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Sheneman KR, Cummins TD, Merchant ML, Hood JL, Uriarte SM, Lawrenz MB. Yersinia pestis Actively Inhibits the Production of Extracellular Vesicles by Human Neutrophils. J Extracell Vesicles 2025; 14:e70074. [PMID: 40240908 PMCID: PMC12003101 DOI: 10.1002/jev2.70074] [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: 12/17/2024] [Accepted: 03/23/2025] [Indexed: 04/18/2025] Open
Abstract
Yersinia pestis is the etiologic agent of the plague. A hallmark of plague is subversion of the host immune response by disrupting host signalling pathways required for inflammation. This non-inflammatory environment permits bacterial colonization and has been shown to be essential for disease manifestation. Previous work has shown that Y. pestis inhibits phagocytosis and degranulation by neutrophils. Manipulation of these key vesicular trafficking pathways suggests that Y. pestis influences extracellular vesicle (EV) secretion, cargo selection, trafficking and/or maturation. Our goals were to define the EV population produced by neutrophils in response to Y. pestis and determine how these vesicles might influence inflammation. Towards these goals, EVs were isolated from human neutrophils infected with Y. pestis or a mutant lacking bacterial effector proteins known to manipulate host cell signalling. Mass spectrometry data revealed that cargoes packaged in EVs isolated from mutant infected cells were enriched with antimicrobial and cytotoxic proteins, contents which differed from uninfected and Y. pestis infected cells. Further, EVs produced in response to Y. pestis lacked inflammatory properties observed in those isolated from neutrophils responding to the mutant. Together, these data demonstrate that Y. pestis actively inhibits the production of antimicrobial EVs produced by neutrophils, likely contributing to immune evasion.
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Affiliation(s)
- Katelyn R. Sheneman
- Department of Microbiology and ImmunologyUniversity of LouisvilleLouisvilleKentuckyUSA
| | - Timothy D. Cummins
- Department of Medicine and Proteomics Technology CenterUniversity of LouisvilleLouisvilleKentuckyUSA
| | - Michael L. Merchant
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKentuckyUSA
| | - Joshua L. Hood
- Department of Pharmacology and ToxicologyUniversity of LouisvilleLouisvilleKentuckyUSA
- Hepatobiology and Toxicology COBREUniversity of LouisvilleLouisvilleKentuckyUSA
| | - Silvia M. Uriarte
- Department of Oral Immunology & Infectious DiseaseUniversity of LouisvilleLouisvilleKentuckyUSA
| | - Matthew B. Lawrenz
- Department of Microbiology and ImmunologyUniversity of LouisvilleLouisvilleKentuckyUSA
- Center for Predictive Medicine for Biodefense and Emerging Infectious DiseasesUniversity of LouisvilleLouisvilleKentuckyUSA
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2
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Beesetti S. Ubiquitin Ligases in Control: Regulating NLRP3 Inflammasome Activation. FRONT BIOSCI-LANDMRK 2025; 30:25970. [PMID: 40152367 DOI: 10.31083/fbl25970] [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: 08/02/2024] [Revised: 09/04/2024] [Accepted: 09/11/2024] [Indexed: 03/29/2025]
Abstract
Ubiquitin ligases play pivotal roles in the regulation of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, a critical process in innate immunity and inflammatory responses. This review explores the intricate mechanisms by which various E3 ubiquitin ligases exert both positive and negative influences on NLRP3 inflammasome activity through diverse post-translational modifications. Negative regulation of NLRP3 inflammasome assembly is mediated by several E3 ligases, including F-box and leucine-rich repeat protein 2 (FBXL2), tripartite motif-containing protein 31 (TRIM31), and Casitas B-lineage lymphoma b (Cbl-b), which induce K48-linked ubiquitination of NLRP3, targeting it for proteasomal degradation. Membrane-associated RING-CH 7 (MARCH7) similarly promotes K48-linked ubiquitination leading to autophagic degradation, while RING finger protein (RNF125) induces K63-linked ubiquitination to modulate NLRP3 function. Ariadne homolog 2 (ARIH2) targets the nucleotide-binding domain (NBD) domain of NLRP3, inhibiting its activation, and tripartite motif-containing protein (TRIM65) employs dual K48 and K63-linked ubiquitination to suppress inflammasome assembly. Conversely, Pellino2 exemplifies a positive regulator, promoting NLRP3 inflammasome activation through K63-linked ubiquitination. Additionally, ubiquitin ligases influence other components critical for inflammasome function. TNF receptor-associated factor 3 (TRAF3) mediates K63 polyubiquitination of apoptosis-associated speck-like protein containing a CARD (ASC), facilitating its degradation, while E3 ligases regulate caspase-1 activation and DEAH-box helicase 33 (DHX33)-NLRP3 complex formation through specific ubiquitination events. Beyond direct inflammasome regulation, ubiquitin ligases impact broader innate immune signaling pathways, modulating pattern-recognition receptor responses and dendritic cell maturation. Furthermore, they intricately control NOD1/NOD2 signaling through K63-linked polyubiquitination of receptor-interacting protein 2 (RIP2), crucial for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) activation. Furthermore, we explore how various pathogens, including bacteria, viruses, and parasites, have evolved sophisticated strategies to hijack the host ubiquitination machinery, manipulating NLRP3 inflammasome activation to evade immune responses. This comprehensive analysis provides insights into the molecular mechanisms underlying inflammasome regulation and their implications for inflammatory diseases, offering potential avenues for therapeutic interventions targeting the NLRP3 inflammasome. In conclusion, ubiquitin ligases emerge as key regulators of NLRP3 inflammasome activation, exhibiting a complex array of functions that finely tune immune responses. Understanding these regulatory mechanisms not only sheds light on fundamental aspects of inflammation but also offers potential therapeutic avenues for inflammatory disorders and infectious diseases.
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Affiliation(s)
- Swarna Beesetti
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN 38105, USA
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3
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Zhang B, Orning P, Lehman JW, Dinis A, Torres-Ulloa L, Elling R, Kelliher MA, Bertin J, Proulx MK, Goguen JD, Ryan L, Kandasamy RK, Espevik T, Pai AA, Fitzgerald KA, Lien E. Raver1 links Ripk1 RNA splicing to caspase-8-mediated pyroptotic cell death, inflammation, and pathogen resistance. Proc Natl Acad Sci U S A 2025; 122:e2420802122. [PMID: 39946533 PMCID: PMC11848402 DOI: 10.1073/pnas.2420802122] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 01/08/2025] [Indexed: 02/19/2025] Open
Abstract
Multiple cell death and inflammatory signaling pathways converge on two critical factors: receptor-interacting serine/threonine kinase 1 (RIPK1) and caspase-8. Careful regulation of these molecules is critical to control apoptosis, pyroptosis, and inflammation. Here, we found a pivotal role of Raver1 as an essential regulator of Ripk1 pre-mRNA splicing, expression, and functionality and the subsequent caspase-8-dependent inflammatory cell death. We show that Raver1 influences mRNA diversity primarily by repressing alternative exon inclusion. Macrophages from Raver1-deficient mice exhibit altered splicing of Ripk1. As a result, Raver1-deficient primary macrophages display diminished cell death and decreased interleukin-18 and interleukin-1ß production, when infected with Yersinia bacteria, or by restraining TGF-ß-activated kinase 1 or IKKβ in the presence of lipopolysaccharide, tumor necrosis factor family members, or interferon-γ. These responses are accompanied by reduced activation of caspase-8, Gasdermin D and E, and caspase-1 in the absence of Raver1. Consequently, Raver1-deficient mice showed heightened susceptibility to Yersinia infection. Raver1 and RIPK1 also controlled the expression and function of the C-type lectin receptor Mincle. Our study underscores the critical regulatory role of Raver1 in modulating innate immune responses and highlights its significance in directing in vivo and in vitro inflammatory processes.
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Affiliation(s)
- Boyao Zhang
- Division of Infectious Diseases and Immunology, Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA01605
| | - Pontus Orning
- Division of Infectious Diseases and Immunology, Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA01605
- Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim7491, Norway
| | - Jesse W. Lehman
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA01655
| | - Alexandre Dinis
- Division of Infectious Diseases and Immunology, Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA01605
| | - Leslie Torres-Ulloa
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA01655
| | - Roland Elling
- Institute for Immunodeficiency, Center of Chronic Immunodeficiency, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg79106, Germany
- Institute for Immunodeficiency, Center for Pediatrics and Adolescent Medicine University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg79106, Germany
| | - Michelle A. Kelliher
- Department of Molecular Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA01605
| | - John Bertin
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA19426
- Sanofi, Immunology and Inflammation Research Therapeutic Area, Cambridge, MA02141
| | - Megan K. Proulx
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA01655
| | - Jon D. Goguen
- Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA01655
| | - Liv Ryan
- Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim7491, Norway
| | - Richard K. Kandasamy
- Division of Infectious Diseases and Immunology, Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA01605
- Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim7491, Norway
- Department of Laboratory Medicine and Pathology, Center for Individualized Medicine, Mayo Clinic, Rochester, MN55905
| | - Terje Espevik
- Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim7491, Norway
- Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim7006, Norway
| | - Athma A. Pai
- RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA01655
| | - Katherine A. Fitzgerald
- Division of Infectious Diseases and Immunology, Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA01605
- Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim7491, Norway
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA01605
| | - Egil Lien
- Division of Infectious Diseases and Immunology, Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA01605
- Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim7491, Norway
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Sheneman KR, Cummins TD, Merchant ML, Hood JL, Uriarte SM, Lawrenz MB. Yersinia pestis actively inhibits the production of extracellular vesicles by human neutrophils. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.20.629761. [PMID: 39763979 PMCID: PMC11702605 DOI: 10.1101/2024.12.20.629761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Yersinia pestis is the etiologic agent of the plague. A hallmark of plague is subversion of the host immune response by disrupting host signaling pathways required for inflammation. This non-inflammatory environment permits bacterial colonization and has been shown to be essential for disease manifestation. Previous work has shown that Y. pestis inhibits phagocytosis and degranulation by neutrophils. Manipulation of these key vesicular trafficking pathways suggests that Y. pestis influences EV secretion, cargo selection, trafficking, and/or maturation. Our goal was to define the EV population produced by neutrophils in response to Y. pestis and determine how these vesicles might influence inflammation. Toward these goals, EVs were isolated from human neutrophils infected with Y. pestis or a mutant lacking bacterial effector proteins known to manipulate host cell signaling. Mass spectrometry data revealed that cargoes packaged in EVs isolated from mutant infected cells were enriched with antimicrobials and cytotoxic proteins, contents which differed from uninfected and Y. pestis infected cells. Further, EVs produced in response to Y. pestis lacked inflammatory properties observed in those isolated from neutrophils responding to the mutant. Together, these data demonstrate that Y. pestis actively inhibits the production of antimicrobial EVs produced by neutrophils, likely contributing to immune evasion.
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Affiliation(s)
| | - Timothy D Cummins
- Department of Medicine and Proteomics Technology Center, University of Louisville
| | | | - Joshua L Hood
- Department of Pharmacology and Toxicology, University of Louisville
- Hepatobiology and Toxicology COBRE, University of Louisville
| | - Silvia M Uriarte
- Department of Oral Immunology & Infectious Disease, University of Louisville
| | - Matthew B Lawrenz
- Department of Microbiology and Immunology, University of Louisville
- Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville
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Seabaugh JA, Anderson DM. Pathogenicity and virulence of Yersinia. Virulence 2024; 15:2316439. [PMID: 38389313 PMCID: PMC10896167 DOI: 10.1080/21505594.2024.2316439] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 02/04/2024] [Indexed: 02/24/2024] Open
Abstract
The genus Yersinia includes human, animal, insect, and plant pathogens as well as many symbionts and harmless bacteria. Within this genus are Yersinia enterocolitica and the Yersinia pseudotuberculosis complex, with four human pathogenic species that are highly related at the genomic level including the causative agent of plague, Yersinia pestis. Extensive laboratory, field work, and clinical research have been conducted to understand the underlying pathogenesis and zoonotic transmission of these pathogens. There are presently more than 500 whole genome sequences from which an evolutionary footprint can be developed that details shared and unique virulence properties. Whereas the virulence of Y. pestis now seems in apparent homoeostasis within its flea transmission cycle, substantial evolutionary changes that affect transmission and disease severity continue to ndergo apparent selective pressure within the other Yersiniae that cause intestinal diseases. In this review, we will summarize the present understanding of the virulence and pathogenesis of Yersinia, highlighting shared mechanisms of virulence and the differences that determine the infection niche and disease severity.
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Affiliation(s)
- Jarett A. Seabaugh
- Department of Veterinary Pathobiology, University of Missouri, Columbia, USA
| | - Deborah M. Anderson
- Department of Veterinary Pathobiology, University of Missouri, Columbia, USA
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Zhang B, Orning P, Lehman JW, Dinis A, Torres-Ulloa L, Elling R, Kelliher MA, Bertin J, Proulx MK, Ryan L, Kandasamy R, Espevik T, Pai AA, Fitzgerald KA, Lien E. Raver1 links Ripk1 RNA splicing to caspase-8-mediated pyroptotic cell death, inflammation, and pathogen resistance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.27.625707. [PMID: 39651143 PMCID: PMC11623576 DOI: 10.1101/2024.11.27.625707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2024]
Abstract
Multiple cell death and inflammatory signaling pathways converge on two critical factors: receptor interacting serine/threonine kinase 1 (RIPK1) and caspase-8. Careful regulation of these molecules is critical to control apoptosis, pyroptosis and inflammation. Here we discovered a pivotal role of Raver1 as an essential regulator of Ripk1 pre-mRNA splicing, expression, and functionality, and the subsequent caspase-8-dependent inflammatory cell death. Macrophages from Raver1 -deficient mice exhibit altered splicing of Ripk1 , accompanied by diminished cell death and reduced activation of caspase-8, Gasdermin D and E, caspase-1, as well as decreased interleukin-18 (IL-18) and IL-1ß production. These effects were triggered by Yersinia bacteria, or by restraining TAK1 or IKKβ in the presence of LPS, TNF family members, or IFNγ. Consequently, animals lacking Raver1 showed heightened susceptibility to Yersinia infection. Raver1 and RIPK1 also controlled the expression and function of the C-type lectin receptor Mincle. Our study underscores the critical regulatory role of Raver1 in modulating innate immune responses and highlights its significance in directing in vivo and in vitro inflammatory processes. Significance Caspase-8 and the kinase RIPK1 are at focal points of several inflammation and cell death pathways. Thus, a careful regulation of their actions is needed. Our work identifies the RNA splicing factor Raver1 as a critical factor directing the splicing of Ripk1 in order to modulate RIPK1/caspase-8-driven pyroptosis, apoptosis and inflammation. Raver1 is central for macrophage responses to Yersinia bacteria, initiated after blockade of kinases TAK1 and IKK, measured as activation of RIPK1, caspase-8, Gasdermin D, caspase-3, IL-1ß and IL-18. Importantly, Raver1 is necessary for host resistance to Yersinia infection in vivo . We propose that Raver1 is key for correct tuning of RIPK1-caspase-8 dependent processes.
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Wertman RS, Yost W, Herrmann BI, Bourne CM, Sorobetea D, Go CK, Saller BS, Groß O, Scott P, Rongvaux A, Taabazuing CY, Brodsky IE. Distinct sequential death complexes regulate pyroptosis and IL-1β release in response to Yersinia blockade of immune signaling. SCIENCE ADVANCES 2024; 10:eadl3629. [PMID: 39058785 PMCID: PMC11277400 DOI: 10.1126/sciadv.adl3629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 06/25/2024] [Indexed: 07/28/2024]
Abstract
Pathogen infection of host cells triggers an inflammatory cell death termed pyroptosis via activation of inflammatory caspases. However, blockade of immune signaling kinases by the Yersinia virulence factor YopJ triggers cell death involving both apoptotic caspase-8 and pyroptotic caspase-1. While caspase-1 is normally activated within inflammasomes, Yersinia-induced caspase-1 activation is independent of known inflammasome components. We report that caspase-8 is an essential initiator, while caspase-1 is an essential amplifier of its own activation through two feed-forward loops involving caspase-1 auto-processing and caspase-1-dependent activation of gasdermin D and NLPR3. Notably, while Yersinia-induced caspase-1 activation and cell death are inflammasome-independent, IL-1β release requires NLPR3 inflammasome activation. Mechanistically, caspase-8 is rapidly activated within multiple foci throughout the cell, followed by assembly of a canonical inflammasome speck, indicating that caspase-8 and canonical inflammasome complex assemblies are kinetically and spatially distinct. Our findings reveal that functionally interconnected but distinct death complexes mediate pyroptosis and IL-1β release in response to pathogen blockade of immune signaling.
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Affiliation(s)
- Ronit Schwartz Wertman
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Winslow Yost
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Beatrice I. Herrmann
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Christopher M. Bourne
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Daniel Sorobetea
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Christina K. Go
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Benedikt S. Saller
- Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany
- Faculty of Biology, University of Freiburg, Freiburg 79106, Germany
| | - Olaf Groß
- Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg 79106, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg 79106, Germany
| | - Phillip Scott
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
| | - Anthony Rongvaux
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA
- Department of Immunology, University of Washington, Seattle, WA 98195, USA
| | - Cornelius Y. Taabazuing
- Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Igor E. Brodsky
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA
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Farag SI, Francis MK, Gurung JM, Wai SN, Stenlund H, Francis MS, Nadeem A. Macrophage innate immune responses delineate between defective translocon assemblies produced by Yersinia pseudotuberculosis YopD mutants. Virulence 2023; 14:2249790. [PMID: 37621095 PMCID: PMC10461508 DOI: 10.1080/21505594.2023.2249790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 06/11/2023] [Accepted: 08/13/2023] [Indexed: 08/26/2023] Open
Abstract
Translocon pores formed in the eukaryotic cell membrane by a type III secretion system facilitate the translocation of immune-modulatory effector proteins into the host cell interior. The YopB and YopD proteins produced and secreted by pathogenic Yersinia spp. harboring a virulence plasmid-encoded type III secretion system perform this pore-forming translocator function. We had previously characterized in vitro T3SS function and in vivo pathogenicity of a number of strains encoding sited-directed point mutations in yopD. This resulted in the classification of mutants into three different classes based upon the severity of the phenotypic defects. To investigate the molecular and functional basis for these defects, we explored the effectiveness of RAW 264.7 cell line to respond to infection by representative YopD mutants of all three classes. Signature cytokine profiles could separate the different YopD mutants into distinct categories. The activation and suppression of certain cytokines that function as central innate immune response modulators correlated well with the ability of mutant bacteria to alter anti-phagocytosis and programmed cell death pathways. These analyses demonstrated that sub-optimal translocon pores impact the extent and magnitude of host cell responsiveness, and this limits the capacity of pathogenic Yersinia spp. to fortify against attack by both early and late arms of the host innate immune response.
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Affiliation(s)
- Salah I. Farag
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden
| | - Monika K. Francis
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden
| | - Jyoti M. Gurung
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden
| | - Sun Nyunt Wai
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden
- The Laboratory for Molecular Infection Medicine Sweden, Umeå University, Umeå, Sweden
| | - Hans Stenlund
- Department of Plant Physiology, Umeå Plant Science Centre (UPSC), Umeå University, Umeå, Sweden
- Swedish Metabolomics Centre (SMC), Umeå, Sweden
| | - Matthew S. Francis
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden
| | - Aftab Nadeem
- Department of Molecular Biology, Umeå University, Umeå, Sweden
- Umeå Centre for Microbial Research, Umeå University, Umeå, Sweden
- The Laboratory for Molecular Infection Medicine Sweden, Umeå University, Umeå, Sweden
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Wertman RS, Go CK, Saller BS, Groß O, Scott P, Brodsky IE. Sequentially activated death complexes regulate pyroptosis and IL-1β release in response to Yersinia blockade of immune signaling. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.14.557714. [PMID: 37745613 PMCID: PMC10515920 DOI: 10.1101/2023.09.14.557714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Abstract
The Yersinia virulence factor YopJ potently inhibits immune signaling in macrophages by blocking activation of the signaling kinases TAK1 and IKK. In response, macrophages trigger a backup pathway of host defense that mediates cell death via the apoptotic enzyme caspase-8 and pyroptotic enzyme caspase-1. While caspase-1 is normally activated within multiprotein inflammasome complexes that contain the adaptor ASC and NLRs, which act as sensors of pathogen virulence, caspase-1 activation following Yersinia blockade of TAK1/IKK surprisingly requires caspase-8 and is independent of all known inflammasome components. Here, we report that caspase-1 activation by caspase-8 requires both caspase-8 catalytic and auto-processing activity. Intriguingly, while caspase-8 serves as an essential initiator of caspase-1 activation, caspase-1 amplifies its own activation through a feed-forward loop involving auto-processing, caspase-1-dependent cleavage of the pore-forming protein GSDMD, and subsequent activation of the canonical NLRP3 inflammasome. Notably, while caspase-1 activation and cell death are independent of inflammasomes during Yersinia infection, IL-1β release requires the canonical NLPR3 inflammasome. Critically, activation of caspase-8 and activation of the canonical inflammasome are kinetically and spatially separable events, as rapid capase-8 activation occurs within multiple foci throughout the cell, followed by delayed subsequent assembly of a single canonical inflammasome. Importantly, caspase-8 auto-processing normally serves to prevent RIPK3/MLKL-mediated necroptosis, and in caspase-8's absence, MLKL triggers NLPR3 inflammasome activation and IL-1β release. Altogether, our findings reveal that functionally interconnected but temporally and spatially distinct death complexes differentially mediate pyroptosis and IL-1β release to ensure robust host defense against pathogen blockade of TAK1 and IKK.
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Affiliation(s)
- Ronit Schwartz Wertman
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA 19104
| | - Christina K. Go
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA 19104
| | - Benedikt S. Saller
- Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany 79106
- Faculty of Biology, University of Freiburg, Freiburg, Germany 79106
| | - Olaf Groß
- Institute of Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany 79106
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany 79106
| | - Phillip Scott
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA 19104
| | - Igor E. Brodsky
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA 19104
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10
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Wu H, Qian D, Bai X, Sun S. Targeted Pyroptosis Is a Potential Therapeutic Strategy for Cancer. JOURNAL OF ONCOLOGY 2022; 2022:2515525. [PMID: 36467499 PMCID: PMC9715319 DOI: 10.1155/2022/2515525] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 10/21/2022] [Accepted: 11/15/2022] [Indexed: 12/01/2023]
Abstract
As a type of regulated cell death (RCD) mode, pyroptosis plays an important role in several kinds of cancers. Pyroptosis is induced by different stimuli, whose pathways are divided into the canonical pathway and the noncanonical pathway depending on the formation of the inflammasomes. The canonical pathway is triggered by the assembly of inflammasomes, and the activation of caspase-1 and then the cleavage of effector protein gasdermin D (GSDMD) are promoted. While in the noncanonical pathway, the caspase-4/5/11 (caspase 4/5 in humans and caspase 11 in mice) directly cleave GSDMD without the assembly of inflammasomes. Pyroptosis is involved in various cancers, such as lung cancer, gastric cancer, hepatic carcinoma, breast cancer, and colorectal carcinoma. Pyroptosis in gastric cancer, hepatic carcinoma, breast cancer, and colorectal carcinoma is related to the canonical pathway, while both the canonical and noncanonical pathway participate in lung cancer. Moreover, simvastatin, metformin, and curcumin have effect on these cancers and simultaneously promote the pyroptosis of cancer cells. Accordingly, pyroptosis may be an important therapeutic target for cancer.
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Affiliation(s)
- Hao Wu
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
- Clinical Medicine, Three Class, 2020 Grade, Kunming Medical University, Kunming, China
| | - Dianlun Qian
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Xiangfeng Bai
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Kunming Medical University, Kunming, China
| | - Shibo Sun
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, China
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Abstract
Despite the maintenance of YopP/J alleles throughout the human-pathogenic Yersinia lineage, the benefit of YopP/J-induced phagocyte death for Yersinia pathogenesis in animals is not obvious. To determine how the sequence divergence of YopP/J has impacted Yersinia virulence, we examined protein polymorphisms in this type III secreted effector protein across 17 Yersinia species and tested the consequences of polymorphism in a murine model of subacute systemic yersiniosis. Our evolutionary analysis revealed that codon 177 has been subjected to positive selection; the Yersinia enterocolitica residue had been altered from a leucine to a phenylalanine in nearly all Yersinia pseudotuberculosis and Yersinia pestis strains examined. Despite this change being minor, as both leucine and phenylalanine have hydrophobic side chains, reversion of YopJF177 to the ancestral YopJL177 variant yielded a Y. pseudotuberculosis strain with enhanced cytotoxicity toward macrophages, consistent with previous findings. Surprisingly, expression of YopJF177L in the mildly attenuated ksgA- background rendered the strain completely avirulent in mice. Consistent with this hypothesis that YopJ activity relates indirectly to Yersinia pathogenesis in vivo, ksgA- strains lacking functional YopJ failed to kill macrophages but actually regained virulence in animals. Also, treatment with the antiapoptosis drug suramin prevented YopJ-mediated macrophage cytotoxicity and enhanced Y. pseudotuberculosis virulence in vivo. Our results demonstrate that Yersinia-induced cell death is detrimental for bacterial pathogenesis in this animal model of illness and indicate that positive selection has driven YopJ/P and Yersinia evolution toward diminished cytotoxicity and increased virulence, respectively.
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Jofre BL, Eliçabe RJ, Silva JE, Pérez Sáez JM, Paez MD, Callegari E, Mariño KV, Di Genaro MS, Rabinovich GA, Davicino RC. Galectin-1 Cooperates with Yersinia Outer Protein (Yop) P to Thwart Protective Immunity by Repressing Nitric Oxide Production. Biomolecules 2021; 11:1636. [PMID: 34827634 PMCID: PMC8615707 DOI: 10.3390/biom11111636] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/26/2021] [Accepted: 10/29/2021] [Indexed: 11/18/2022] Open
Abstract
Yersinia enterocolitica (Ye) inserts outer proteins (Yops) into cytoplasm to infect host cells. However, in spite of considerable progress, the mechanisms implicated in this process, including the association of Yops with host proteins, remain unclear. Here, we evaluated the functional role of Galectin-1 (Gal1), an endogenous β-galactoside-binding protein, in modulating Yop interactions with host cells. Our results showed that Gal1 binds to Yops in a carbohydrate-dependent manner. Interestingly, Gal1 binding to Yops protects these virulence factors from trypsin digestion. Given that early control of Ye infection involves activation of macrophages, we evaluated the role of Gal1 and YopP in the modulation of macrophage function. Although Gal1 and YopP did not influence production of superoxide anion and/or TNF by Ye-infected macrophages, they coordinately inhibited nitric oxide (NO) production. Notably, recombinant Gal1 (rGal1) did not rescue NO increase observed in Lgals1-/- macrophages infected with the YopP mutant Ye ∆yopP. Whereas NO induced apoptosis in macrophages, no significant differences in cell death were detected between Gal1-deficient macrophages infected with Ye ∆yopP, and WT macrophages infected with Ye wt. Strikingly, increased NO production was found in WT macrophages treated with MAPK inhibitors and infected with Ye wt. Finally, rGal1 administration did not reverse the protective effect in Peyer Patches (PPs) of Lgals1-/- mice infected with Ye ∆yopP. Our study reveals a cooperative role of YopP and endogenous Gal1 during Ye infection.
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Affiliation(s)
- Brenda Lucila Jofre
- División de Inmunología, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis CP5700, Argentina; (B.L.J.); (R.J.E.); (J.E.S.); (M.S.D.G.)
- Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Luis C5700, Argentina
| | - Ricardo Javier Eliçabe
- División de Inmunología, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis CP5700, Argentina; (B.L.J.); (R.J.E.); (J.E.S.); (M.S.D.G.)
- Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Luis C5700, Argentina
| | - Juan Eduardo Silva
- División de Inmunología, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis CP5700, Argentina; (B.L.J.); (R.J.E.); (J.E.S.); (M.S.D.G.)
- Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Luis C5700, Argentina
| | - Juan Manuel Pérez Sáez
- Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires C1428ADN, Argentina; (J.M.P.S.); (G.A.R.)
| | - Maria Daniela Paez
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 66544, USA; (M.D.P.); (E.C.)
| | - Eduardo Callegari
- Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 66544, USA; (M.D.P.); (E.C.)
| | - Karina Valeria Mariño
- Laboratorio de Glicómica Funcional y Molecular, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires C1428ADN, Argentina;
| | - María Silvia Di Genaro
- División de Inmunología, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis CP5700, Argentina; (B.L.J.); (R.J.E.); (J.E.S.); (M.S.D.G.)
- Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Luis C5700, Argentina
| | - Gabriel Adrián Rabinovich
- Laboratorio de Glicomedicina, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (IBYME-CONICET), Buenos Aires C1428ADN, Argentina; (J.M.P.S.); (G.A.R.)
- Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires C1428, Argentina
| | - Roberto Carlos Davicino
- División de Inmunología, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, San Luis CP5700, Argentina; (B.L.J.); (R.J.E.); (J.E.S.); (M.S.D.G.)
- Instituto Multidisciplinario de Investigaciones Biológicas (IMIBIO), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Luis C5700, Argentina
- Roberto Davicino, División de Inmunología, Facultad de Química, Bioquímica y Farmacia, Universidad Nacional de San Luis, Ejercito de los Andes 950, San Luis CP5700, Argentina
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Mohammadi M, Abdi M, Alidadi M, Mohamed W, Zibara K, Ragerdi Kashani I. Medroxyprogesterone acetate attenuates demyelination, modulating microglia activation, in a cuprizone neurotoxic demyelinating mouse model. AMERICAN JOURNAL OF NEURODEGENERATIVE DISEASE 2021; 10:57-68. [PMID: 34824899 PMCID: PMC8610806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Accepted: 10/15/2021] [Indexed: 06/13/2023]
Abstract
Clinical data reported a reduction of Multiple sclerosis (MS) symptoms during pregnancy when progesterone levels are high. Medroxyprogesterone acetate (MPA) is a synthetic progestin contraceptive with unknown neuroprotective effects. This study investigated the effect of a contraceptive dose of MPA on microglia polarization and neuroinflammation in the neurotoxic cuprizone (CPZ)-induced demyelinating mouse model of MS. Mice received 1 mg of MPA weekly, achieving similar serum concentrations in human contraceptive users. Results revealed that MPA therapy significantly reduced the demyelination in the corpus callosum. In addition, MPA treatment induced a significant reduction in microglia M1-markers (iNOS, IL-1β and TNF-α) while M2-markers (Arg-1, IL-10 and TGF-β) were significantly increased. Moreover, MPA resulted in a significant decrease in the number of iNOS positive cells (M1), whereas TREM-2 positive cells (M2) significantly increased. Furthermore, MPA decreased the protein expression levels of NF-κB and NLRP3 inflammasome as well as mRNA expression levels of the downstream product IL-18. In summary, MPA reduces the level of demyelination and has an anti-inflammatory role in CNS demyelination by inducing M2 microglia polarization and suppressing the M1 phenotype through the inhibition of NF-κB and NLRP3 inflammasome. Our results suggest that MPA should be a suitable contraceptive pharmacological agent in demyelinating diseases.
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Affiliation(s)
- Maryam Mohammadi
- Department of Anatomy, School of Medicine, Tehran University of Medical SciencesTehran, Iran
| | - Mahdad Abdi
- Department of Anatomy, School of Medicine, Tehran University of Medical SciencesTehran, Iran
| | - Mehdi Alidadi
- Department of Anatomy, School of Medicine, Tehran University of Medical SciencesTehran, Iran
| | - Wael Mohamed
- Department of Basic Medical Science, Kulliyyah of Medicine, International Islamic University MalaysiaKuantan, Pahang, Malaysia
- Clinical Pharmacology Department, Menoufia Medical SchoolMenoufia, Egypt
| | - Kazem Zibara
- PRASE and Biology Department, Faculty of Sciences, Lebanese UniversityBeirut, Lebanon
| | - Iraj Ragerdi Kashani
- Department of Anatomy, School of Medicine, Tehran University of Medical SciencesTehran, Iran
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14
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Ma S, Zhang H, Xu J. Characterization, Antioxidant and Anti-Inflammation Capacities of Fermented Flammulina velutipes Polyphenols. Molecules 2021; 26:molecules26206205. [PMID: 34684784 PMCID: PMC8537206 DOI: 10.3390/molecules26206205] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/04/2022] Open
Abstract
This work investigated the preparation, characterization, antioxidant, and anti-inflammation capacities of Flammulina velutipes polyphenols (FVP) and fermented FVP (FFVP). The results revealed that the new syringic acid, accounting for 22.22%, was obtained after fermentation (FFVP). FFVP exhibits higher antioxidant and anti-inflammation activities than FVP, enhancing cell viability and phagocytosis, inhibiting the secretion of NO and ROS, and reducing the inflammatory response of RAW264.7 cells. This study revealed that FFVP provides a theoretical reference for in-depth study of its regulatory mechanisms and further development of functional antioxidants that are applicable in the food and health industry.
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Affiliation(s)
- Sheng Ma
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200436, China;
- Shanghai Key Laboratory for Veterinary and Biotechnology, Shanghai 200436, China
| | - Hongcai Zhang
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200436, China;
- Shanghai Key Laboratory for Veterinary and Biotechnology, Shanghai 200436, China
- Correspondence: (H.Z.); (J.X.)
| | - Jianxiong Xu
- School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200436, China;
- Shanghai Key Laboratory for Veterinary and Biotechnology, Shanghai 200436, China
- Correspondence: (H.Z.); (J.X.)
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15
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Che LH, Liu JW, Huo JP, Luo R, Xu RM, He C, Li YQ, Zhou AJ, Huang P, Chen YY, Ni W, Zhou YX, Liu YY, Li HY, Zhou R, Mo H, Li JM. A single-cell atlas of liver metastases of colorectal cancer reveals reprogramming of the tumor microenvironment in response to preoperative chemotherapy. Cell Discov 2021; 7:80. [PMID: 34489408 PMCID: PMC8421363 DOI: 10.1038/s41421-021-00312-y] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 07/18/2021] [Indexed: 02/08/2023] Open
Abstract
Metastasis is the primary cause of cancer-related mortality in colorectal cancer (CRC) patients. How to improve therapeutic options for patients with metastatic CRC is the core question for CRC treatment. However, the complexity and diversity of stromal context of the tumor microenvironment (TME) in liver metastases of CRC have not been fully understood, and the influence of stromal cells on response to chemotherapy is unclear. Here we performed an in-depth analysis of the transcriptional landscape of primary CRC, matched liver metastases and blood at single-cell resolution, and a systematic examination of transcriptional changes and phenotypic alterations of the TME in response to preoperative chemotherapy (PC). Based on 111,292 single-cell transcriptomes, our study reveals that TME of treatment-naïve tumors is characterized by the higher abundance of less-activated B cells and higher heterogeneity of tumor-associated macrophages (TAMs). By contrast, in tumors treated with PC, we found activation of B cells, lower diversity of TAMs with immature and less activated phenotype, lower abundance of both dysfunctional T cells and ECM-remodeling cancer-associated fibroblasts, and an accumulation of myofibroblasts. Our study provides a foundation for future investigation of the cellular mechanisms underlying liver metastasis of CRC and its response to PC, and opens up new possibilities for the development of therapeutic strategies for CRC.
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Affiliation(s)
- Li-Heng Che
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jing-Wen Liu
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jian-Ping Huo
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Rong Luo
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Rui-Ming Xu
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Cai He
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yu-Qing Li
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Ai-Jun Zhou
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Piao Huang
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yong-Yu Chen
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Wen Ni
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yun-Xia Zhou
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yuan-Yuan Liu
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Hui-Yan Li
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Rong Zhou
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Hui Mo
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jian-Ming Li
- Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China.
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Hajra D, Nair AV, Chakravortty D. An elegant nano-injection machinery for sabotaging the host: Role of Type III secretion system in virulence of different human and animal pathogenic bacteria. Phys Life Rev 2021; 38:25-54. [PMID: 34090822 DOI: 10.1016/j.plrev.2021.05.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 05/23/2021] [Indexed: 01/22/2023]
Abstract
Various Gram-negative bacteria possess a specialized membrane-bound protein secretion system known as the Type III secretion system (T3SS), which transports the bacterial effector proteins into the host cytosol thereby helping in bacterial pathogenesis. The T3SS has a special needle-like translocon that can sense the contact with the host cell membrane and translocate effectors. The export apparatus of T3SS recognizes these effector proteins bound to chaperones and translocates them into the host cell. Once in the host cell cytoplasm, these effector proteins result in modulation of the host system and promote bacterial localization and infection. Using molecular biology, bioinformatics, genetic techniques, electron microscopic studies, and mathematical modeling, the structure and function of the T3SS and the corresponding effector proteins in various bacteria have been studied. The strategies used by different human pathogenic bacteria to modulate the host system and thereby enhance their virulence mechanism using T3SS have also been well studied. Here we review the history, evolution, and general structure of the T3SS, highlighting the details of its comparison with the flagellar export machinery. Also, this article provides mechanistic details about the common role of T3SS in subversion and manipulation of host cellular processes. Additionally, this review describes specific T3SS apparatus and the role of their specific effectors in bacterial pathogenesis by considering several human and animal pathogenic bacteria.
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Affiliation(s)
- Dipasree Hajra
- Department of Microbiology & Cell Biology, Indian Institute of Science, India
| | - Abhilash Vijay Nair
- Department of Microbiology & Cell Biology, Indian Institute of Science, India
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Zhong J, Yu R, Zhou Q, Liu P, Liu Z, Bian Y. Naringenin prevents TNF-α-induced gut-vascular barrier disruption associated with inhibiting the NF-κB-mediated MLCK/p-MLC and NLRP3 pathways. Food Funct 2021; 12:2715-2725. [PMID: 33667286 DOI: 10.1039/d1fo00155h] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The microvasculature endothelium accurately regulates the passage of molecules across the gut-vascular barrier (GVB), which plays an essential role in intestinal immunity. Naringenin is reported to have therapeutic potential against several intestinal disorders. However, the effect of naringenin on GVB disruption has been rarely studied. This study aims to investigate the effect of naringenin on GVB function and the potential mechanism. In the present study, the in vitro GVB disruption of rat intestinal microvascular endothelial cells (RIMVEC) was induced by 50 ng mL-1 of tumor necrosis factor-α (TNF-α). The integrity of the in vitro GVB was determined by Evans blue (EB)-albumin efflux assay and trans-endothelial electrical resistance (TER). Meanwhile, the expression of tight junction proteins and the related NF-κB, MLCK/p-MLC and NLRP3 pathways were determined using enzyme-linked immunosorbent assay (ELISA), real-time quantitative polymerase chain reaction (RT-qPCR), western blot analysis and immunofluorescence. The results show that naringenin (100 μM) inhibits TNF-α-induced interleukin (IL)-6 hypersecretion, alleviates GVB disruption and mitigates the change in the tight junction protein expression pattern. Naringenin inhibits the GVB-disruption-associated activation of the MLCK/p-MLC system and TLR4/NF-κB/NLRP3 pathways. Furthermore, naringenin shows a similar effect to that of NF-κB inhibitor Bay 11-7082 in reducing the TNF-α-induced activation of NLRP3, p-MLC and secondary GVB disruption. The results suggest that naringenin evidently alleviates TNF-α-induced in vitro GVB disruption via the maintenance of a tight junction protein pattern, partly with the inhibition of the NF-κB-mediated MLCK/p-MLC and NLRP3 pathway activation.
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Affiliation(s)
- Jia Zhong
- Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P. R. China.
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18
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Modification of the Pulmonary MyD88 Inflammatory Response Underlies the Role of the Yersinia pestis Pigmentation Locus in Primary Pneumonic Plague. Infect Immun 2021; 89:IAI.00595-20. [PMID: 33257532 DOI: 10.1128/iai.00595-20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 11/17/2020] [Indexed: 01/28/2023] Open
Abstract
Pneumonic plague, caused by Yersinia pestis, is a rapidly progressing bronchopneumonia involving focal bacterial growth, neutrophilic congestion, and alveolar necrosis. Within a short time after inhalation of Y. pestis, inflammatory cytokines are expressed via the Toll/interleukin-1 (IL-1) adaptor myeloid differentiation primary response 88 (MyD88), which facilitates the primary lung infection. We previously showed that Y. pestis lacking the 102-kb chromosomal pigmentation locus (pgm) is unable to cause inflammatory damage in the lungs, whereas the wild-type (WT) strain induces the toxic MyD88 pulmonary inflammatory response. In this work, we investigated the involvement of the pgm in skewing the inflammatory response during pneumonic plague. We show that the early MyD88-dependent and -independent cytokine responses to pgm- Y. pestis infection of the lungs are similar yet distinct from those that occur during pgm+ infection. Furthermore, we found that MyD88 was necessary to prevent growth of the iron-starved pgm- Y. pestis despite the presence of iron chelators lactoferrin and transferrin. However, while this induced neutrophil recruitment, there was no hyperinflammatory response, and pulmonary disease was mild without MyD88. In contrast, growth in blood and tissues progressed rapidly in the absence of MyD88, due to an almost total loss of serum interferon gamma (IFN-γ). We further show that the expression of MyD88 by myeloid cells is important to control bacteremia but not the primary lung infection. The combined data indicate distinct roles for myeloid and nonmyeloid MyD88 and suggest that expression of the pgm is necessary to skew the inflammatory response in the lungs to cause pneumonic plague.
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Lang L, Xu B, Yuan J, Li S, Lian S, Chen Y, Guo J, Yang H. GABA-mediated activated microglia induce neuroinflammation in the hippocampus of mice following cold exposure through the NLRP3 inflammasome and NF-κB signaling pathways. Int Immunopharmacol 2020; 89:106908. [PMID: 33166810 DOI: 10.1016/j.intimp.2020.106908] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/25/2020] [Accepted: 08/15/2020] [Indexed: 01/26/2023]
Abstract
Chronic cold stress has long-term dramatic effects on the animal immune and neuroendocrine systems. As one of the important regions of the brain, the hippocampus is the main region involved in response to stressors. Nevertheless, the impact to the hippocampus following cold exposure and the underlying mechanism involved are not clear. To evaluate the response of the hippocampus during chronic cold stress, male C57BL/6 mice were exposed to 4 °C, 3 h per day for 1 week, after which neuroinflammation and the molecular and signaling pathways in the hippocampus response to cold stress were investigated. To confirm the potential mechanism, BV2 cells were treated with γ-aminobutyric acid (GABA) and BAY 11-7082 and MCC950, then the activation of microglia and key proteins involved in the regulation of inflammation were measured. We demonstrated that chronic cold stress induced the activation of microglia, the emergence of neuroinflammation, and the impairment of neurons in the hippocampus, which might be the result of GABA-mediated activation of nod-like receptor protein 3 (NLRP3) inflammasome and the nuclear factor kappa B (NF-κB) signaling pathway.
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Affiliation(s)
- Limin Lang
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, No. 5 Xinfeng Road, Sartu District, Daqing 163319, PR China
| | - Bin Xu
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, No. 5 Xinfeng Road, Sartu District, Daqing 163319, PR China
| | - Jianbin Yuan
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, No. 5 Xinfeng Road, Sartu District, Daqing 163319, PR China
| | - Shize Li
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, No. 5 Xinfeng Road, Sartu District, Daqing 163319, PR China
| | - Shuai Lian
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, No. 5 Xinfeng Road, Sartu District, Daqing 163319, PR China
| | - Yan Chen
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, No. 5 Xinfeng Road, Sartu District, Daqing 163319, PR China
| | - Jingru Guo
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, No. 5 Xinfeng Road, Sartu District, Daqing 163319, PR China.
| | - Huanmin Yang
- Heilongjiang Provincial Key Laboratory of Prevention and Control of Bovine Diseases, College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, No. 5 Xinfeng Road, Sartu District, Daqing 163319, PR China.
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Difference in Strain Pathogenicity of Septicemic Yersinia pestis Infection in a TLR2 -/- Mouse Model. Infect Immun 2020; 88:IAI.00792-19. [PMID: 31907194 DOI: 10.1128/iai.00792-19] [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: 10/05/2019] [Accepted: 12/16/2019] [Indexed: 11/20/2022] Open
Abstract
Yersinia pestis is the causative agent of bubonic, pneumonic, and septicemic plague. We demonstrate that Toll-like receptor 2-deficient (TLR2-/-) mice are resistant to septicemic infection by the KIM5 strain of Y. pestis but not to infection by the CO92 Δpgm strain. This resistance is dependent on TLR2, the route of infection, and the isoform of YopJ. Elevated bacterial burdens were found in the spleens of CO92 Δpgm-infected animals by 24 h postinfection and in the livers by 4 days. The YopJ isoform present contributed directly to cytotoxicity and inflammatory cytokine production of bone marrow-derived macrophages from TLR2-/- mice. Immune cell trafficking is altered in CO92 Δpgm infections, with an increased neutrophil infiltration to the spleen 5 days postinfection. Immune cell infiltration to the liver was greater and earlier in KIM5-infected TLR2-/- mice. The functionality of the immune cells was assessed by the ability to develop reactive oxygen and nitrogen species. Our data suggest an inhibition of granulocytes in forming these species in CO92 Δpgm-infected TLR2-/- mice. These findings suggest that resistance to KIM5 in TLR2-/- mice is dependent on early immune cell trafficking and functionality.
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Redundant and Cooperative Roles for Yersinia pestis Yop Effectors in the Inhibition of Human Neutrophil Exocytic Responses Revealed by Gain-of-Function Approach. Infect Immun 2020; 88:IAI.00909-19. [PMID: 31871100 DOI: 10.1128/iai.00909-19] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 12/16/2019] [Indexed: 12/13/2022] Open
Abstract
Yersinia pestis causes a rapid, lethal disease referred to as plague. Y. pestis actively inhibits the innate immune system to generate a noninflammatory environment during early stages of infection to promote colonization. The ability of Y. pestis to create this early noninflammatory environment is in part due to the action of seven Yop effector proteins that are directly injected into host cells via a type 3 secretion system (T3SS). While each Yop effector interacts with specific host proteins to inhibit their function, several Yop effectors either target the same host protein or inhibit converging signaling pathways, leading to functional redundancy. Previous work established that Y. pestis uses the T3SS to inhibit neutrophil respiratory burst, phagocytosis, and release of inflammatory cytokines. Here, we show that Y. pestis also inhibits release of granules in a T3SS-dependent manner. Moreover, using a gain-of-function approach, we discovered previously hidden contributions of YpkA and YopJ to inhibition and that cooperative actions by multiple Yop effectors are required to effectively inhibit degranulation. Independent from degranulation, we also show that multiple Yop effectors can inhibit synthesis of leukotriene B4 (LTB4), a potent lipid mediator released by neutrophils early during infection to promote inflammation. Together, inhibition of these two arms of the neutrophil response likely contributes to the noninflammatory environment needed for Y. pestis colonization and proliferation.
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22
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Teng JF, Mei QB, Zhou XG, Tang Y, Xiong R, Qiu WQ, Pan R, Law BYK, Wong VKW, Yu CL, Long HA, Xiao XL, Zhang F, Wu JM, Qin DL, Wu AG. Polyphyllin VI Induces Caspase-1-Mediated Pyroptosis via the Induction of ROS/NF-κB/NLRP3/GSDMD Signal Axis in Non-Small Cell Lung Cancer. Cancers (Basel) 2020; 12:193. [PMID: 31941010 PMCID: PMC7017302 DOI: 10.3390/cancers12010193] [Citation(s) in RCA: 244] [Impact Index Per Article: 48.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Revised: 01/08/2020] [Accepted: 01/10/2020] [Indexed: 12/24/2022] Open
Abstract
Trillium tschonoskii Maxim (TTM), a traditional Chinese medicine, has been demonstrated to have a potent anti-tumor effect. Recently, polyphyllin VI (PPVI), a main saponin isolated from TTM, was reported by us to significantly suppress the proliferation of non-small cell lung cancer (NSCLC) via the induction of apoptosis and autophagy in vitro and in vivo. In this study, we further found that the NLRP3 inflammasome was activated in PPVI administrated A549-bearing athymic nude mice. As is known to us, pyroptosis is an inflammatory form of caspase-1-dependent programmed cell death that plays an important role in cancer. By using A549 and H1299 cells, the in vitro effect and action mechanism by which PPVI induces activation of the NLRP3 inflammasome in NSCLC were investigated. The anti-proliferative effect of PPVI in A549 and H1299 cells was firstly measured and validated by MTT assay. The activation of the NLRP3 inflammasome was detected by using Hoechst33324/PI staining, flow cytometry analysis and real-time live cell imaging methods. We found that PPVI significantly increased the percentage of cells with PI signal in A549 and H1299, and the dynamic change in cell morphology and the process of cell death of A549 cells indicated that PPVI induced an apoptosis-to-pyroptosis switch, and, ultimately, lytic cell death. In addition, belnacasan (VX-765), an inhibitor of caspase-1, could remarkably decrease the pyroptotic cell death of PPVI-treated A549 and H1299 cells. Moreover, by detecting the expression of NLRP3, ASC, caspase-1, IL-1β, IL-18 and GSDMD in A549 and h1299 cells using Western blotting, immunofluorescence imaging and flow cytometric analysis, measuring the caspase-1 activity using colorimetric assay, and quantifying the cytokines level of IL-1β and IL-18 using ELISA, the NLRP3 inflammasome was found to be activated in a dose manner, while VX-765 and necrosulfonamide (NSA), an inhibitor of GSDMD, could inhibit PPVI-induced activation of the NLRP3 inflammasome. Furthermore, the mechanism study found that PPVI could activate the NF-κB signaling pathway via increasing reactive oxygen species (ROS) levels in A549 and H1299 cells, and N-acetyl-L-cysteine (NAC), a scavenger of ROS, remarkably inhibited the cell death, and the activation of NF-κB and the NLRP3 inflammasome in PPVI-treated A549 and H1299 cells. Taken together, these data suggested that PPVI-induced, caspase-1-mediated pyroptosis via the induction of the ROS/NF-κB/NLRP3/GSDMD signal axis in NSCLC, which further clarified the mechanism of PPVI in the inhibition of NSCLC, and thereby provided a possibility for PPVI to serve as a novel therapeutic agent for NSCLC in the future.
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Affiliation(s)
- Jin-Feng Teng
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
| | - Qi-Bing Mei
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
| | - Xiao-Gang Zhou
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
| | - Yong Tang
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
| | - Rui Xiong
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
| | - Wen-Qiao Qiu
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
| | - Rong Pan
- Department of Human Anatomy, School of Preclinical Medicine, Southwest Medical University, Luzhou 646000, China; (R.P.); (C.-L.Y.)
| | - Betty Yuen-Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (B.Y.-K.L.); (V.K.-W.W.)
| | - Vincent Kam-Wai Wong
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China; (B.Y.-K.L.); (V.K.-W.W.)
| | - Chong-Lin Yu
- Department of Human Anatomy, School of Preclinical Medicine, Southwest Medical University, Luzhou 646000, China; (R.P.); (C.-L.Y.)
| | - Han-An Long
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
| | - Xiu-Li Xiao
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
| | - Feng Zhang
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
| | - Jian-Ming Wu
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
- Education Ministry Key Laboratory of Medical Electrophysiology, Southwest Medical University, Luzhou 646000, China
| | - Da-Lian Qin
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
- Education Ministry Key Laboratory of Medical Electrophysiology, Southwest Medical University, Luzhou 646000, China
| | - An-Guo Wu
- Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, School of Pharmacy, Southwest Medical University, Luzhou 646000, China; (J.-F.T.); (Q.-B.M.); (X.-G.Z.); (Y.T.); (R.X.); (W.-Q.Q.); (F.Z.); (D.-L.Q.)
- Education Ministry Key Laboratory of Medical Electrophysiology, Southwest Medical University, Luzhou 646000, China
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23
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Dai MY, Chen FF, Wang Y, Wang MZ, Lv YX, Liu RY. Particulate matters induce acute exacerbation of allergic airway inflammation via the TLR2/NF-κB/NLRP3 signaling pathway. Toxicol Lett 2019; 321:146-154. [PMID: 31836503 DOI: 10.1016/j.toxlet.2019.12.013] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 12/07/2019] [Accepted: 12/10/2019] [Indexed: 12/23/2022]
Abstract
BACKGROUND Exposure to particulate matters (PMs) can lead to an acute exacerbation of allergic airway diseases, increasing the severity of symptoms and mortality. However, little is known about the underlying molecular mechanism. This study aimed to investigate the effects of PMs on acute exacerbation of allergic airway inflammation and seek potential therapeutic targets. METHODS Non-allergic control and ovalbumin (OVA)-allergic wide-type (WT) and Toll-like receptor 2 knockout (Tlr2-/-) mice were exposed to 100 μg of PM (diameter 5.85 μm) or saline by the oropharyngeal instillation. The responses were examined three days after exposure. In the RAW264.7 macrophage cell line, Tlr2 was knocked down by small-interfering RNA or the NF-κB inhibitor JSH-23 was used, and then the cells were stimulated with PMs for 12 h before comparison of the inflammatory responses. RESULTS PM exposure led to increased inflammatory cell recruitment and airway intensity of PAS + staining in OVA-allergic WT mice, accompanied with an accumulation of inflammatory cells and elevated inflammatory cytokines, such as IL-6 and IL-18, in the bronchoalveolar lavage fluid (BALF). Furthermore, the protein levels of TLR2 and the NLRP3 inflammasome were elevated concomitantly with the airway inflammation post-OVA/PMs challenge. Tlr2 deficiency effectively inhibited the airway inflammation, including pulmonary inflammatory cell recruitment, mucus secretion, serum OVA-specific immunoglobulin E (IgE), and BALF inflammatory cytokine production. Additionally, the P-induced NLRP3 activation in the RAW 264.7 cell line was diminished by the knockdown of Tlr2 or JSH-23 treatment in vitro. CONCLUSION Our results indicated that PMs exacerbate the allergic airway inflammation mediated by the TLR2/ NF-κB/NLRP3 signaling pathway. Inhibition of NF-κB seems to be a possible treatment.
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Affiliation(s)
- Meng-Yuan Dai
- Department of Respiratory and Critical Care, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Department of Geriatric Respiratory and Critical Care, Provincial Key Laboratory of Molecular Medicine for Geriatric Disease, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Fang-Fang Chen
- Department of Geriatric Respiratory and Critical Care, Provincial Key Laboratory of Molecular Medicine for Geriatric Disease, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yong Wang
- Department of Respiratory and Critical Care, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Mu-Zi Wang
- Department of Geriatric Respiratory and Critical Care, Provincial Key Laboratory of Molecular Medicine for Geriatric Disease, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yun-Xiang Lv
- Department of Geriatric Respiratory and Critical Care, Provincial Key Laboratory of Molecular Medicine for Geriatric Disease, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Rong-Yu Liu
- Department of Respiratory and Critical Care, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China; Department of Geriatric Respiratory and Critical Care, Provincial Key Laboratory of Molecular Medicine for Geriatric Disease, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
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24
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Zhou Z, Li H, Tian S, Yi W, Zhou Y, Yang H, Li X, Wu B, Li X, Wu J, Wang Z, Hu S, Fang R. Critical roles of NLRP3 inflammasome in IL-1β secretion induced by Corynebacterium pseudotuberculosis in vitro. Mol Immunol 2019; 116:11-17. [PMID: 31563023 DOI: 10.1016/j.molimm.2019.09.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 08/01/2019] [Accepted: 09/14/2019] [Indexed: 12/19/2022]
Abstract
Corynebacterium pseudotuberculosis is a prominent human and animal pathogen causing chronic inflammatory diseases. Interleukin-1β (IL-1β) is involved in the response to such pathogenic infections. However, the mechanism by which IL-1β is secreted during C. pseudotuberculosis infection remains unclear. This study aimed to investigate the mechanism underlying IL-1β secretion by macrophages infected with C. pseudotuberculosis. Herein, we firstly revealed that nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC) and caspase-1 (Casp1) play critical roles in IL-1β secretion rather than IL-1β precursor (pro-IL-1β) expression in C. pseudotuberculosis-infected macrophages. Toll like receptor 4 (TLR4) is partially involved in IL-1β secretion, while absent in melanoma 2 (AIM2) is not involved in IL-1β secretion by C. pseudotuberculosis-infected macrophages. In addition, nuclear factor kappa B (NF-κB) and p38 mitogen-activated protein kinases (p38 MAPK) inhibitors almost attenuated IL-1β secretion, implying that NF-κB and p38MAPK pathway are involved in IL-1β secretion in C. pseudotuberculosis-infected macrophages. Furthermore, C. pseudotuberculosis were significantly more numerous in Nlrp3-/-, Asc-/-, and Casp-1-/- macrophages than in WT macrophages at 24 h after infection (P < 0.05), indicating that NLRP3 inflammasome components limit C. pseudotuberculosis replication in macrophages. Together, these data provide novel insights into the mechanisms underlying IL-1β secretion in C. pseudotuberculosis-infected macrophages and further the current understanding of the host pro-inflammatory immune response against this pathogen.
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Affiliation(s)
- Zuoyong Zhou
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China; Veterinary Science Engineering Research Center of Chongqing, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Hexian Li
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Shangquan Tian
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Wenyi Yi
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Yang Zhou
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China; Veterinary Science Engineering Research Center of Chongqing, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Haoyue Yang
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Xiao Li
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Bi Wu
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Xiaoxia Li
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Junjun Wu
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Zhiying Wang
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China; Veterinary Science Engineering Research Center of Chongqing, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Shijun Hu
- College of Animal Science, Rongchang Campus of Southwest University, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China; Veterinary Science Engineering Research Center of Chongqing, No. 160 Xueyuan Road, Rongchang District, Chongqing, 402460, China.
| | - Rendong Fang
- College of Animal Science and Technology, Southwest University, No. 2 Tiansheng Road, Beibei District, Chongqing, 400715, China.
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25
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Tartey S, Kanneganti TD. Differential role of the NLRP3 inflammasome in infection and tumorigenesis. Immunology 2019; 156:329-338. [PMID: 30666624 DOI: 10.1111/imm.13046] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2019] [Indexed: 12/13/2022] Open
Abstract
Dysregulated inflammation is one of the hallmarks of cancer initiation and progression. Emerging evidence indicates that inflammasomes play a central role in regulating immune cell functions in various infections and cancer. Inflammasomes are multimeric complexes consisting of nucleotide-binding oligomerization domain (NOD) -like receptors (NLRs). Among the NLRs, NOD1, NOD2 and NLRP3 respond to a variety of endogenous (i.e. damage-associated molecular patterns) and exogenous (i.e. pathogen-associated molecular patterns) stimuli. The NLRP3 inflammasome is associated with the onset and progression of autoinflammatory and autoimmune diseases, including metabolic disorders, multiple sclerosis, inflammatory bowel disease, and cryopyrin-associated periodic fever syndrome. NLRP3 is also associated with a wide variety of infections and tumorigenesis that are closely correlated with chemotherapy response and prognosis. In this review, we explore the rapidly expanding body of research on the expression and functions of NLRP3 in infections and cancers and outline novel inhibitors targeting the NLRP3 inflammasome that could be developed as therapeutic alternatives to current anticancer treatment.
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Affiliation(s)
- Sarang Tartey
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
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26
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Bastedo DP, Lo T, Laflamme B, Desveaux D, Guttman DS. Diversity and Evolution of Type III Secreted Effectors: A Case Study of Three Families. Curr Top Microbiol Immunol 2019; 427:201-230. [DOI: 10.1007/82_2019_165] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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27
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Orning P, Weng D, Starheim K, Ratner D, Best Z, Lee B, Brooks A, Xia S, Wu H, Kelliher MA, Berger SB, Gough PJ, Bertin J, Proulx MM, Goguen JD, Kayagaki N, Fitzgerald KA, Lien E. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science 2018; 362:1064-1069. [PMID: 30361383 DOI: 10.1126/science.aau2818] [Citation(s) in RCA: 747] [Impact Index Per Article: 106.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 10/17/2018] [Indexed: 12/12/2022]
Abstract
Limited proteolysis of gasdermin D (GSDMD) generates an N-terminal pore-forming fragment that controls pyroptosis in macrophages. GSDMD is processed via inflammasome-activated caspase-1 or -11. It is currently unknown whether macrophage GSDMD can be processed by other mechanisms. Here, we describe an additional pathway controlling GSDMD processing. The inhibition of TAK1 or IκB kinase (IKK) by the Yersinia effector protein YopJ elicits RIPK1- and caspase-8-dependent cleavage of GSDMD, which subsequently results in cell death. GSDMD processing also contributes to the NLRP3 inflammasome-dependent release of interleukin-1β (IL-1β). Thus, caspase-8 acts as a regulator of GSDMD-driven cell death. Furthermore, this study establishes the importance of TAK1 and IKK activity in the control of GSDMD cleavage and cytotoxicity.
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Affiliation(s)
- Pontus Orning
- Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.,Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Dan Weng
- Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.,Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing 210094, China
| | - Kristian Starheim
- Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.,Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Dmitry Ratner
- Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Zachary Best
- Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Bettina Lee
- Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA
| | - Alexandria Brooks
- Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Shiyu Xia
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA
| | - Hao Wu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA
| | - Michelle A Kelliher
- Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Scott B Berger
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA
| | - Peter J Gough
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA
| | - John Bertin
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-inflammation Therapeutic Area, GlaxoSmithKline, Collegeville, PA 19426, USA
| | - Megan M Proulx
- Department of Microbiology and Physiology, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - Jon D Goguen
- Department of Microbiology and Physiology, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - Nobuhiko Kayagaki
- Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA
| | - Katherine A Fitzgerald
- Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA.,Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
| | - Egil Lien
- Program in Innate Immunity, Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA 01605, USA. .,Centre of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway
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28
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Arifuzzaman M, Ang WXG, Choi HW, Nilles ML, St John AL, Abraham SN. Necroptosis of infiltrated macrophages drives Yersinia pestis dispersal within buboes. JCI Insight 2018; 3:122188. [PMID: 30232285 DOI: 10.1172/jci.insight.122188] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 08/07/2018] [Indexed: 12/18/2022] Open
Abstract
When draining lymph nodes become infected by Yersinia pestis (Y. pestis), a massive influx of phagocytic cells occurs, resulting in distended and necrotic structures known as buboes. The bubonic stage of the Y. pestis life cycle precedes septicemia, which is facilitated by trafficking of infected mononuclear phagocytes through these buboes. However, how Y. pestis convert these immunocytes recruited by host to contain the pathogen into vehicles for bacterial dispersal and the role of immune cell death in this context are unknown. We show that the lymphatic spread requires Yersinia outer protein J (YopJ), which triggers death of infected macrophages by downregulating a suppressor of receptor-interacting protein kinase 1-mediated (RIPK1-mediated) cell death programs. The YopJ-triggered cell death was identified as necroptotic, which released intracellular bacteria, allowing them to infect new neighboring cell targets. Dying macrophages also produced chemotactic sphingosine 1-phosphate, enhancing cell-to-cell contact, further promoting infection. This necroptosis-driven expansion of infected macrophages in buboes maximized the number of bacteria-bearing macrophages reaching secondary lymph nodes, leading to sepsis. In support, necrostatins confined bacteria within macrophages and protected mice from lethal infection. These findings define necrotization of buboes as a mechanism for bacterial spread and a potential target for therapeutic intervention.
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Affiliation(s)
| | | | - Hae Woong Choi
- Department of Pathology, Duke University, Durham, North Carolina, USA
| | - Matthew L Nilles
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota, USA
| | - Ashley L St John
- Department of Pathology, Duke University, Durham, North Carolina, USA.,Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore, Singapore
| | - Soman N Abraham
- Department of Molecular Genetics and Microbiology and.,Department of Pathology, Duke University, Durham, North Carolina, USA.,Program in Emerging Infectious Diseases, Duke-National University of Singapore, Singapore, Singapore.,Department of Immunology, Duke University, Durham, North Carolina, USA
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Liu BC, Sarhan J, Panda A, Muendlein HI, Ilyukha V, Coers J, Yamamoto M, Isberg RR, Poltorak A. Constitutive Interferon Maintains GBP Expression Required for Release of Bacterial Components Upstream of Pyroptosis and Anti-DNA Responses. Cell Rep 2018; 24:155-168.e5. [PMID: 29972777 PMCID: PMC6063733 DOI: 10.1016/j.celrep.2018.06.012] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 03/19/2018] [Accepted: 06/01/2018] [Indexed: 12/12/2022] Open
Abstract
Legionella pneumophila elicits caspase-11-driven macrophage pyroptosis through guanylate-binding proteins (GBPs) encoded on chromosome 3. It has been proposed that microbe-driven IFN upregulates GBPs to facilitate pathogen vacuole rupture and bacteriolysis preceding caspase-11 activation. We show here that macrophage death occurred independently of microbial-induced IFN signaling and that GBPs are dispensable for pathogen vacuole rupture. Instead, the host-intrinsic IFN status sustained sufficient GBP expression levels to drive caspase-1 and caspase-11 activation in response to cytosol-exposed bacteria. In addition, endogenous GBP levels were sufficient for the release of DNA from cytosol-exposed bacteria, preceding the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway for Ifnb induction. Mice deficient for chromosome 3 GBPs were unable to mount a rapid IL-1/chemokine (C-X-C motif) ligand 1 (CXCL1) response during Legionella-induced pneumonia, with defective bacterial clearance. Our results show that rapid GBP activity is controlled by host-intrinsic cytokine signaling and that GBP activities precede immune amplification responses, including IFN induction, inflammasome activation, and cell death.
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Affiliation(s)
- Beiyun C Liu
- Graduate Program in Immunology, Tufts University Sackler School of Biomedical Sciences, Boston, MA 02111, USA
| | - Joseph Sarhan
- Graduate Program in Immunology, Tufts University Sackler School of Biomedical Sciences, Boston, MA 02111, USA; MSTP, Tufts University School of Medicine, Boston, MA 02111, USA
| | | | - Hayley I Muendlein
- Graduate Program in Genetics, Tufts University Sackler School of Biomedical Sciences, Boston, MA 02111, USA
| | - Vladimir Ilyukha
- Petrozavodsk State University, Republic of Karelia, Russian Federation
| | - Jörn Coers
- Department of Molecular Genetics and Microbiology, and Immunology, Duke University Medical Center, Durham, NC 27710, USA
| | - Masahiro Yamamoto
- Department of Immunoparasitology, Research Institute for Microbial Diseases, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan
| | - Ralph R Isberg
- Howard Hughes Medical Institute, Boston MA, USA; Department of Molecular Biology & Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA.
| | - Alexander Poltorak
- Petrozavodsk State University, Republic of Karelia, Russian Federation; Department of Immunology, Tufts University School of Medicine, Boston, MA 02111, USA.
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30
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Zhang YM, Zhang XH, Zhu P, Tan RH, Zhao JS, Wang F, Zhang JJ, Yan W, Xi Y, Wan JB, Kang JX, Zou ZQ, Bu SZ. Endogenous synthesis of n-3 polyunsaturated fatty acids in fat-1 transgenic mice ameliorates streptozocin-induced diabetic nephropathy. J Funct Foods 2018. [DOI: 10.1016/j.jff.2018.04.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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31
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Transplantation of Human Umbilical Cord Blood Mononuclear Cells Attenuated Ischemic Injury in MCAO Rats via Inhibition of NF-κB and NLRP3 Inflammasome. Neuroscience 2017; 369:314-324. [PMID: 29175152 DOI: 10.1016/j.neuroscience.2017.11.027] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 11/15/2017] [Accepted: 11/16/2017] [Indexed: 12/28/2022]
Abstract
Accumulated evidence displayed that transplantation of stem cells may be a promising approach for the treatment of neurological disorders. However, the underlying mechanisms remain to be well elucidated. Moreover, some investigators cannot reproduce similar results as the previous. The present results showed that transplantation of fresh human umbilical cord blood mononuclear cells (cbMNCs) attenuated ischemic damage in middle cerebral artery occlusion (MCAO) rats, accompanied with improvement of neurologic deficits, learning and memory function. The increase in neovascularization and related molecules such as vascular endothelial growth factor (VEGF), Angiopoietin-1 (Ang-1) and endothelium-specific receptor tyrosine kinase 2 (Tie-2) in the injured brain was observed in cbMNCs-treated rats. Moreover, nuclear factor-κB (NF-κB) activation and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome were also inhibited by the cells graft, resulting in reduction in cleaved caspase-1 and mature interleukin-1β (IL-1β) content. These results suggested that the protective actions of the cells on the cerebral ischemia may be related to inhibition of NF-κB pathway and NLRP3 inflammasome.
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32
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Induction of Type I Interferon through a Noncanonical Toll-Like Receptor 7 Pathway during Yersinia pestis Infection. Infect Immun 2017; 85:IAI.00570-17. [PMID: 28847850 PMCID: PMC5649010 DOI: 10.1128/iai.00570-17] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2017] [Accepted: 08/21/2017] [Indexed: 12/12/2022] Open
Abstract
Yersinia pestis causes bubonic, pneumonic, and septicemic plague, diseases that are rapidly lethal to most mammals, including humans. Plague develops as a consequence of bacterial neutralization of the host's innate immune response, which permits uncontrolled growth and causes the systemic hyperactivation of the inflammatory response. We previously found that host type I interferon (IFN) signaling is induced during Y. pestis infection and contributes to neutrophil depletion and disease. In this work, we show that type I IFN expression is derived from the recognition of intracellular Y. pestis by host Toll-like receptor 7 (TLR7). Type I IFN expression proceeded independent of myeloid differentiation factor 88 (MyD88), which is the only known signaling adaptor for TLR7, suggesting that a noncanonical mechanism occurs in Y. pestis-infected macrophages. In the murine plague model, TLR7 was a significant contributor to the expression of serum IFN-β, whereas MyD88 was not. Furthermore, like the type I IFN response, TLR7 contributed to the lethality of septicemic plague and was associated with the suppression of neutrophilic inflammation. In contrast, TLR7 was important for defense against disease in the lungs. Together, these data demonstrate that an atypical TLR7 signaling pathway contributes to type I IFN expression during Y. pestis infection and suggest that the TLR7-driven type I IFN response plays an important role in determining the outcome of plague.
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33
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Liang X, Zhang D, Liu W, Yan Y, Zhou F, Wu W, Yan Z. Reactive oxygen species trigger NF-κB-mediated NLRP3 inflammasome activation induced by zinc oxide nanoparticles in A549 cells. Toxicol Ind Health 2017; 33:737-745. [DOI: 10.1177/0748233717712409] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inhaled zinc oxide nanoparticles (ZnO-NPs) induce lung inflammation associated with oxidative stress. The NLRP3 inflammasome plays a pivotal role in the development of lung inflammation. However, the underlying effects of the NLRP3 inflammasome on ZnO-NPs-induced inflammation remain obscure. In the present study, reactive oxygen species (ROS) generation, expression of NLRP3, caspase-1 p10, and cytokines release of interleukin (IL)-1β and IL-18 were determined after A549 cells were exposed to ZnO-NPs. The ROS scavenger N-acetyl-L-cysteine (NAC), nuclear factor kappa B (NF-κB inhibitor BAY11-7082, and NLRP3 inhibitor glibenclamide (GEL) were used to explore the mechanism of NLRP3 inflammasome activation-induced by ZnO-NPs. ZnO-NPs stimulation induced ROS generation and NF-κB p65 phosphorylation. Similarly, the expression of NLRP3 and caspase-1 p10 and the release of IL-1β and IL-18 were significantly increased after ZnO-NPs treatment, which indicated that the NLRP3 inflammasome was activated by ZnO-NPs. Meanwhile, NAC pretreatment inhibited ZnO-NPs-induced activation of NF-κB and NLRP3 inflammasome. The NF-κB inhibitor BAY11-7082 did not affect ROS production but significantly reduced the NLRP3 inflammasome activation induced by ZnO-NPs. Furthermore, the ability of ZnO-NPs to increase the production of IL-1β and IL-18 was significantly inhibited by GEL. The ZnO-NPs induced the activation of the NLRP3 inflammasome in A549 cells, which might be via a ROS-NF-κB-NLRP3 signaling pathway.
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Affiliation(s)
- Xiao Liang
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Di Zhang
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Wenjia Liu
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Yingjie Yan
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Fang Zhou
- College of Public Health, Zhengzhou University, Zhengzhou, China
| | - Weidong Wu
- School of Public Health, Xinxiang Medical University, Xinxiang, China
| | - Zhen Yan
- College of Public Health, Zhengzhou University, Zhengzhou, China
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34
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Hu GQ, Song PX, Chen W, Qi S, Yu SX, Du CT, Deng XM, Ouyang HS, Yang YJ. Cirtical role for Salmonella effector SopB in regulating inflammasome activation. Mol Immunol 2017; 90:280-286. [PMID: 28846926 DOI: 10.1016/j.molimm.2017.07.011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Revised: 05/08/2017] [Accepted: 07/19/2017] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Salmonella is known to evolve many mechanisms to avoid or delay inflammasome activation which remain largely unknown. In this study, we investigated whether the SopB protein critical to bacteria virulence capacity was an effector that involved in the regulation of inflammasome activation. METHODS BMDMs from NLRC4-, NLRP3-, caspase-1/-11-, IFI16- and AIM2-deficient mice were pretreated with LPS, and subsequently stimulated with a series of SopB-related strains of Salmonella, inflammasome induced cell death, IL-1β secretion, cleaved caspase-1 production and ASC speckle formation were detected. RESULTS We found that SopB could inhibit host IL-1β secretion, caspase-1 activation and inflammasome induced cell death using a series of SopB-related strains of Salmonella; however the reduction of IL-1β secretion was not dependent on sensor that contain PYD domain, such as NLRP3, AIM2 or IFI16, but dependent on NLRC4. Notably, SopB specifically prevented ASC oligomerization and the enzymatic activity of SopB was responsible for the inflammasome inhibition. Furthermore, inhibition of Akt signaling induced enhanced inflammasome activation. CONCLUSIONS These results revealed a novel role in inhibition of NLRC4 inflammasome for Salmonella effector SopB.
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Affiliation(s)
- Gui-Qiu Hu
- Key Laboratory of Zoonosis, Ministry of Education, College of Animal Medicine, Jilin University, Changchun 130062, China
| | - Pei-Xuan Song
- Key Laboratory of Zoonosis, Ministry of Education, College of Animal Medicine, Jilin University, Changchun 130062, China
| | - Wei Chen
- Key Laboratory of Zoonosis, Ministry of Education, College of Animal Medicine, Jilin University, Changchun 130062, China
| | - Shuai Qi
- Key Laboratory of Zoonosis, Ministry of Education, College of Animal Medicine, Jilin University, Changchun 130062, China
| | - Shui-Xing Yu
- Key Laboratory of Zoonosis, Ministry of Education, College of Animal Medicine, Jilin University, Changchun 130062, China
| | - Chong-Tao Du
- Key Laboratory of Zoonosis, Ministry of Education, College of Animal Medicine, Jilin University, Changchun 130062, China
| | - Xu-Ming Deng
- Key Laboratory of Zoonosis, Ministry of Education, College of Animal Medicine, Jilin University, Changchun 130062, China
| | - Hong-Sheng Ouyang
- Key Laboratory of Zoonosis, Ministry of Education, College of Animal Medicine, Jilin University, Changchun 130062, China
| | - Yong-Jun Yang
- Key Laboratory of Zoonosis, Ministry of Education, College of Animal Medicine, Jilin University, Changchun 130062, China.
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35
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Philip NH, Zwack EE, Brodsky IE. Activation and Evasion of Inflammasomes by Yersinia. Curr Top Microbiol Immunol 2017; 397:69-90. [PMID: 27460805 DOI: 10.1007/978-3-319-41171-2_4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The innate immune system plays an essential role in initiating the early response against microbial infection, as well as instructing and shaping subsequent responses. Microbial pathogens are enormously diverse in terms of the niches they occupy, their metabolic properties and requirements, and the cellular pathways that they target. Nevertheless, innate sensing of pathogens triggers a relatively stereotyped set of responses that involve transcriptional induction of key inflammatory mediators, as well as post-translational assembly and activation of a multiprotein inflammatory complex termed 'the inflammasome.' Along with classical Pattern Recognition Receptors, the inflammasome activation pathway has emerged as a key regulator of tissue homeostasis and immune defense. Components of the inflammasome generally exist within the cell in a soluble, monomeric state, and oligomerize in response to diverse enzymatic activities associated with infection or cellular stress. Inflammasome assembly triggers activation of the pro-enzyme caspase-1, resulting in the cleavage of caspase-1 targets. The most extensively studied targets are the cytokines of the IL-1 family, but the recent discovery of Gasdermin D as a novel target of caspase-1 and the related inflammatory caspase, caspase-11, has begun to mechanistically define the links between caspase-1 activation and cell death. Cell death is a hallmark of macrophage infection by many pathogens, including the gram-negative bacterial pathogens of the genus Yersinia. Intriguingly, the activities of the Yersinia-secreted effector proteins and the type III secretion system (T3SS) itself have been linked to both inflammasome activation and evasion during infection. The balance between these activating and inhibitory activities shapes the outcome of Yersinia infection. Here, we describe the current state of knowledge on interactions between Yersinia and the inflammasome system, with the goal of integrating these findings within the general framework of inflammasome responses to microbial pathogens.
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Affiliation(s)
- Naomi H Philip
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19104, USA.,Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.,Immunology Graduate Group, Philadelphia, PA, 19104, USA
| | - Erin E Zwack
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19104, USA.,Cell and Molecular Biology Graduate Group, Philadelphia, PA, 19104, USA
| | - Igor E Brodsky
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, 19104, USA. .,Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
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Abstract
Glutathionylation, the formation of reversible mixed disulfides between glutathione and protein cysteine residues, is a posttranslational modification previously observed for intracellular proteins of bacteria. Here we show that Yersinia pestis LcrV, a secreted protein capping the type III secretion machine, is glutathionylated at Cys273 and that this modification promotes association with host ribosomal protein S3 (RPS3), moderates Y. pestis type III effector transport and killing of macrophages, and enhances bubonic plague pathogenesis in mice and rats. Secreted LcrV was purified and analyzed by mass spectrometry to reveal glutathionylation, a modification that is abolished by the codon substitution Cys273Ala in lcrV Moreover, the lcrVC273A mutation enhanced the survival of animals in models of bubonic plague. Investigating the molecular mechanism responsible for these virulence attributes, we identified macrophage RPS3 as a ligand of LcrV, an association that is perturbed by the Cys273Ala substitution. Furthermore, macrophages infected by the lcrVC273A variant displayed accelerated apoptotic death and diminished proinflammatory cytokine release. Deletion of gshB, which encodes glutathione synthetase of Y. pestis, resulted in undetectable levels of intracellular glutathione, and we used a Y. pestis ΔgshB mutant to characterize the biochemical pathway of LcrV glutathionylation, establishing that LcrV is modified after its transport to the type III needle via disulfide bond formation with extracellular oxidized glutathione.IMPORTANCEYersinia pestis, the causative agent of plague, has killed large segments of the human population; however, the molecular bases for the extraordinary virulence attributes of this pathogen are not well understood. We show here that LcrV, the cap protein of bacterial type III secretion needles, is modified by host glutathione and that this modification contributes to the high virulence of Y. pestis in mouse and rat models for bubonic plague. These data suggest that Y. pestis exploits glutathione in host tissues to activate a virulence strategy, thereby accelerating plague pathogenesis.
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Grabowski B, Schmidt MA, Rüter C. Immunomodulatory Yersinia outer proteins (Yops)-useful tools for bacteria and humans alike. Virulence 2017; 8:1124-1147. [PMID: 28296562 DOI: 10.1080/21505594.2017.1303588] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Human-pathogenic Yersinia produce plasmid-encoded Yersinia outer proteins (Yops), which are necessary to down-regulate anti-bacterial responses that constrict bacterial survival in the host. These Yops are effectively translocated directly from the bacterial into the target cell cytosol by the type III secretion system (T3SS). Cell-penetrating peptides (CPPs) in contrast are characterized by their ability to autonomously cross cell membranes and to transport cargo - independent of additional translocation systems. The recent discovery of bacterial cell-penetrating effector proteins (CPEs) - with the prototype being the T3SS effector protein YopM - established a new class of autonomously translocating immunomodulatory proteins. CPEs represent a vast source of potential self-delivering, anti-inflammatory therapeutics. In this review, we give an update on the characteristic features of the plasmid-encoded Yops and, based on recent findings, propose the further development of these proteins for potential therapeutic applications as natural or artificial cell-penetrating forms of Yops might be of value as bacteria-derived biologics.
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Affiliation(s)
- Benjamin Grabowski
- a Institute of Infectiology - Centre for Molecular Biology of Inflammation (ZMBE), University of Münster , Münster , Germany
| | - M Alexander Schmidt
- a Institute of Infectiology - Centre for Molecular Biology of Inflammation (ZMBE), University of Münster , Münster , Germany
| | - Christian Rüter
- a Institute of Infectiology - Centre for Molecular Biology of Inflammation (ZMBE), University of Münster , Münster , Germany
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38
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Fann DYW, Lim YA, Cheng YL, Lok KZ, Chunduri P, Baik SH, Drummond GR, Dheen ST, Sobey CG, Jo DG, Chen CLH, Arumugam TV. Evidence that NF-κB and MAPK Signaling Promotes NLRP Inflammasome Activation in Neurons Following Ischemic Stroke. Mol Neurobiol 2017; 55:1082-1096. [DOI: 10.1007/s12035-017-0394-9] [Citation(s) in RCA: 170] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 01/06/2017] [Indexed: 12/21/2022]
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Yang H, Wang T, Tian G, Zhang Q, Wu X, Xin Y, Yan Y, Tan Y, Cao S, Liu W, Cui Y, Yang R, Du Z. Host transcriptomic responses to pneumonic plague reveal that Yersinia pestis inhibits both the initial adaptive and innate immune responses in mice. Int J Med Microbiol 2017; 307:64-74. [DOI: 10.1016/j.ijmm.2016.11.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 11/06/2016] [Accepted: 11/10/2016] [Indexed: 01/12/2023] Open
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40
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Ratner D, Orning MPA, Proulx MK, Wang D, Gavrilin MA, Wewers MD, Alnemri ES, Johnson PF, Lee B, Mecsas J, Kayagaki N, Goguen JD, Lien E. The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation. PLoS Pathog 2016; 12:e1006035. [PMID: 27911947 PMCID: PMC5135138 DOI: 10.1371/journal.ppat.1006035] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 10/31/2016] [Indexed: 12/25/2022] Open
Abstract
Type III secretion systems (T3SS) are central virulence factors for many pathogenic Gram-negative bacteria, and secreted T3SS effectors can block key aspects of host cell signaling. To counter this, innate immune responses can also sense some T3SS components to initiate anti-bacterial mechanisms. The Yersinia pestis T3SS is particularly effective and sophisticated in manipulating the production of pro-inflammatory cytokines IL-1β and IL-18, which are typically processed into their mature forms by active caspase-1 following inflammasome formation. Some effectors, like Y. pestis YopM, may block inflammasome activation. Here we show that YopM prevents Y. pestis induced activation of the Pyrin inflammasome induced by the RhoA-inhibiting effector YopE, which is a GTPase activating protein. YopM blocks YopE-induced Pyrin-mediated caspase-1 dependent IL-1β/IL-18 production and cell death. We also detected YopM in a complex with Pyrin and kinases RSK1 and PKN1, putative negative regulators of Pyrin. In contrast to wild-type mice, Pyrin deficient mice were also highly susceptible to an attenuated Y. pestis strain lacking YopM, emphasizing the importance of inhibition of Pyrin in vivo. A complex interplay between the Y. pestis T3SS and IL-1β/IL-18 production is evident, involving at least four inflammasome pathways. The secreted effector YopJ triggers caspase-8- dependent IL-1β activation, even when YopM is present. Additionally, the presence of the T3SS needle/translocon activates NLRP3 and NLRC4-dependent IL-1β generation, which is blocked by YopK, but not by YopM. Taken together, the data suggest YopM specificity for obstructing the Pyrin pathway, as the effector does not appear to block Y. pestis-induced NLRP3, NLRC4 or caspase-8 dependent caspase-1 processing. Thus, we identify Y. pestis YopM as a microbial inhibitor of the Pyrin inflammasome. The fact that so many of the Y. pestis T3SS components are participating in regulation of IL-1β/IL-18 release suggests that these effects are essential for maximal control of innate immunity during plague. Many pathogenic Gram-negative bacteria express type III secretion systems (T3SS) that translocate bacterial proteins into host cells with the potential of altering normal cell processes. Yersinia pestis, the causative agent of plague, harbors a T3SS which is particularly effective in suppressing innate immunity and release of pro-inflammatory cytokines IL-1β and IL-18, potent triggers of anti-bacterial responses. These cytokines are produced via processing by active caspase-1 in inflammasome complexes. Pyrin is an inflammasome component that recognizes alterations in certain host cell signals. Here we show that the T3SS effector protein YopM inhibits effector YopE-mediated Pyrin-induced caspase-1 activation, IL-1β, IL-18 and cell death triggered by Y. pestis. We also found that blocking the Pyrin pathway is important for disease development in a mouse model of bubonic plague. Thus, YopM is a microbial molecule blocking Pyrin inflammasomes.
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Affiliation(s)
- Dmitry Ratner
- UMass Medical School, Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, Worcester, Massachusetts, United States of America
| | - M. Pontus A. Orning
- UMass Medical School, Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, Worcester, Massachusetts, United States of America
- Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Megan K. Proulx
- UMass Medical School, Department of Microbiology and Physiological Systems, Worcester, Massachusetts, United States of America
| | - Donghai Wang
- UMass Medical School, Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, Worcester, Massachusetts, United States of America
- Department of Medicine, School of Medicine, Duke University, Durham, North Carolina, United States of America
| | - Mikhail A. Gavrilin
- Davis Heart and Lung Research Institute, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Mark D. Wewers
- Davis Heart and Lung Research Institute, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Emad S. Alnemri
- Department of Biochemistry and Molecular Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America
| | - Peter F. Johnson
- Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America
| | - Bettina Lee
- Department of Physiological Chemistry, Genentech, Inc., South San Francisco, California, United States of America
| | - Joan Mecsas
- Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America
| | - Nobuhiko Kayagaki
- Department of Physiological Chemistry, Genentech, Inc., South San Francisco, California, United States of America
| | - Jon D. Goguen
- UMass Medical School, Department of Microbiology and Physiological Systems, Worcester, Massachusetts, United States of America
| | - Egil Lien
- UMass Medical School, Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, Worcester, Massachusetts, United States of America
- Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- * E-mail:
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41
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Ratner D, Orning MPA, Lien E. Bacterial secretion systems and regulation of inflammasome activation. J Leukoc Biol 2016; 101:165-181. [PMID: 27810946 DOI: 10.1189/jlb.4mr0716-330r] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 09/19/2016] [Accepted: 09/20/2016] [Indexed: 01/03/2023] Open
Abstract
Innate immunity is critical for host defenses against pathogens, but many bacteria display complex ways of interacting with innate immune signaling, as they may both activate and evade certain pathways. Gram-negative bacteria can exhibit specialized nanomachine secretion systems for delivery of effector proteins into mammalian cells. Bacterial types III, IV, and VI secretion systems (T3SS, T4SS, and T6SS) are known for their impact on caspase-1-activating inflammasomes, necessary for producing bioactive inflammatory cytokines IL-1β and IL-18, key participants of anti-bacterial responses. Here, we discuss how these secretion systems can mediate triggering and inhibition of inflammasome signaling. We propose that a fine balance between secretion system-mediated activation and inhibition can determine net activation of inflammasome activity and control inflammation, clearance, or spread of the infection.
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Affiliation(s)
- Dmitry Ratner
- Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA; and
| | - M Pontus A Orning
- Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA; and.,Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norges Teknisk-Naturvitenskapelige Universitet, Trondheim, Norway
| | - Egil Lien
- Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA; and .,Centre of Molecular Inflammation Research, Department of Cancer Research and Molecular Medicine, Norges Teknisk-Naturvitenskapelige Universitet, Trondheim, Norway
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Uncovering an Important Role for YopJ in the Inhibition of Caspase-1 in Activated Macrophages and Promoting Yersinia pseudotuberculosis Virulence. Infect Immun 2016; 84:1062-1072. [PMID: 26810037 DOI: 10.1128/iai.00843-15] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 01/19/2016] [Indexed: 02/06/2023] Open
Abstract
Pathogenic Yersinia species utilize a type III secretion system to translocate Yop effectors into infected host cells. Yop effectors inhibit innate immune responses in infected macrophages to promote Yersinia pathogenesis. In turn,Yersinia-infected macrophages respond to translocation of Yops by activating caspase-1, but different mechanisms of caspase-1 activation occur, depending on the bacterial genotype and the state of phagocyte activation. In macrophages activated with lipopolysaccharide (LPS) prior to Yersinia pseudotuberculosis infection, caspase-1 is activated by a rapid inflammasome-dependent mechanism that is inhibited by translocated YopM. The possibility that other effectors cooperate with YopM to inhibit caspase-1 activation in LPS-activated macrophages has not been investigated. Toward this aim, epistasis analysis was carried out in which the phenotype of aY. pseudotuberculosis yopM mutant was compared to that of a yopJ yopM, yopE yopM, yopH yopM, yopT yopM, or ypkA yopM mutant. Activation of caspase-1 was measured by cleavage of the enzyme, release of interleukin-1β (IL-1β), and pyroptosis in LPS-activated macrophages infected with wild-type or mutant Y. pseudotuberculosis strains. Results show enhanced activation of caspase-1 after infection with the yopJ yopM mutant relative to infection by any other single or double mutant. Similar results were obtained with the yopJ, yopM, and yopJ yopM mutants ofY ersinia pestis Following intravenous infection of mice, theY. pseudotuberculosis yopJ mutant was as virulent as the wild type, while the yopJ yopM mutant was significantly more attenuated than the yopM mutant. In summary, through epistasis analysis this work uncovered an important role for YopJ in inhibiting caspase-1 in activated macrophages and in promoting Yersinia virulence.
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Pha K, Navarro L. Yersinia type III effectors perturb host innate immune responses. World J Biol Chem 2016; 7:1-13. [PMID: 26981193 PMCID: PMC4768113 DOI: 10.4331/wjbc.v7.i1.1] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 09/02/2015] [Accepted: 11/04/2015] [Indexed: 02/05/2023] Open
Abstract
The innate immune system is the first line of defense against invading pathogens. Innate immune cells recognize molecular patterns from the pathogen and mount a response to resolve the infection. The production of proinflammatory cytokines and reactive oxygen species, phagocytosis, and induced programmed cell death are processes initiated by innate immune cells in order to combat invading pathogens. However, pathogens have evolved various virulence mechanisms to subvert these responses. One strategy utilized by Gram-negative bacterial pathogens is the deployment of a complex machine termed the type III secretion system (T3SS). The T3SS is composed of a syringe-like needle structure and the effector proteins that are injected directly into a target host cell to disrupt a cellular response. The three human pathogenic Yersinia spp. (Y. pestis, Y. enterocolitica, and Y. pseudotuberculosis) are Gram-negative bacteria that share in common a 70 kb virulence plasmid which encodes the T3SS. Translocation of the Yersinia effector proteins (YopE, YopH, YopT, YopM, YpkA/YopO, and YopP/J) into the target host cell results in disruption of the actin cytoskeleton to inhibit phagocytosis, downregulation of proinflammatory cytokine/chemokine production, and induction of cellular apoptosis of the target cell. Over the past 25 years, studies on the Yersinia effector proteins have unveiled tremendous knowledge of how the effectors enhance Yersinia virulence. Recently, the long awaited crystal structure of YpkA has been solved providing further insights into the activation of the YpkA kinase domain. Multisite autophosphorylation by YpkA to activate its kinase domain was also shown and postulated to serve as a mechanism to bypass regulation by host phosphatases. In addition, novel Yersinia effector protein targets, such as caspase-1, and signaling pathways including activation of the inflammasome were identified. In this review, we summarize the recent discoveries made on Yersinia effector proteins and their contribution to Yersinia pathogenesis.
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Abstract
AbstractRecognition of extracellular pathogenassociated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) results in activation of host defense signaling pathways. Some virulent microbes can attenuate and escape antimicrobial immunity by manipulating these signaling pathways. However, impairment of the primary innate response may potentiate the activation of secondary defense program, centered around Nucleotide-binding domain and Leucine-rich repeat containing Receptor (NLRs) for inflammasome formation and IL-1β production. This review analyzes the current knowledge regarding association of innate immune signaling pathways with inflammasome activation in response to bacterial infection.
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Shao A, Wu H, Hong Y, Tu S, Sun X, Wu Q, Zhao Q, Zhang J, Sheng J. Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome. Mol Neurobiol 2015; 53:3462-3476. [PMID: 26091790 DOI: 10.1007/s12035-015-9242-y] [Citation(s) in RCA: 124] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 05/26/2015] [Indexed: 01/10/2023]
Abstract
Early brain injury (EBI), highlighted with inflammation and apoptosis, occurring within 72 h after subarachnoid hemorrhage (SAH), is associated with the prognosis of SAH. Recent studies have revealed that hydrogen-rich saline (HS) exerted multiple neuroprotective properties in many neurological diseases including SAH, involved to anti-oxidative and anti-apoptotic effect. We have previously reported that HS could attenuate neuronal apoptosis as well as vasospasm. However, the underlying mechanism of HS on inflammation in SAH-induced EBI remains unclear. In this study, we explored the influence of HS on nuclear factor-κB (NF-κB) pathway and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome at early stage after SAH, by injecting HS intraperitoneally to SAH rats. One hundred and twenty-nine SD rats were randomly divided into four groups: sham group, SAH group, SAH+vehicle group, and SAH+HS group. SAH model was conducted using endovascular perforation method; all rats were sacrificed at 24 h after SAH. Protein level of pIκBα, cytosolic and nuclear p65, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, interleukin-1β (IL-1β), and cleaved caspase-3 were measured by western blot. mRNA level of IL-1β, interleukin-6 (IL-6), tumor necrosis factor-c (TNF-α) were evaluated by RT-PCR. Cellular injury and death was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and Nissl staining, respectively. Our results showed that pIκBα, nuclear p65, NLRP3, ASC, caspase-1, IL-1β, cleaved caspase-3 proteins, as well as the mRNA of IL-1β, IL-6, and TNF-ɑ increased at 24 h after SAH, while cytosolic p65 decreased. TUNEL and Nissl staining presented severe cellular injury at 24 h post-SAH. However, after HS administration, the changes mentioned above were reversed. In conclusion, HS may inhibit inflammation in EBI and improve neurobehavioral outcome after SAH, partially via inactivation of NF-κB pathway and NLRP3 inflammasome. Graphical Abstract Schematic representation of the mechanism of HS-mediated anti-inflammatory effect in EBI after SAH. The NF-κB inflammatory pathway and NLRP3 inflammasome are involved in the anti-neuroinflammatory effect of HS post-SAH. SAH-induced oxidative stress enhances the activation of NF-κB, thus promoting the translocation of p65 subunit into nucleus and increasing the mRNA level of its downstream proinflammatory cytokines (IL-1β, IN-6, TNF-α) and NLRP3. Elevated expression of NLRP3 mRNA increases the assembly of NLRP3 inflammasome. In addition, oxidative stress after SAH stimulates the activation of NLRP3 inflammasome, therefore, promoting caspase-1 activation and the cleavage of pro-IL-1β into mature IL-1β. Finally, activation of NF-κB pathway and NLRP3 inflammasome contribute to the inflammation response and cellular injury in EBI after SAH. HS treatment reversed the detrimental effect mentioned above via inactivation of NF-κB pathway and NLRP3 inflammasome. NF-κB nuclear factor-κB, IκB inhibitor of NF-κB, IKK Iκ kinase, NLRP3 nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3, ASC apoptosis-associated speck-like protein containing a caspase recruitment domain.
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Affiliation(s)
- Anwen Shao
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Haijian Wu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Yuan Hong
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Sheng Tu
- Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Xuejun Sun
- Department of Diving Medicine, The Second Military Medical University, Shanghai, 200433, China
| | - Qun Wu
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
| | - Qiong Zhao
- Department of Thoracic Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
| | - Jianmin Zhang
- Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. .,Brain Research Institute, Zhejiang University, Hangzhou, 310009, China.
| | - Jifang Sheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.,Department of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China
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Lai XH, Xu Y, Chen XM, Ren Y. Macrophage cell death upon intracellular bacterial infection. ACTA ACUST UNITED AC 2015; 2:e779. [PMID: 26690967 DOI: 10.14800/macrophage.779] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Macrophage-pathogen interaction is a complex process and the outcome of this tag-of-war for both sides is to live or die. Without attempting to be comprehensive, this review will discuss the complexity and significance of the interaction outcomes between macrophages and some facultative intracellular bacterial pathogens as exemplified by Francisella, Salmonella, Shigella and Yersinia. Upon bacterial infection, macrophages can die by a variety of ways, such as apoptosis, autophagic cell death, necrosis, necroptosis, oncosis, pyronecrosis, pyroptosis etc, which is the focus of this review.
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Affiliation(s)
- Xin-He Lai
- Institute of Inflammation and Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China ; Institute of Translational Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yunsheng Xu
- Institute of Inflammation and Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China ; Institute of Translational Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China ; Department of Dermato-venerology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xiao-Ming Chen
- Institute of Inflammation and Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China ; Institute of Translational Medicine, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China ; Department of Pediatric Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yi Ren
- Institute of Inflammation and Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China ; Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL, USA)
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Sellge G, Kufer TA. PRR-signaling pathways: Learning from microbial tactics. Semin Immunol 2015; 27:75-84. [PMID: 25911384 DOI: 10.1016/j.smim.2015.03.009] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Accepted: 03/13/2015] [Indexed: 12/13/2022]
Abstract
Recognition of bacterial pathogens by the mammalian host relies on the induction of early innate immune responses initiated by the activation of pattern-recognition receptors (PRRs) upon sensing of their cognate microbe-associated-patterns (MAMPs). Successful pathogens have evolved to intercept PRR activation and signaling at multiple steps. The molecular dissection of the underlying mechanisms revealed many of the basic mechanisms used by the immune system. Here we provide an overview of the different strategies used by bacterial pathogens and commensals to subvert and reprogram PPR-mediated innate immune responses. A particular attention is given to recent discoveries highlighting novel molecular details of the host inflammatory response in mammalian cells and current advances in our understanding of the interaction of commensals with PRR-mediated responses.
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Affiliation(s)
- Gernot Sellge
- Department of Medicine III, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany
| | - Thomas A Kufer
- Institute of Nutritional Medicine, Department of Immunology, University of Hohenheim, Fruwirthstr. 12, 70599 Stuttgart, Germany.
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Sivaraman V, Pechous RD, Stasulli NM, Eichelberger KR, Miao EA, Goldman WE. Yersinia pestis activates both IL-1β and IL-1 receptor antagonist to modulate lung inflammation during pneumonic plague. PLoS Pathog 2015; 11:e1004688. [PMID: 25781467 PMCID: PMC4363893 DOI: 10.1371/journal.ppat.1004688] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Accepted: 01/19/2015] [Indexed: 11/25/2022] Open
Abstract
Pneumonic plague is the most rapid and lethal form of Yersinia pestis infection. Increasing evidence suggests that Y. pestis employs multiple levels of innate immune evasion and/or suppression to produce an early “pre-inflammatory” phase of pulmonary infection, after which the disease is highly inflammatory in the lung and 100% fatal. In this study, we show that IL-1β/IL-18 cytokine activation occurs early after bacteria enter the lung, and this activation eventually contributes to pulmonary inflammation and pathology during the later stages of infection. However, the inflammatory effects of IL-1β/IL-1-receptor ligation are not observed during this first stage of pneumonic plague. We show that Y. pestis also activates the induction of IL-1 receptor antagonist (IL-1RA), and this activation likely contributes to the ability of Y. pestis to establish the initial pre-inflammatory phase of disease. Inhalation of respiratory droplets containing Yersinia pestis results in a rapidly developing and lethal pneumonia. Interestingly, early interactions between Y. pestis and host cells in the lung contribute to significant immune evasion, but also ultimately result in severe innate immune activation. Our results demonstrate that Y. pestis activates pro-inflammatory cytokines IL-1β and IL-18 in the lung early during infection. However, there is very little early pulmonary inflammation while Y. pestis continues to multiply in the lung compartment. We show that the host protein IL-1RA is activated concurrently with IL-1β, attenuating early immune activation by this cytokine. We propose that this allows the organism to replicate to high titers, eventually triggering a vigorous inflammatory response and facilitating aerosol transmission. Therefore, evaluating early host activation of IL-1RA by Y. pestis may provide therapeutic targets against pneumonic plague.
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Affiliation(s)
- Vijay Sivaraman
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- Department of Biology, North Carolina Central University, Durham, North Carolina, United States of America
| | - Roger D. Pechous
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Nikolas M. Stasulli
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Kara R. Eichelberger
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Edward A. Miao
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - William E. Goldman
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
- * E-mail:
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Li J, Chai QY, Zhang Y, Li BX, Wang J, Qiu XB, Liu CH. Mycobacterium tuberculosis Mce3E suppresses host innate immune responses by targeting ERK1/2 signaling. THE JOURNAL OF IMMUNOLOGY 2015; 194:3756-67. [PMID: 25780035 DOI: 10.4049/jimmunol.1402679] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2014] [Accepted: 02/12/2015] [Indexed: 11/19/2022]
Abstract
Crucial to the pathogenesis of the tuberculosis (TB)-causing pathogen Mycobacterium tuberculosis is its ability to subvert host immune defenses to promote its intracellular survival. The mammalian cell entry protein 3E (Mce3E), located in the region of difference 15 of the M. tuberculosis genome and absent in Mycobacterium bovis bacillus Calmette-Guérin, has an essential role in facilitating the internalization of mammalian cells by mycobacteria. However, relatively little is known about the role of Mce3E in modulation of host innate immune responses. In this study, we demonstrate that Mce3E inhibits the activation of the ERK1/2 signaling pathway, leading to the suppression of Tnf and Il6 expression, and the promotion of mycobacterial survival within macrophages. Mce3E interacts and colocalizes with ERK1/2 at the endoplasmic reticulum in a DEF motif (an ERK-docking motif)-dependent manner, relocates ERK1/2 from cytoplasm to the endoplasmic reticulum, and finally reduces the association of ERK1/2 with MEK1 and blocks the nuclear translocation of phospho-ERK1/2. A DEF motif mutant form of Mce3E (F294A) loses its ability to suppress Tnf and Il6 expression and to promote intracellular survival of mycobacteria. Inhibition of the ERK1/2 pathway in macrophages using U0126, a specific inhibitor of the ERK pathway, also leads to the suppressed Tnf and Il6 expression and the enhanced intracellular survival of mycobacteria. Taken together, these results suggest that M. tuberculosis Mce3E exploits the ERK1/2 signaling pathway to suppress host innate immune responses, providing a potential Mce3E-ERK1/2 interface-based drug target against M. tuberculosis.
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Affiliation(s)
- Jie Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; and
| | - Qi-Yao Chai
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; and
| | - Yong Zhang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; and
| | - Bing-Xi Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; and
| | - Jing Wang
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; and
| | - Xiao-Bo Qiu
- Department of Cell Biology, Ministry of Education Key Laboratory of Cell Proliferation and Regulation Biology, College of Life Sciences, Beijing Normal University, Beijing 100875, China
| | - Cui Hua Liu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China; and
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Dhariwala MO, Anderson DM. Bacterial programming of host responses: coordination between type I interferon and cell death. Front Microbiol 2014; 5:545. [PMID: 25389418 PMCID: PMC4211556 DOI: 10.3389/fmicb.2014.00545] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2014] [Accepted: 09/30/2014] [Indexed: 01/24/2023] Open
Abstract
During mammalian infection, bacteria induce cell death from an extracellular or intracellular niche that can protect or hurt the host. Data is accumulating that associate type I interferon (IFN) signaling activated by intracellular bacteria with programmed death of immune effector cells and enhanced virulence. Multiple pathways leading to IFN-dependent host cell death have been described, and in some cases it is becoming clear how these mechanisms contribute to virulence. Yet common mechanisms of IFN-enhanced bacterial pathogenesis are not obvious and no specific interferon stimulated genes have yet been identified that cause sensitivity to pathogen-induced cell death. In this review, we will summarize some bacterial infections caused by facultative intracellular pathogens and what is known about how type I IFN signaling may promote the replication of extracellular bacteria rather than stimulate protection. Each of these pathogens can survive phagocytosis but their intracellular life cycles are very different, they express distinct virulence factors and trigger different pathways of immune activation and crosstalk. These differences likely lead to widely varying amounts of type I IFN expression and a different inflammatory environment, but these may not be important to the pathologic effects on the host. Instead, each pathogen induces programmed cell death of key immune cells that have been sensitized by the activation of the type I IFN response. We will discuss how IFN-dependent host cell death may increase host susceptibility and try to understand common pathways of pathogenesis that lead to IFN-enhanced bacterial virulence.
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Affiliation(s)
- Miqdad O Dhariwala
- Department of Veterinary Pathobiology, University of Missouri Columbia, MO, USA
| | - Deborah M Anderson
- Department of Veterinary Pathobiology, University of Missouri Columbia, MO, USA
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