (OGD/R) was performed. In vivo, transient middle cerebral artery occlusion (tMCAO) rat models and lentiviral silencing targeting IL-1R1 were performed. The NLRP3 inflammasome activation was evaluated by enzyme-linked immunosorbent assay, western blotting, immunoprecipitation, immunohistochemistry, and immunofluorescence. In the co-culture system after OGD/R treatment, NLRP3 inflammasomes in neurons and endothelial cells were activated by microglial IL-1β via IL-1β/IL-1R1/TRAF6 signaling pathway, with the basal protein level of NLRP3. In addition, ruptured lysosomes engulfing ASC specks which were possibly secreted from microglia triggered the enhanced NLRP3 expression. In cortices of tMCAO rats at 24 h of reperfusion, silencing IL-1R1, mainly presented in neurons and endothelial cells, was efficient to block the subsequent inflammatory damage and leukocyte brain infiltration, leading to better neurological outcome. Neuronal and endothelial NLRP3 inflammasomes were activated by microglia in cerebral ischemia and reperfusion injury mainly via IL-1β/IL-1R1/TRAF6 signaling, which might be therapeutically targetable.
Collapse
Affiliation(s)
- Jingrui Pan
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, China
| | - Jialing Peng
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, China
- Department of Neurology, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Xiangpen Li
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, China
| | - Hongxuan Wang
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, China
| | - Xiaoming Rong
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, China
| | - Ying Peng
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, No. 107 West Yanjiang Road, Guangzhou, 510120, China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
| |
Collapse
|
|
25
|
Khanna K, Yan H, Mehra M, Rohatgi N, Mbalaviele G, Faccio R. Tmem178 negatively regulates IL-1β production through inhibition of the NLRP3 inflammasome. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.07.531385. [PMID: 36945522 PMCID: PMC10028891 DOI: 10.1101/2023.03.07.531385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
Objective Inflammasomes modulate the release of bioactive IL-1β. Excessive IL-1β levels are detected in patients with systemic juvenile idiopathic arthritis (sJIA) and cytokine storm syndrome (CSS) with mutated and unmutated inflammasome components, raising questions on the mechanisms of IL-1β regulation in these disorders. Methods To investigate how the NLRP3 inflammasome is modulated in sJIA, we focused on Tmem178, a negative regulator of calcium levels in macrophages, and measured IL-1β and caspase-1 activation in wild-type (WT) and Tmem178 -/- macrophages following calcium chelators, silencing of Stim1, a component of store-operated calcium entry (SOCE), or by expressing a Tmem178 mutant lacking Stim1 binding site. Mitochondrial function in both genotypes was assessed by measuring oxidative respiration, mitochondrial reactive oxygen species (mtROS), and mitochondrial damage. CSS development was analyzed in Perforin -/- /Tmem178 -/- mice infected with LCMV in which inflammasome or IL-1 signaling was pharmacologically inhibited. Human TMEM178 and IL-1B transcripts were analyzed in a dataset of peripheral blood monocytes from healthy controls and active sJIA patients. Results TMEM178 levels are reduced in monocytes from sJIA patients while IL-1B show increased levels. Accordingly, Tmem178 -/- macrophages produce elevated IL-1β compared to WT cells. The elevated intracellular calcium levels following SOCE activation in Tmem178 -/- macrophages induce mitochondrial damage, release mtROS, and ultimately, promote NLRP3 inflammasome activation. In vivo , inhibition of inflammasome or IL-1 neutralization prolongs Tmem178 -/- mouse survival to LCMV-induced CSS. Conclusion Downregulation of Tmem178 levels may represent a new biomarker to identify sJIA/CSS patients that could benefit from receiving drugs targeting inflammasome signaling.
Collapse
|
|
26
|
Dual Role of Mitogen-Activated Protein Kinase 8 Interacting Protein-1 in Inflammasome and Pancreatic β-Cell Function. Int J Mol Sci 2023; 24:ijms24054990. [PMID: 36902422 PMCID: PMC10002854 DOI: 10.3390/ijms24054990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Inflammasomes have been implicated in the pathogenesis of type 2 diabetes (T2D). However, their expression and functional importance in pancreatic β-cells remain largely unknown. Mitogen-activated protein kinase 8 interacting protein-1 (MAPK8IP1) is a scaffold protein that regulates JNK signaling and is involved in various cellular processes. The precise role of MAPK8IP1 in inflammasome activation in β-cells has not been defined. To address this gap in knowledge, we performed a set of bioinformatics, molecular, and functional experiments in human islets and INS-1 (832/13) cells. Using RNA-seq expression data, we mapped the expression pattern of proinflammatory and inflammasome-related genes (IRGs) in human pancreatic islets. Expression of MAPK8IP1 in human islets was found to correlate positively with key IRGs, including the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3), Gasdermin D (GSDMD) and Apoptosis-associated speck-like protein containing a CARD (ASC), but correlate inversely with Nuclear factor kappa β1 (NF-κβ1), Caspase-1 (CASP-1), Interleukin-18 (IL-18), Interleukin-1β (IL-1β) and Interleukin 6 (IL-6). Ablation of Mapk8ip1 by siRNA in INS-1 cells down-regulated the basal expression levels of Nlrp3, NLR family CARD domain containing 4 (Nlrc4), NLR family CARD domain containing 1 (Nlrp1), Casp1, Gsdmd, Il-1β, Il-18, Il-6, Asc, and Nf-κβ1 at the mRNA and/or protein level and decreased palmitic acid (PA)-induced inflammasome activation. Furthermore, Mapk8ip1-silened cells substantially reduced reactive oxygen species (ROS) generation and apoptosis in palmitic acid-stressed INS-1 cells. Nonetheless, silencing of Mapk8ip1 failed to preserve β-cell function against inflammasome response. Taken together, these findings suggest that MAPK8IP1 is involved in regulating β-cells by multiple pathways.
Collapse
|
|
27
|
Kanayama M, Izumi Y, Akiyama M, Hayashi T, Atarashi K, Roers A, Sato T, Ohteki T. Myeloid-like B cells boost emergency myelopoiesis through IL-10 production during infection. J Exp Med 2023; 220:213845. [PMID: 36719648 PMCID: PMC9930167 DOI: 10.1084/jem.20221221] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 11/16/2022] [Accepted: 01/03/2023] [Indexed: 02/01/2023] Open
Abstract
Emergency myelopoiesis (EM) is a hematopoietic response against systemic infections that quickly supplies innate immune cells. As lymphopoiesis is strongly suppressed during EM, the role of lymphocytes in that process has not received much attention. Here, we found that myeloid-like B cells (M-B cells), which express myeloid markers, emerge in the bone marrow (BM) after the induction of EM. M-B cells were mainly derived from pre-B cells and preferentially expressed IL-10, which directly stimulates hematopoietic progenitors to enhance their survival and myeloid-biased differentiation. Indeed, lacking IL-10 in B cells, blocking IL-10 in the BM with a neutralizing antibody, and deleting the IL-10 receptor in hematopoietic progenitors significantly suppressed EM, which failed to clear microbes in a cecal ligation and puncture model. Thus, a distinct B cell subset generated during infection plays a pivotal role in boosting EM, which suggests the on-demand reinforcement of EM by adaptive immune cells.
Collapse
Affiliation(s)
- Masashi Kanayama
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yuta Izumi
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Megumi Akiyama
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toyoki Hayashi
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Koji Atarashi
- Department of Microbiology and Immunology, Keio UniversitySchool of Medicine, Tokyo, Japan
| | - Axel Roers
- Institute for Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Taku Sato
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshiaki Ohteki
- Department of Biodefense Research, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan,Correspondence to Toshiaki Ohteki:
| |
Collapse
|
|
28
|
Nunzi E, Mezzasoma L, Bellezza I, Zelante T, Orvietani P, Coata G, Giardina I, Sagini K, Manni G, Di Michele A, Gargaro M, Talesa VN, Di Renzo GC, Fallarino F, Romani R. Microbiota-Associated HAF-EVs Regulate Monocytes by Triggering or Inhibiting Inflammasome Activation. Int J Mol Sci 2023; 24:ijms24032527. [PMID: 36768851 PMCID: PMC9916438 DOI: 10.3390/ijms24032527] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/21/2023] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
In pregnancy, human amniotic fluid extracellular vesicles (HAF-EVs) exert anti-inflammatory effects on T cells and on monocytes, supporting their immunoregulatory roles. The specific mechanisms are still not completely defined. The aim of this study was to investigate the ability of HAF-EVs, isolated from pregnant women who underwent amniocentesis and purified by gradient ultracentrifugation, to affect inflammasome activation in the human monocytes. Proteomic studies revealed that HAF-EV samples expressed several immunoregulatory molecules as well as small amounts of endotoxin. Surprisingly, metagenomic analysis shows the presence of specific bacterial strain variants associated with HAF-EVs as potential sources of the endotoxin. Remarkably, we showed that a single treatment of THP-1 cells with HAF-EVs triggered inflammasome activation, whereas the same treatment followed by LPS and ATP sensitization prevented inflammasome activation, a pathway resembling monocyte refractories. A bioinformatics analysis of microbiota-HAF-EVs functional pathways confirmed the presence of enzymes for endotoxin biosynthesis as well as others associated with immunoregulatory functions. Overall, these data suggest that HAF-EVs could serve as a source of the isolation of a specific microbiota during early pregnancy. Moreover, HAF-EVs could act as a novel system to balance immune training and tolerance by modulating the inflammasome in monocytes or other cells.
Collapse
Affiliation(s)
- Emilia Nunzi
- Department of Medicine and Surgery, University of Perugia, Polo Unico Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
| | - Letizia Mezzasoma
- Department of Medicine and Surgery, University of Perugia, Polo Unico Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
| | - Ilaria Bellezza
- Department of Medicine and Surgery, University of Perugia, Polo Unico Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
| | - Teresa Zelante
- Department of Medicine and Surgery, University of Perugia, Polo Unico Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
| | - Pierluigi Orvietani
- Department of Medicine and Surgery, University of Perugia, Polo Unico Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
| | - Giuliana Coata
- Department of Medicine and Surgery, University of Perugia, Polo Unico Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
| | - Irene Giardina
- Department of Obstetrics and Gynecology, University Hospital of Perugia, Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
| | - Krizia Sagini
- Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0379 Oslo, Norway
| | - Giorgia Manni
- Department of Medicine and Surgery, University of Perugia, Polo Unico Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
| | - Alessandro Di Michele
- Department of Physics and Geology, University of Perugia, Via Pascoli, 06123 Perugia, Italy
| | - Marco Gargaro
- Department of Medicine and Surgery, University of Perugia, Polo Unico Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
| | - Vincenzo N. Talesa
- Department of Medicine and Surgery, University of Perugia, Polo Unico Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
| | - Gian Carlo Di Renzo
- Department of Obstetrics, Gynecology and Perinatology IM Sechenov First State University, 117997 Moscow, Russia
| | - Francesca Fallarino
- Department of Medicine and Surgery, University of Perugia, Polo Unico Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
- Correspondence: (F.F.); (R.R.)
| | - Rita Romani
- Department of Medicine and Surgery, University of Perugia, Polo Unico Sant’Andrea delle Fratte, P.e Lucio Severi 1, 06132 Perugia, Italy
- Correspondence: (F.F.); (R.R.)
| |
Collapse
|
|
29
|
Marques-da-Silva C, Poudel B, Baptista RP, Peissig K, Hancox LS, Shiau JC, Pewe LL, Shears MJ, Kanneganti TD, Sinnis P, Kyle DE, Gurung P, Harty JT, Kurup SP. AIM2 sensors mediate immunity to Plasmodium infection in hepatocytes. Proc Natl Acad Sci U S A 2023; 120:e2210181120. [PMID: 36595704 PMCID: PMC9926219 DOI: 10.1073/pnas.2210181120] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 11/18/2022] [Indexed: 01/05/2023] Open
Abstract
Malaria, caused by Plasmodium parasites is a severe disease affecting millions of people around the world. Plasmodium undergoes obligatory development and replication in the hepatocytes, before initiating the life-threatening blood-stage of malaria. Although the natural immune responses impeding Plasmodium infection and development in the liver are key to controlling clinical malaria and transmission, those remain relatively unknown. Here we demonstrate that the DNA of Plasmodium parasites is sensed by cytosolic AIM2 (absent in melanoma 2) receptors in the infected hepatocytes, resulting in Caspase-1 activation. Remarkably, Caspase-1 was observed to undergo unconventional proteolytic processing in hepatocytes, resulting in the activation of the membrane pore-forming protein, Gasdermin D, but not inflammasome-associated proinflammatory cytokines. Nevertheless, this resulted in the elimination of Plasmodium-infected hepatocytes and the control of malaria infection in the liver. Our study uncovers a pathway of natural immunity critical for the control of malaria in the liver.
Collapse
Affiliation(s)
- Camila Marques-da-Silva
- Department of Cellular Biology, University of Georgia, Athens, GA30605
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA30605
| | - Barun Poudel
- Department of Internal Medicine, University of Iowa, Iowa City, IA52242
| | - Rodrigo P. Baptista
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA30605
- Institute of Bioinformatics, University of Georgia, Athens, GA30605
| | - Kristen Peissig
- Department of Cellular Biology, University of Georgia, Athens, GA30605
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA30605
| | - Lisa S. Hancox
- Department of Pathology, University of Iowa, Iowa City, IA52242
| | - Justine C. Shiau
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA30605
- Department of Infectious Diseases, University of Georgia, Athens, GA30605
| | - Lecia L. Pewe
- Department of Pathology, University of Iowa, Iowa City, IA52242
| | - Melanie J. Shears
- Johns Hopkins Malaria Research Institute, Johns Hopkins University, Baltimore, MD21205
- Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, MD21205
| | | | - Photini Sinnis
- Johns Hopkins Malaria Research Institute, Johns Hopkins University, Baltimore, MD21205
- Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, MD21205
| | - Dennis E. Kyle
- Department of Cellular Biology, University of Georgia, Athens, GA30605
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA30605
- Department of Infectious Diseases, University of Georgia, Athens, GA30605
| | - Prajwal Gurung
- Department of Internal Medicine, University of Iowa, Iowa City, IA52242
- Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA52242
| | - John T. Harty
- Department of Pathology, University of Iowa, Iowa City, IA52242
- Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA52242
| | - Samarchith P. Kurup
- Department of Cellular Biology, University of Georgia, Athens, GA30605
- Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA30605
| |
Collapse
|
|
30
|
Puchowicz MA, Parveen K, Sethuraman A, Ishrat T, Xu K, LaManna J. Pro-survival Phenotype of HIF-1α: Neuroprotection Through Inflammatory Mechanisms. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1438:33-36. [PMID: 37845436 DOI: 10.1007/978-3-031-42003-0_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2023]
Abstract
Hypoxia-inducible factor 1 (HIF-1) is a major player in the oxygen sensor system as well as a transcription factor. HIF-1 is also associated in the pathogenesis of many brain diseases including Alzheimer's disease (AD), epilepsy and stroke. HIF-1 regulates the expression of many genes such as those involved in glycolysis, erythropoiesis, angiogenesis and proliferation in hypoxic condition. Despite several studies, the mechanism through which HIF-1 confers neuroprotection remains unclear, one of them is modulating metabolic profiles and inflammatory pathways. Characterization of the neuroprotective role of HIF-1 may be through its stabilization and the regulation of target genes that aid in the early adaptation to the oxidative stressors. It is interesting to note that mounting data from recent years point to an additional crucial regulatory role for hypoxia-inducible factors (HIFs) in inflammation. HIFs in immune cells regulate the production of glycolytic energy as well as innate immunity, pro-inflammatory gene expression, and mediates activation of pro-survival pathways. The present review highlights the contribution of HIF-1 to neuroprotection where inflammation is the crucial factor in the pathogenesis contributing to neural death. The potential mechanisms that contribute to neuroprotection as a result of the downstream targets of HIF-1α are discussed. Such mechanisms include those mediated through IL-10, an anti-inflammatory molecule involved in activating pro-survival signaling mechanisms via AKT/ERK and JAK/STAT pathways.
Collapse
Affiliation(s)
- Michelle A Puchowicz
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.
- Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, OH, USA.
| | - Kehkashan Parveen
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Aarti Sethuraman
- Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Tauheed Ishrat
- Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Kui Xu
- Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, OH, USA
| | - Joseph LaManna
- Department of Physiology & Biophysics, Case Western Reserve University, Cleveland, OH, USA
| |
Collapse
|
|
31
|
Hartmann A, Vila-Verde C, Guimarães FS, Joca SR, Lisboa SF. The NLRP3 Inflammasome in Stress Response: Another Target for the Promiscuous Cannabidiol. Curr Neuropharmacol 2023; 21:284-308. [PMID: 35410608 PMCID: PMC10190150 DOI: 10.2174/1570159x20666220411101217] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 03/14/2022] [Accepted: 03/27/2022] [Indexed: 11/22/2022] Open
Abstract
Many psychiatric patients do not respond to conventional therapy. There is a vast effort to investigate possible mechanisms involved in treatment resistance, trying to provide better treatment options, and several data points toward a possible involvement of inflammatory mechanisms. Microglia, glial, and resident immune cells are involved in complex responses in the brain, orchestrating homeostatic functions, such as synaptic pruning and maintaining neuronal activity. In contrast, microglia play a major role in neuroinflammation, neurodegeneration, and cell death. Increasing evidence implicate microglia dysfunction in neuropsychiatric disorders. The mechanisms are still unclear, but one pathway in microglia has received increased attention in the last 8 years, i.e., the NLRP3 inflammasome pathway. Stress response and inflammation, including microglia activation, can be attenuated by Cannabidiol (CBD). CBD has antidepressant, anti-stress, antipsychotic, anti-inflammatory, and other properties. CBD effects are mediated by direct or indirect modulation of many receptors, enzymes, and other targets. This review will highlight some findings for neuroinflammation and microglia involvement in stress-related psychiatric disorders, particularly addressing the NLRP3 inflammasome pathway. Moreover, we will discuss evidence and mechanisms for CBD effects in psychiatric disorders and animal models and address its potential effects on stress response via neuroinflammation and NLRP3 inflammasome modulation.
Collapse
Affiliation(s)
- Alice Hartmann
- Department of Pharmacology, School of Medicine of Ribeirão Preto (FMRP), University of São Paulo (USP), Ribeirão Preto, Brazil
| | - Carla Vila-Verde
- Department of Pharmacology, School of Medicine of Ribeirão Preto (FMRP), University of São Paulo (USP), Ribeirão Preto, Brazil
| | - Francisco S. Guimarães
- Department of Pharmacology, School of Medicine of Ribeirão Preto (FMRP), University of São Paulo (USP), Ribeirão Preto, Brazil
- Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil
| | - Sâmia R. Joca
- Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil
- BioMolecular Sciences Department, School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP);
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Sabrina F. Lisboa
- Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), University of São Paulo, São Paulo, Brazil
- BioMolecular Sciences Department, School of Pharmaceutical Sciences of Ribeirão Preto (FCFRP), University of São Paulo (USP);
| |
Collapse
|
|
32
|
Exosomes derived from heat shock preconditioned bone marrow mesenchymal stem cells alleviate cisplatin-induced ototoxicity in mice. J Biol Eng 2022; 16:24. [PMID: 36175910 PMCID: PMC9520862 DOI: 10.1186/s13036-022-00304-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 09/02/2022] [Indexed: 11/21/2022] Open
Abstract
NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome contributes to the development of cisplatin-induced ototoxicity. Whether heat shock pretreatment could be utilized to up-regulate 70 kilodalton heat shock proteins (HSP70) expression in bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (HS-BMSC-Exo) to alleviate cisplatin-induced ototoxicity is deciphered in this study. Heat shock pretreatment was performed on BMSCs to induce HS-BMSC-Exo, which were further trans-tympanically administrated into cisplatin intraperitoneally injected C57BL/6 mice. Auditory brainstem response (ABR) was assessed to indicate auditory sensitivity at 8, 16, 24, and 32 kHz. Myosin 7a staining was utilized to detect the mature hair cells. The relative expressions of the NLRP3 inflammasome complex were determined with Western blot in the cochlea. Diminished auditory sensitivity and increased hair cell loss could be observed in the cisplatin exposed mice with increased content of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, NLRP3, ASC, cleaved caspase-1, and pro-caspase-1, and decreased content of IL-10, which could be reversed by HS-BMSC-Exo or BMSC-Exo administration. It was worth noting that HS-BMSC-Exo demonstrated more treatment benefits than BMSC-Exo in cisplatin-induced ototoxicity. Heat shock precondition may provide a new therapeutic option to produce exosomal HSP70, and HS-BMSC-Exo could be utilized to relieve cisplatin-induced ototoxicity.
Collapse
|
|
33
|
Di Carlo S, Häcker G, Gentle IE. GM‐CSF suppresses antioxidant signaling and drives IL‐1β secretion through NRF2 downregulation. EMBO Rep 2022; 23:e54226. [PMID: 35695080 PMCID: PMC9346485 DOI: 10.15252/embr.202154226] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 05/11/2022] [Accepted: 05/24/2022] [Indexed: 11/09/2022] Open
Abstract
GM‐CSF is a potent inflammatory cytokine regulating myeloid cell differentiation, hematopoiesis, and various other functions. It is functionally associated with a number of inflammatory pathologies including rheumatoid arthritis and inflammatory bowel disease. GM‐CSF has been found to promote NLRP3‐dependent IL‐1β secretion, which may have a significant role in driving inflammatory pathologies. However, the molecular mechanisms remain unknown. Here, we show that GM‐CSF induces IL‐1β secretion through a ROS‐dependent pathway. TNF is required for reactive oxygen species (ROS) generation that strikingly does not promote NLRP3 activation, but instead drives ubiquitylation of IL‐1β, promoting its cleavage through basal NRLP3 activity. GM‐CSF regulates this pathway through suppression of antioxidant responses via preventing upregulation of NRF2. Thus, the pro‐inflammatory effect of GM‐CSF on IL‐1β is through suppression of antioxidant responses, which leads to ubiquitylation of IL‐1β and enhanced processing. This study highlights the role of metabolic regulation of inflammatory signaling and reveals a novel mechanism for GM‐CSF to promote inflammation.
Collapse
Affiliation(s)
- Sara Di Carlo
- Institute of Medical Microbiology and Hygiene Faculty of Medicine Medical Center – University of Freiburg Freiburg Germany
| | - Georg Häcker
- Institute of Medical Microbiology and Hygiene Faculty of Medicine Medical Center – University of Freiburg Freiburg Germany
- BIOSS Centre for Biological Signalling Studies University of Freiburg Freiburg Germany
| | - Ian E Gentle
- Institute of Medical Microbiology and Hygiene Faculty of Medicine Medical Center – University of Freiburg Freiburg Germany
| |
Collapse
|
|
34
|
Renner P, Crone M, Kornas M, Pioli KT, Pioli PD. Intracellular flow cytometry staining of antibody-secreting cells using phycoerythrin-conjugated antibodies: pitfalls and solutions. Antib Ther 2022; 5:151-163. [PMID: 35928457 PMCID: PMC9344851 DOI: 10.1093/abt/tbac013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/02/2022] [Accepted: 06/07/2022] [Indexed: 11/13/2022] Open
Abstract
Background Antibody-secreting cells are terminally differentiated B cells that play a critical role in humoral immunity through immunoglobulin secretion along with possessing the potential to be long-lived. It is now appreciated that ASCs regulate multiple aspects of biology through the secretion of various cytokines. In this regard, ICFC is a key tool used to assess the presence of intracellular proteins such as cytokines and transcription factors. Methods Paraformaldehyde plus saponin or the eBioscience Foxp3/Transcription Factor Staining Buffer Set were used to evaluate the non-specific intracellular retention of phycoerythrin-containing antibody conjugates by ASCs. Results We showed that the use of phycoerythrin-containing antibody conjugates led to a false interpretation of ASC intracellular protein expression compared with other cell types. This was mainly due to the inappropriate retention of these antibodies specifically within ASCs. Furthermore, we demonstrated how to reduce this retention which allowed for a more accurate comparison of intracellular protein expression between ASCs and other cell types such as B lymphocytes. Using this methodology, our data revealed that spleen ASCs expressed toll-like receptor 7 as well as the pro-form of the inflammatory cytokine interleukin-1β. Conclusion Increasing the number of centrifugation steps performed on ASCs post-fixation leads to inappropriate retention of phycoerythrin-containing antibody conjugates during ICFC.
Collapse
Affiliation(s)
- Patrick Renner
- Department of Investigative Medicine , Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, United States
| | - Michael Crone
- Department of Investigative Medicine , Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, United States
| | - Matthew Kornas
- Department of Investigative Medicine , Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, United States
| | - KimAnh T Pioli
- Department of Investigative Medicine , Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, United States
- Department of Biochemistry , Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada
| | - Peter D Pioli
- Department of Investigative Medicine , Western Michigan University Homer Stryker M.D. School of Medicine, Kalamazoo, United States
- Department of Biochemistry , Microbiology and Immunology, University of Saskatchewan, Saskatoon, Canada
| |
Collapse
|
|
35
|
Martynova E, Rizvanov A, Urbanowicz RA, Khaiboullina S. Inflammasome Contribution to the Activation of Th1, Th2, and Th17 Immune Responses. Front Microbiol 2022; 13:851835. [PMID: 35369454 PMCID: PMC8969514 DOI: 10.3389/fmicb.2022.851835] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Accepted: 02/22/2022] [Indexed: 12/24/2022] Open
Abstract
Inflammasomes are cytosolic polyprotein complexes formed in response to various external and internal stimuli, including viral and bacterial antigens. The main product of the inflammasome is active caspase 1 which proteolytically cleaves, releasing functional interleukin-1 beta (IL-1β) and interleukin-18 (IL-18). These cytokines play a central role in shaping immune response to pathogens. In this review, we will focus on the mechanisms of inflammasome activation, as well as their role in development of Th1, Th2, and Th17 lymphocytes. The contribution of cytokines IL-1β, IL-18, and IL-33, products of activated inflammasomes, are summarized. Additionally, the role of cytokines released from tissue cells in promoting differentiation of lymphocyte populations is discussed.
Collapse
Affiliation(s)
| | | | - Richard A. Urbanowicz
- Department of Infection Biology and Microbiomes, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom
| | | |
Collapse
|
|
36
|
Ahmed S, Panda SR, Kwatra M, Sahu BD, Naidu VGM. Perillyl Alcohol Attenuates NLRP3 Inflammasome Activation and Rescues Dopaminergic Neurons in Experimental In Vitro and In Vivo Models of Parkinson's Disease. ACS Chem Neurosci 2022; 13:53-68. [PMID: 34904823 DOI: 10.1021/acschemneuro.1c00550] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
NLRP3 activation plays a key role in the initiation and progression of a variety of neurodegenerative diseases. However, understanding the molecular mechanisms involved in the bidirectional signaling required to activate the NLRP3 inflammasomes is the key to treating several diseases. Hence, the present study aimed to investigate the role of lipopolysaccharide (LPS) and hydrogen peroxide (H2O2) in activating NLRP3 inflammasome-driven neurodegeneration and elucidated the neuroprotective role of perillyl alcohol (PA) in in vitro and in vivo models of Parkinson's disease (PD). Initial priming of microglial cells with LPS following treatment with H2O2 induced NF-κB translocation to the nucleus with a robust generation of free radicals that act as signal 2 in augmenting NLRP3 inflammasome assembly and its downstream targets. PA treatment suppresses the nuclear translocation of NF-κB, enhances PARKIN translocation into the mitochondria, and maintains cellular redox homeostasis in both mouse and human microglial cells that limit NLRP3 inflammasome activation along with processing of active caspase-1, IL-1β, and IL-18. To further correlate the in vitro study with the in vivo MPTP model, treatment with PA also inhibited the nuclear translocation of NF-κB and downregulated the NLRP3 inflammasome activation. PA administration upregulated various antioxidant enzymes' levels and restored the level of dopamine and other neurotransmitters in the striatum of the mouse brain, subsequently improving the behavioral activities. Therefore, we conclude that NLRP3 inflammasome activation required a signal from damaged mitochondria for its activation. Further pharmacological scavenging of free radicals restricts microglia activation and simultaneously supports neuronal survival via targeting the NLRP3 inflammasome pathway in PD.
Collapse
Affiliation(s)
- Sahabuddin Ahmed
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, Kamrup, Assam 781101, India
| | - Samir Ranjan Panda
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, Kamrup, Assam 781101, India
| | - Mohit Kwatra
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, Kamrup, Assam 781101, India
| | - Bidya Dhar Sahu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, Kamrup, Assam 781101, India
| | - VGM Naidu
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Guwahati, Changsari, Kamrup, Assam 781101, India
| |
Collapse
|
|
37
|
Chronic Ketosis Modulates HIF1α-Mediated Inflammatory Response in Rat Brain. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1395:75-79. [PMID: 36527617 DOI: 10.1007/978-3-031-14190-4_13] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hypoxia inducible factor alpha (HIF1α) is associated with neuroprotection conferred by diet-induced ketosis but the underlying mechanism remains unclear. In this study we use a ketogenic diet in rodents to induce a metabolic state of chronic ketosis, as measured by elevated blood ketone bodies. Chronic ketosis correlates with neuroprotection in both aged and following focal cerebral ischaemia and reperfusion (via middle cerebral artery occlusion, MCAO) in mouse and rat models. Ketone bodies are known to be used efficiently by the brain and metabolism of ketone bodies is associated with increased cytosolic succinate levels that inhibits prolyl hydroxylases allowing HIF1α to accumulate. Ketosis also regulates inflammatory pathways, and HIF1α is reported to be essential for gene expression of interleukin10 (IL10). Therefore we hypothesised that ketosis-stabilised HIF1α modulates the expression of inflammatory cytokines orchestrating neuroprotection. To test changes in cytokine levels in rodent brain, eight-week-old rats were fed either the standard chow diet (SD) or the ketogenic (KG) diet for 4 weeks before ischaemia experiments (MCAO) were performed and the brain tissues were collected. Consistent with our hypothesis, immunoblotting analysis shows IL10 levels were significantly higher in KG diet rat brain compared to SD, whereas the TNFα and IL6 levels were significantly lower in the brains of KG diet fed group.
Collapse
|
|
38
|
Lin CH, Lin HY, Ho EP, Ke YC, Cheng MF, Shiue CY, Wu CH, Liao PH, Hsu AYH, Chu LA, Liu YD, Lin YH, Tai YC, Shun CT, Chiu HM, Wu MS. Mild Chronic Colitis Triggers Parkinsonism in LRRK2 Mutant Mice Through Activating TNF-α Pathway. Mov Disord 2021; 37:745-757. [PMID: 34918781 DOI: 10.1002/mds.28890] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 11/30/2021] [Accepted: 11/30/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Leucine-rich repeat kinase 2 (LRRK2) is a common risk gene for Parkinson's disease (PD) and inflammatory bowel disorders. However, the penetrance of the most prevalent LRRK2 mutation, G2019S, is <50%. Factors other than genetic mutations are needed in PD process. OBJECTIVES To examine whether and how gut inflammation may act as an environmental trigger to neurodegeneration in PD. METHODS A mild and chronic dextran sodium sulfate (DSS)-induced colitis mice model harboring LRRK2 G2019S mutation was established. The colitis severity, immune responses, locomotor function, dopaminergic neuron, and microglia integrity were compared between littermate controls, transgenic LRRK2 wild type (WT), and LRRK2 G2019S mice. RESULTS The LRRK2 G2019S mice are more vulnerable to DSS-induced colitis than littermate controls or LRRK2 WT animals with increased intestinal expressions of pattern-recognition receptors, including toll-like receptors (TLRs), nuclear factor (NF)-κB activation, and pro-inflammatory cytokines secretion, especially tumor necrosis factor (TNF)-α. Notably, the colonic expression of α-synuclein was significantly increased in LRRK2 G2019S colitis mice. We subsequently observed more aggravated locomotor defect, microglia activation, and dopaminergic neuron loss in LRRK2 G2019S colitis mice than control animals. Treatment with anti-TNF-α monoclonal antibody, adalimumab, abrogated both gut and neuroinflammation, mitigated neurodegeneration, and improved locomotor function in LRRK2 G2019S colitis mice. Finally, we validated increased colonic expressions of LRRK2, TLRs, and NF-κB pathway proteins and elevated plasma TNF-α level in PD patients compared to controls, especially in those with LRRK2 risk variants. CONCLUSIONS Our findings demonstrate that chronic colitis promotes parkinsonism in genetically susceptible mice and TNF-α plays a detrimental role in the gut-brain axis of PD. © 2021 International Parkinson and Movement Disorder Society.
Collapse
Affiliation(s)
- Chin-Hsien Lin
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Han-Yi Lin
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - En-Pong Ho
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Ci Ke
- Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Fang Cheng
- Department of Nuclear Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chyng-Yann Shiue
- Department of Nuclear Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chi-Han Wu
- Department of Nuclear Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | | | | | - Li-An Chu
- Department of Biomedical Engineering and Environmental Science, National Tsing Hua University, Hsinchu, Taiwan.,National Center for High-Performance Computing, Hsinchu, Taiwan
| | - Ya-Ding Liu
- Department of Biomedical Engineering and Environmental Science, National Tsing Hua University, Hsinchu, Taiwan.,National Center for High-Performance Computing, Hsinchu, Taiwan
| | - Ya-Hui Lin
- Department of Biomedical Engineering and Environmental Science, National Tsing Hua University, Hsinchu, Taiwan.,National Center for High-Performance Computing, Hsinchu, Taiwan
| | - Yi-Cheng Tai
- Department of Neurology, E-Da Hospital, Kaohsiung, Taiwan
| | - Chia-Tung Shun
- Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Han-Mo Chiu
- Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan
| |
Collapse
|
|
39
|
Liu L, Yang Y, Fang R, Zhu W, Wu J, Li X, Patankar JV, Li W. Giardia duodenalis and Its Secreted PPIB Trigger Inflammasome Activation and Pyroptosis in Macrophages through TLR4-Induced ROS Signaling and A20-Mediated NLRP3 Deubiquitination. Cells 2021; 10:cells10123425. [PMID: 34943932 PMCID: PMC8700504 DOI: 10.3390/cells10123425] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/18/2021] [Accepted: 12/03/2021] [Indexed: 12/21/2022] Open
Abstract
The extracellular protozoan parasite Giardia duodenalis is a well-known and important causative agent of diarrhea on a global scale. Macrophage pyroptosis has been recognized as an important innate immune effector mechanism against intracellular pathogens. Yet, the effects of noninvasive Giardia infection on macrophage pyroptosis and the associated molecular triggers and regulators remain poorly defined. Here we initially observed that NLRP3 inflammasome-mediated pyroptosis was activated in Giardia-treated macrophages, and inhibition of ROS, NLRP3, or caspase-1 could block GSDMD cleavage, IL-1β, IL-18 and LDH release, and the cell viability reduction. We also confirmed that Giardia-induced NLRP3 inflammasome activation was involved in its K63 deubiquitination. Thus, six candidate deubiquitinases were screened, among which A20 was identified as an effective regulator. We then screened TLRs on macrophage membranes and found that upon stimulation TLR4 was tightly correlated to ROS enhancement, A20-mediated NLRP3 deubiquitination, and pyroptotic signaling. In addition, several Giardia-secreted proteins were predicted as trigger factors via secretome analysis, of which peptidyl-prolyl cis-trans isomerase B (PPIB) independently induced macrophage pyroptosis. This was similar to the findings from the trophozoite treatment, and also led to the TLR4-mediated activation of NLRP3 through K63 deubiquitination by A20. Collectively, the results of this study have significant implications for expanding our understanding of host defense mechanisms after infection with G. duodenalis.
Collapse
Affiliation(s)
- Lin Liu
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; (L.L.); (Y.Y.); (R.F.); (W.Z.); (J.W.); (X.L.)
| | - Yongwu Yang
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; (L.L.); (Y.Y.); (R.F.); (W.Z.); (J.W.); (X.L.)
| | - Rui Fang
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; (L.L.); (Y.Y.); (R.F.); (W.Z.); (J.W.); (X.L.)
| | - Weining Zhu
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; (L.L.); (Y.Y.); (R.F.); (W.Z.); (J.W.); (X.L.)
| | - Jingxue Wu
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; (L.L.); (Y.Y.); (R.F.); (W.Z.); (J.W.); (X.L.)
| | - Xiaoyun Li
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; (L.L.); (Y.Y.); (R.F.); (W.Z.); (J.W.); (X.L.)
| | - Jay V. Patankar
- Department of Medicine 1, University of Erlangen-Nuremberg, 91052 Erlangen, Germany;
| | - Wei Li
- Heilongjiang Provincial Key Laboratory of Zoonosis, College of Veterinary Medicine, Northeast Agricultural University, Harbin 150030, China; (L.L.); (Y.Y.); (R.F.); (W.Z.); (J.W.); (X.L.)
- Correspondence: or
| |
Collapse
|
|
40
|
Gong Q, Wang M, Jiang Y, Zha C, Yu D, Lei F, Luo Y, Feng Y, Yang S, Li J, Du L. The abrupt pathological deterioration of cisplatin-induced acute kidney injury: Emerging of a critical time point. Pharmacol Res Perspect 2021; 9:e00895. [PMID: 34817124 PMCID: PMC8611776 DOI: 10.1002/prp2.895] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 10/26/2021] [Indexed: 12/23/2022] Open
Abstract
Cisplatin (CP), an anticancer drug, often causes kidney damage. However, the mechanism of CP-induced acute kidney injury (AKI) is not completely understood. AKI was induced by intravenous injection (i.v.) of cisplatin at doses of 5, 8, and 10 mg/kg. Anemoside B4 (B4) (20 mg/kg, i.m.) and dexamethasone (DXM) (0.5 mg/kg, i.v.) were used for AKI treatment. Biochemical indicators were assessed using an automatic biochemical analyzer, protein expression was analyzed by western blotting, and morphological changes in the kidney were examined by PAS staining. The serum creatinine (Cre) and blood urea nitrogen (BUN) levels did not change significantly in the first 2 days but abruptly increased on the third day after CP injection. The serum albumin (ALB) and total protein (TP) levels decreased in both a time- and dose-dependent manner. The urine protein level increased, the clearing rate of Cre decreased distinctly, and morphologic changes appeared in a dose-dependent manner. The protein expression of p53/caspase-3, NLRP3, IL-6, and TNF-α was obviously upregulated on day 3; concurrently, nephrin and podocin were downregulated. The expression of LC3II and p62 was upregulated significantly as the CP dose increased. B4 and DXM obviously decreased the BUN and Cre levels after 3 or 5 days of treatment. AKI appeared distinctly in a time-dependent manner at 2 to 5 days after the administration of 5 mg/kg CP and in a dose-dependent manner upon the administration of 5, 8, and 10 mg/kg CP. The third day was a significant time point for renal deterioration, and treatment with B4 and DXM within the first 3 days provided significant protection against AKI.
Collapse
Affiliation(s)
- Qin Gong
- School of PharmacyJiangxi University of Traditional Chinese MedicineNanchangChina
- Pharmacology LaboratoryState Key Laboratory of Innovative Drugs and Efficient Energy‐saving Pharmaceutical EquipmentNanchangChina
| | - Mulan Wang
- Pharmacology LaboratoryState Key Laboratory of Innovative Drugs and Efficient Energy‐saving Pharmaceutical EquipmentNanchangChina
| | - Ya Jiang
- School of PharmacyJiangxi University of Traditional Chinese MedicineNanchangChina
| | - Chengliang Zha
- Pharmacology LaboratoryState Key Laboratory of Innovative Drugs and Efficient Energy‐saving Pharmaceutical EquipmentNanchangChina
| | - Dong Yu
- School of PharmacyJiangxi University of Traditional Chinese MedicineNanchangChina
| | - Fan Lei
- School of Life SciencesTsinghua UniversityBeijingChina
| | - Yingying Luo
- School of PharmacyJiangxi University of Traditional Chinese MedicineNanchangChina
- Pharmacology LaboratoryState Key Laboratory of Innovative Drugs and Efficient Energy‐saving Pharmaceutical EquipmentNanchangChina
| | - Yulin Feng
- School of PharmacyJiangxi University of Traditional Chinese MedicineNanchangChina
- Pharmacology LaboratoryState Key Laboratory of Innovative Drugs and Efficient Energy‐saving Pharmaceutical EquipmentNanchangChina
| | - Shilin Yang
- School of PharmacyJiangxi University of Traditional Chinese MedicineNanchangChina
- Pharmacology LaboratoryState Key Laboratory of Innovative Drugs and Efficient Energy‐saving Pharmaceutical EquipmentNanchangChina
| | - Jun Li
- School of PharmacyJiangxi University of Traditional Chinese MedicineNanchangChina
- Pharmacology LaboratoryState Key Laboratory of Innovative Drugs and Efficient Energy‐saving Pharmaceutical EquipmentNanchangChina
| | - Lijun Du
- School of PharmacyJiangxi University of Traditional Chinese MedicineNanchangChina
- Pharmacology LaboratoryState Key Laboratory of Innovative Drugs and Efficient Energy‐saving Pharmaceutical EquipmentNanchangChina
- School of Life SciencesTsinghua UniversityBeijingChina
| |
Collapse
|
|
41
|
María Irene CC, Juan Germán RC, Gamaliel LL, Dulce Adriana ME, Estela Isabel B, Brenda Nohemí M, Payan Jorge B, Zyanya Lucía ZB, Myriam BDV, Fernanda CG, Adrian OL, Martha Isabel M, Rogelio HP. Profiling the immune response to Mycobacterium tuberculosis Beijing family infection: a perspective from the transcriptome. Virulence 2021; 12:1689-1704. [PMID: 34228582 PMCID: PMC8265813 DOI: 10.1080/21505594.2021.1936432] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 03/24/2021] [Accepted: 05/14/2021] [Indexed: 01/15/2023] Open
Abstract
Tuberculosis continues to be an important public health problem. Particularly considering Beijing-family strains of Mycobacterium tuberculosis, which have been associated with drug-resistance and hypervirulence. The Beijing-like SIT190 (BL) is the most prevalent Beijing strain in Colombia. The pathogenic mechanism and immune response against this pathogen is unknown. Thus, we compared the course of pulmonary TB in BALB/c mice infected with Classical-Beijing strain 391 and BL strain 323. The disease course was different among infected animals with Classical-Beijing and BL strain. Mice infected with BL had a 100% mortality at 45 days post-infection (dpi), with high bacillary loads and massive pneumonia, whereas infected animals with Classical-Beijing survived until 60 dpi and showed extensive pneumonia and necrosis. Lung RNA extraction was carried out at early (day 3 dpi), intermediate (day 14 dpi), and late (days 28 and 60 dpi) time points of infection. Transcriptional analysis of infected mice with Classical-Beijing showed several over-expressed genes, associated with a pro-inflammatory profile, including those for coding for CCL3 and CCL4 chemokines, both biomarkers of disease severity. Conversely, mice infected with BL displayed a profile which included the over-expression of several genes associated with immune-suppression, including Nkiras, Dleu2, and Sphk2, highlighting an anti-inflammatory milieu which would allow high bacterial replication followed by an intense inflammatory response. In summary, both Beijing strains induced a non-protective immune response which induced extensive tissue damage, BL strain induced rapidly extensive pneumonia and death, whereas Classical-Beijing strain produced slower extensive pneumonia later associated with extensive necrosis.
Collapse
Affiliation(s)
- Cerezo-Cortés María Irene
- Universidad Nacional De Colombia, Facultad De Medicina, Departamento De Microbiología, Laboratorio De Micobacterias
| | | | - López-Leal Gamaliel
- Departamento De Microbiología Molecular, Instituto De Biotecnología, Universidad Nacional Autónoma De México, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos, México
| | - Mata-Espinosa Dulce Adriana
- Sección De Patología Experimental, Departamento De Patología, Instituto Nacional De Ciencias Médicas Y Nutrición Salvador Zubirán, Ciudad De México, México
| | - Bini Estela Isabel
- Sección De Patología Experimental, Departamento De Patología, Instituto Nacional De Ciencias Médicas Y Nutrición Salvador Zubirán, Ciudad De México, México
| | - Marquina–Casitllo Brenda Nohemí
- Sección De Patología Experimental, Departamento De Patología, Instituto Nacional De Ciencias Médicas Y Nutrición Salvador Zubirán, Ciudad De México, México
| | - Barrios Payan Jorge
- Sección De Patología Experimental, Departamento De Patología, Instituto Nacional De Ciencias Médicas Y Nutrición Salvador Zubirán, Ciudad De México, México
| | - Zatarain-Barrón Zyanya Lucía
- Sección De Patología Experimental, Departamento De Patología, Instituto Nacional De Ciencias Médicas Y Nutrición Salvador Zubirán, Ciudad De México, México
| | - Bobadilla del Valle Myriam
- Departamento De Microbiología Clínica, Instituto Nacional De Ciencias Médicas Y Nutrición Salvador Zubirán Ciudad De México, México
| | - Cornejo-Granados Fernanda
- Departamento De Microbiología Molecular, Instituto De Biotecnología, Universidad Nacional Autónoma De México, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos, México
| | - Ochoa-Leyva Adrian
- Departamento De Microbiología Molecular, Instituto De Biotecnología, Universidad Nacional Autónoma De México, Avenida Universidad 2001, Colonia Chamilpa, Cuernavaca, Morelos, México
| | - Murcia Martha Isabel
- Universidad Nacional De Colombia, Facultad De Medicina, Departamento De Microbiología, Laboratorio De Micobacterias
| | - Hernández-Pando Rogelio
- Sección De Patología Experimental, Departamento De Patología, Instituto Nacional De Ciencias Médicas Y Nutrición Salvador Zubirán, Ciudad De México, México
| |
Collapse
|
|
42
|
Badanjak K, Mulica P, Smajic S, Delcambre S, Tranchevent LC, Diederich N, Rauen T, Schwamborn JC, Glaab E, Cowley SA, Antony PMA, Pereira SL, Venegas C, Grünewald A. iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson's Disease. Front Cell Dev Biol 2021; 9:740758. [PMID: 34805149 PMCID: PMC8602578 DOI: 10.3389/fcell.2021.740758] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 10/08/2021] [Indexed: 11/13/2022] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disease with unknown cause in the majority of patients, who are therefore considered "idiopathic" (IPD). PD predominantly affects dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the pathology is not limited to this cell type. Advancing age is considered the main risk factor for the development of IPD and greatly influences the function of microglia, the immune cells of the brain. With increasing age, microglia become dysfunctional and release pro-inflammatory factors into the extracellular space, which promote neuronal cell death. Accordingly, neuroinflammation has also been described as a feature of PD. So far, studies exploring inflammatory pathways in IPD patient samples have primarily focused on blood-derived immune cells or brain sections, but rarely investigated patient microglia in vitro. Accordingly, we decided to explore the contribution of microglia to IPD in a comparative manner using, both, iPSC-derived cultures and postmortem tissue. Our meta-analysis of published RNAseq datasets indicated an upregulation of IL10 and IL1B in nigral tissue from IPD patients. We observed increased expression levels of these cytokines in microglia compared to neurons using our single-cell midbrain atlas. Moreover, IL10 and IL1B were upregulated in IPD compared to control microglia. Next, to validate these findings in vitro, we generated IPD patient microglia from iPSCs using an established differentiation protocol. IPD microglia were more readily primed as indicated by elevated IL1B and IL10 gene expression and higher mRNA and protein levels of NLRP3 after LPS treatment. In addition, IPD microglia had higher phagocytic capacity under basal conditions-a phenotype that was further exacerbated upon stimulation with LPS, suggesting an aberrant microglial function. Our results demonstrate the significance of microglia as the key player in the neuroinflammation process in IPD. While our study highlights the importance of microglia-mediated inflammatory signaling in IPD, further investigations will be needed to explore particular disease mechanisms in these cells.
Collapse
Affiliation(s)
- Katja Badanjak
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
| | - Patrycja Mulica
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
| | - Semra Smajic
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
| | - Sylvie Delcambre
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
| | | | - Nico Diederich
- Centre Hospitalier de Luxembourg (CHL), Luxembourg, Luxembourg
| | - Thomas Rauen
- Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Münster, Germany
| | - Jens C. Schwamborn
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
| | - Enrico Glaab
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
| | - Sally A. Cowley
- James Martin Stem Cell Facility, Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
| | - Paul M. A. Antony
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
- Disease Modeling and Screening Platform (DMSP), Luxembourg Institute of Systems Biomedicine, University of Luxembourg and Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Sandro L. Pereira
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
| | - Carmen Venegas
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
| | - Anne Grünewald
- Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| |
Collapse
|
|
43
|
Cystatin C Deficiency Increases LPS-Induced Sepsis and NLRP3 Inflammasome Activation in Mice. Cells 2021; 10:cells10082071. [PMID: 34440840 PMCID: PMC8391971 DOI: 10.3390/cells10082071] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Revised: 08/05/2021] [Accepted: 08/10/2021] [Indexed: 11/16/2022] Open
Abstract
Cystatin C is a potent cysteine protease inhibitor that plays an important role in various biological processes including cancer, cardiovascular diseases and neurodegenerative diseases. However, the role of CstC in inflammation is still unclear. In this study we demonstrated that cystatin C-deficient mice were significantly more sensitive to the lethal LPS-induced sepsis. We further showed increased caspase-11 gene expression and enhanced processing of pro-inflammatory cytokines IL-1β and IL-18 in CstC KO bone marrow-derived macrophages (BMDM) upon LPS and ATP stimulation. Pre-treatment of BMDMs with the cysteine cathepsin inhibitor E-64d did not reverse the effect of CstC deficiency on IL-1β processing and secretion, suggesting that the increased cysteine cathepsin activity determined in CstC KO BMDMs is not essential for NLRP3 inflammasome activation. The CstC deficiency had no effect on (mitochondrial) reactive oxygen species (ROS) generation, the MAPK signaling pathway or the secretion of anti-inflammatory cytokine IL-10. However, CstC-deficient BMDMs showed dysfunctional autophagy, as autophagy induction via mTOR and AMPK signaling pathways was suppressed and accumulation of SQSTM1/p62 indicated a reduced autophagic flux. Collectively, our study demonstrates that the excessive inflammatory response to the LPS-induced sepsis in CstC KO mice is dependent on increased caspase-11 expression and impaired autophagy, but is not associated with increased cysteine cathepsin activity.
Collapse
|
|
44
|
Jacobse J, Li J, Rings EHHM, Samsom JN, Goettel JA. Intestinal Regulatory T Cells as Specialized Tissue-Restricted Immune Cells in Intestinal Immune Homeostasis and Disease. Front Immunol 2021; 12:716499. [PMID: 34421921 PMCID: PMC8371910 DOI: 10.3389/fimmu.2021.716499] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 07/16/2021] [Indexed: 12/28/2022] Open
Abstract
FOXP3+ regulatory T cells (Treg cells) are a specialized population of CD4+ T cells that restrict immune activation and are essential to prevent systemic autoimmunity. In the intestine, the major function of Treg cells is to regulate inflammation as shown by a wide array of mechanistic studies in mice. While Treg cells originating from the thymus can home to the intestine, the majority of Treg cells residing in the intestine are induced from FOXP3neg conventional CD4+ T cells to elicit tolerogenic responses to microbiota and food antigens. This process largely takes place in the gut draining lymph nodes via interaction with antigen-presenting cells that convert circulating naïve T cells into Treg cells. Notably, dysregulation of Treg cells leads to a number of chronic inflammatory disorders, including inflammatory bowel disease. Thus, understanding intestinal Treg cell biology in settings of inflammation and homeostasis has the potential to improve therapeutic options for patients with inflammatory bowel disease. Here, the induction, maintenance, trafficking, and function of intestinal Treg cells is reviewed in the context of intestinal inflammation and inflammatory bowel disease. In this review we propose intestinal Treg cells do not compose fixed Treg cell subsets, but rather (like T helper cells), are plastic and can adopt different programs depending on microenvironmental cues.
Collapse
Affiliation(s)
- Justin Jacobse
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Jing Li
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
| | - Edmond H. H. M. Rings
- Department of Pediatrics, Willem-Alexander Children’s Hospital, Leiden University Medical Center, Leiden, Netherlands
- Department of Pediatrics, Sophia Children’s Hospital, Erasmus University, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Janneke N. Samsom
- Laboratory of Pediatrics, Division of Gastroenterology and Nutrition, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Jeremy A. Goettel
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN, United States
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, United States
- Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, United States
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, United States
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, United States
| |
Collapse
|
|
45
|
Kovács EG, Alatshan A, Budai MM, Czimmerer Z, Bíró E, Benkő S. Caffeine Has Different Immunomodulatory Effect on the Cytokine Expression and NLRP3 Inflammasome Function in Various Human Macrophage Subpopulations. Nutrients 2021; 13:2409. [PMID: 34371919 PMCID: PMC8308523 DOI: 10.3390/nu13072409] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/05/2021] [Accepted: 07/08/2021] [Indexed: 12/14/2022] Open
Abstract
Besides its well-known psychoactive effects, caffeine has a broad range of actions. It regulates several physiological mechanisms as well as modulates both native and adaptive immune responses by various ways. Although caffeine is assumed to be a negative regulator of inflammation, the effect on the secretion of pro- and anti-inflammatory cytokines is highly controversial. Macrophages are major mediators of inflammatory responses; however, the various subpopulations develop different effects ranging from the initiation to the resolution of inflammation. Here we report a comparative analysis of the effect of caffeine on two subpopulations of human monocyte-derived macrophages differentiated in the presence of macrophage colony-stimulating factor (M-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), resulting in M-MΦs and GM-MΦs, respectively. We showed that although TNF-α secretion was downregulated in both LPS-activated MΦ subtypes by caffeine, the secretion of IL-8, IL-6, and IL-1β as well as the expression of Nod-like receptors was enhanced in M-MΦs, while it did not change in GM-MΦs. We showed that caffeine (1) altered adenosine receptor expression, (2) changed Akt/AMPK/mTOR signaling pathways, and (3) inhibited STAT1/IL-10 signaling axis in M-MΦs. We hypothesized that these alterations play an important modulatory role in the upregulation of NLRP3 inflammasome-mediated IL-1β secretion in LPS-activated M-MΦs following caffeine treatment.
Collapse
Affiliation(s)
- Elek Gergő Kovács
- Departments of Physiology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, Hungary; (E.G.K.); (A.A.); (M.M.B.); (E.B.)
- Doctoral School of Molecular Cellular and Immune Biology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, Hungary
| | - Ahmad Alatshan
- Departments of Physiology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, Hungary; (E.G.K.); (A.A.); (M.M.B.); (E.B.)
- Doctoral School of Molecular Cellular and Immune Biology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, Hungary
| | - Marietta Margit Budai
- Departments of Physiology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, Hungary; (E.G.K.); (A.A.); (M.M.B.); (E.B.)
- Departments of Immunology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, Hungary
| | - Zsolt Czimmerer
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, H-4032 Debrecen, Hungary;
| | - Eduárd Bíró
- Departments of Physiology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, Hungary; (E.G.K.); (A.A.); (M.M.B.); (E.B.)
- Doctoral School of Molecular Cellular and Immune Biology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, Hungary
| | - Szilvia Benkő
- Departments of Physiology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, Hungary; (E.G.K.); (A.A.); (M.M.B.); (E.B.)
- Doctoral School of Molecular Cellular and Immune Biology, Faculty of Medicine, University of Debrecen, H-4012 Debrecen, Hungary
| |
Collapse
|
|
46
|
Cui ZY, Wang G, Zhang J, Song J, Jiang YC, Dou JY, Lian LH, Nan JX, Wu YL. Parthenolide, bioactive compound of Chrysanthemum parthenium L., ameliorates fibrogenesis and inflammation in hepatic fibrosis via regulating the crosstalk of TLR4 and STAT3 signaling pathway. Phytother Res 2021; 35:5680-5693. [PMID: 34250656 DOI: 10.1002/ptr.7214] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 05/21/2021] [Accepted: 06/19/2021] [Indexed: 01/05/2023]
Abstract
The current study focused on the regulatory effects of parthenolide (PNL), a bioactive component derived from Chrysanthemum parthenium L., against hepatic fibrosis via regulating the crosstalk of toll-like receptor 4 (TLR4) and signal transducer and activator of transcription 3 (STAT3) in activated hepatic stellate cells (HSCs). HSCs or Raw 264.7 macrophages were activated by TGF-β or LPS for 1 hr, respectively, and then treated with PNL, CLI-095 (TLR4 inhibitor), or Niclosamide (STAT3 inhibitor) for the indicated time to detect the crosstalk of TLR4 and STAT3. PNL significantly decreased the expressions of α-SMA, collagen I, and the ratio of TIMP1 and MMP13 in TGF-β-activated HSCs. PNL significantly reduced the releases of pro-inflammatory cytokines, including IL-6, IL-1β, IL-1α, IL-18, and regulated signaling P2X7r/NLRP3 axis activation. PNL obviously induced the apoptosis of activated HSCs by regulating bcl-2 and caspases family. PNL significantly inhibited the expressions of TLR4 and STAT3, including their downstream signaling. PNL could regulate the crosstalk of TLR4 and STAT3, which were verified by their inhibitors in activated HSCs or Raw 264.7 cell macrophages. Thus, PNL could decrease the expressions of fibrosis markers, reduce the releases of inflammatory cytokines, and also induce the apoptosis of activated HSCs. In conclusion, PNL could bi-directionally inhibit TLR4 and STAT3 signaling pathway, suggesting that blocking the crosstalk of TLR4 and STAT3 might be the potential mechanism of PNL against hepatic fibrosis.
Collapse
Affiliation(s)
- Zhen-Yu Cui
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Ge Wang
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Jing Zhang
- Research and Development Center, Liaoning Shengjing Stem cell technology Co., Ltd, Shenyang, China
| | - Jian Song
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Yu-Chen Jiang
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Jia-Yi Dou
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Li-Hua Lian
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Ji-Xing Nan
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.,Clinical Research Centre, Affiliated Hospital of Yanbian University, Yanji, China
| | - Yan-Ling Wu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| |
Collapse
|
|
47
|
Asl SS, Jalili C, Artimani T, Ramezani M, Mirzaei F. Inflammasome can Affect Adult Neurogenesis: A Review Article. Open Neurol J 2021. [DOI: 10.2174/1874205x02115010025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Adult neurogenesis is the process of producing new neurons in the adult brain and is limited to two major areas: the hippocampal dentate gyrus and the Subventricular Zone (SVZ). Adult neurogenesis is affected by some physiological, pharmacological, and pathological factors. The inflammasome is a major signalling platform that regulates caspase-1 and induces proinflammatory cytokines production such as interleukin-1β (IL1-β) and IL-18.
Inflammasomes may be stimulated through multiple signals, and some of these signaling factors can affect neurogenesis. In the current review, “adult neurogenesis and inflammasome” were searched in PubMed, Scopus, and Google Scholar. Reviewing various research works showed correlations between inflammasome and neurogenesis by different intermediate factors, such as interferons (IFN), interleukins (IL), α-synuclein, microRNAs, and natural compounds. Concerning the significant role of neurogenesis in the health of the nervous system and memory, understanding factors inducing neurogenesis is crucial for identifying new therapeutic aims. Hence in this review, we will discuss the different mechanisms by which inflammasome influences adult neurogenesis.
Collapse
|
|
48
|
Ohm RG, Mulumba M, Chingle RM, Ahsanullah, Zhang J, Chemtob S, Ong H, Lubell WD. Diversity-Oriented A 3-Macrocyclization for Studying Influences of Ring-Size and Shape of Cyclic Peptides: CD36 Receptor Modulators. J Med Chem 2021; 64:9365-9380. [PMID: 34161728 DOI: 10.1021/acs.jmedchem.1c00642] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Cyclic peptide diversity has been broadened by elaborating the A3-macrocyclization to include various di-amino carboxylate components with different Nε-amine substituents. Triple-bond reduction provided new cyclic peptide macrocycles with Z-olefin and completely saturated structures. Moreover, cyclic azasulfurylpeptides were prepared by exchanging the propargylglycine (Pra) component for an amino sulfamide surrogate. Examination of such diversity-oriented methods on potent cyclic azapeptide modulators of the cluster of differentiation 36 receptor (CD36) identified the importance of the triple bond as well as the Nε-allyl lysine and azaPra residues for high CD36 binding affinity. Cyclic azapeptides which engaged CD36 effectively reduced pro-inflammatory nitric oxide and downstream cytokine and chemokine production in macrophages stimulated with a Toll-like receptor-2 agonist. Studying the triple bond and amine components in the multiple-component A3-macrocyclization has given a diverse array of macrocycles and pertinent information to guide the development of ideal CD36 modulators with biomedical potential for curbing macrophage-driven inflammation.
Collapse
Affiliation(s)
- Ragnhild G Ohm
- Département de Chimie, Université de Montréal, C.P. 6128, Succursale, Centre-Ville, Montréal, Québec H3C 3J7, Canada
| | - Mukandila Mulumba
- Faculté de Pharmacie, Université de Montréal, C.P. 6128, Succursale, Centre-Ville, Montréal, Québec H3C 3J7, Canada
| | - Ramesh M Chingle
- Département de Chimie, Université de Montréal, C.P. 6128, Succursale, Centre-Ville, Montréal, Québec H3C 3J7, Canada
| | - Ahsanullah
- Département de Chimie, Université de Montréal, C.P. 6128, Succursale, Centre-Ville, Montréal, Québec H3C 3J7, Canada
| | - Jinqiang Zhang
- Département de Chimie, Université de Montréal, C.P. 6128, Succursale, Centre-Ville, Montréal, Québec H3C 3J7, Canada
| | - Sylvain Chemtob
- Département de Pédiatrie, Université de Montréal, C.P. 6128, Succursale, Centre-Ville, Montréal, Québec H3C 3J7, Canada
| | - Huy Ong
- Faculté de Pharmacie, Université de Montréal, C.P. 6128, Succursale, Centre-Ville, Montréal, Québec H3C 3J7, Canada
| | - William D Lubell
- Département de Chimie, Université de Montréal, C.P. 6128, Succursale, Centre-Ville, Montréal, Québec H3C 3J7, Canada
| |
Collapse
|
|
49
|
Khan A, Johnson R, Wittmer C, Maile M, Tatsukawa K, Wong JL, Gill MB, Stocking EM, Natala SR, Paulino AD, Bowden-Verhoek JK, Wrasidlo W, Masliah E, Bonhaus DW, Price DL. NPT520-34 improves neuropathology and motor deficits in a transgenic mouse model of Parkinson's disease. Brain 2021; 144:3692-3709. [PMID: 34117864 DOI: 10.1093/brain/awab214] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 04/12/2021] [Accepted: 05/11/2021] [Indexed: 12/09/2022] Open
Abstract
NPT520-34 is a clinical-stage, small molecule being developed for the treatment of Parkinson's disease and other neurodegenerative disorders. The therapeutic potential of NPT520-34 was first suggested by findings from cell-based assays of alpha-synuclein (ASYN) clearance. As reported here, NPT520-34 was subsequently evaluated for therapeutically relevant actions in a transgenic animal model of Parkinson's disease that overexpresses human ASYN and in an acute lipopolysaccharide (LPS)-challenge model using wild-type mice. Daily administration of NPT520-34 to mThy1-ASYN (Line 61) transgenic mice for one or three months resulted in reduced ASYN pathology, reduced expression of markers of neuroinflammation, and improvements in multiple indices of motor function. In an LPS-challenge model using wild-type mice, a single-dose of NPT520-34 reduced LPS-evoked increases in the expression of several pro-inflammatory cytokines in plasma. These findings demonstrate the beneficial effects of NPT520-34 on both inflammation and protein-pathology endpoints, with consequent improvements in motor function in an animal model of Parkinson's disease. These findings further suggest that NPT520-34 may have two complementary actions: (1) to increase the clearance of neurotoxic protein aggregates and (2) to directly attenuate inflammation. NPT520-34 treatment may thereby address two of the predominate underlying pathophysiological aspects of neurodegenerative disorders such as Parkinson's disease.
Collapse
Affiliation(s)
- Asma Khan
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Robert Johnson
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Carrie Wittmer
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Michelle Maile
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Keith Tatsukawa
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Julian L Wong
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Martin B Gill
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Emily M Stocking
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Srinivasa R Natala
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Amy D Paulino
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Jon K Bowden-Verhoek
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Wolfgang Wrasidlo
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Eliezer Masliah
- Departments of Neuroscience and Pathology, University of California, San Diego, La Jolla, CA 92093, USA
| | - Douglas W Bonhaus
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| | - Diana L Price
- Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121, USA
| |
Collapse
|
|
50
|
Dexmedetomidine attenuates lipopolysaccharide-induced acute liver injury in rats by inhibiting caveolin-1 downstream signaling pathway. Biosci Rep 2021; 41:227822. [PMID: 33558888 PMCID: PMC7938455 DOI: 10.1042/bsr20204279] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/07/2021] [Accepted: 02/08/2021] [Indexed: 12/27/2022] Open
Abstract
Objective: The aim of the present study is to investigate the anti-injury and anti-inflammatory effects of dexmedetomidine (Dex) in acute liver injury induced by lipopolysaccharide (LPS) in Sprague–Dawley rats and its possible mechanism. Methods: The acute liver injury model of male rats was established by injecting LPS into tail vein. The mean arterial pressure (MAP) of rats was recorded at 0–7 h, and lactic acid was detected at different time points. Wet/dry weight ratio (W/D) was calculated. Pathological changes of rat liver were observed by HE staining. ALT and AST levels in serum were detected. The activities of myeloperoxidase (MPO) and superoxide dismutase (SOD) in liver tissue homogenate and the levels of IL-1β and IL-18 in serum were detected by ELISA. Protein levels of Caveolin-1 (Cav-1), TLR-4 and NLRP3 in liver tissue were tested by immunohistochemistry method. The expression of Cav-1, TLR-4 and NLRP3 mRNA in liver tissue was detected by quantitative polymerase chain reaction (qPCR) to explore its related mechanism. Results: Compared with NS group, serum lactic acid, W/D of liver tissue, MPO, SOD, IL-1β and IL-18 were significantly increased and MAP decreased significantly in LPS group and D+L group. However, compared with NS group, D group showed no significant difference in various indicators. Compared with LPS group, MPO, SOD, IL-1β and IL-18 were significantly decreased and MAP was significantly increased in D+L group. D+L group could significantly increase the level of Cav-1 protein and decrease the level of TLR-4 and NLRP3 protein in liver tissue caused by sepsis. The expression of Cav-1 mRNA was significantly up-regulated and the expression of TLR-4 and NLRP3 mRNA was inhibited in D+L group. Conclusion: Dex pretreatment protects against LPS-induced actue liver injury via inhibiting the activation of the NLRP3 signaling pathway by up-regulating the expression of Cav-1 by sepsis.
Collapse
|