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  1. Article ; Online: The prevalence of Dupuytren's disease in patients with diabetes mellitus.

    Ganesan, Sandhya / Tantone, Ryan P / Komatsu, David E / Hurst, Lawrence C

    Communications medicine

    2023  Volume 3, Issue 1, Page(s) 96

    Abstract: Background: Dupuytren's disease (DD) is a fibroproliferative hand disorder associated with various medical conditions, including diabetes mellitus (DM). The reported prevalence of DM among DD patients varies widely, primarily due to small sample sizes ... ...

    Abstract Background: Dupuytren's disease (DD) is a fibroproliferative hand disorder associated with various medical conditions, including diabetes mellitus (DM). The reported prevalence of DM among DD patients varies widely, primarily due to small sample sizes in previous studies.
    Methods: This was a retrospective cohort study using data from the TriNetX Research Database. We analyzed the overall prevalence of DD between 2010 and 2020, comparing the DM, type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM) cohorts. Within the DM group, patients were further categorized based on hemoglobin A1c (HbA1c) values and prescribed anti-diabetic agents (insulin or metformin). We compared the prevalence of DD diagnosis in each group using prevalence ratios and differences.
    Results: There is a higher prevalence of DD in patients with T2DM than in patients with T1DM (relative risk [RR]: 1.641; 95% confidence interval [CI]: [1.356, 1.986]). Among patients with diabetes, there is a higher prevalence of DD in those taking insulin compared to those taking metformin (RR: 0.801, 95% CI: [0.774, 0.83]). The prevalence of DD varies depending on HbA1c levels, with a prevalence of 0.463% in patients having levels within the diabetic range, while lower prevalences of 0.392% and 0.416% are found in patients with prediabetes or uncontrolled diabetes, respectively.
    Conclusions: This study provides further insight into the relationship between DM and DD. These findings may be attributed to the increased accumulation of advanced glycosylated end products (AGEs) in patients with diabetes. Future research exploring the connection between AGE accumulation and DD development may enhance our understanding of the relationship between DD and DM.
    Language English
    Publishing date 2023-07-13
    Publishing country England
    Document type Journal Article
    ISSN 2730-664X
    ISSN (online) 2730-664X
    DOI 10.1038/s43856-023-00332-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Host cell depletion of tryptophan by IFNγ-induced Indoleamine 2,3-dioxygenase 1 (IDO1) inhibits lysosomal replication of Coxiella burnetii.

    Ganesan, Sandhya / Roy, Craig R

    PLoS pathogens

    2019  Volume 15, Issue 8, Page(s) e1007955

    Abstract: Most intracellular pathogens that reside in a vacuole prevent transit of their compartment to lysosomal organelles. Effector mechanisms induced by the pro-inflammatory cytokine Interferon-gamma (IFNγ) can promote the delivery of pathogen-occupied ... ...

    Abstract Most intracellular pathogens that reside in a vacuole prevent transit of their compartment to lysosomal organelles. Effector mechanisms induced by the pro-inflammatory cytokine Interferon-gamma (IFNγ) can promote the delivery of pathogen-occupied vacuoles to lysosomes for proteolytic degradation and are therefore important for host defense against intracellular pathogens. The bacterial pathogen Coxiella burnetii is unique in that, transport to the lysosome is essential for replication. The bacterium modulates membrane traffic to create a specialized autophagolysosomal compartment called the Coxiella-containing vacuole (CCV). Importantly, IFNγ signaling inhibits intracellular replication of C. burnetii, raising the question of which IFNγ-activated mechanisms restrict replication of a lysosome-adapted pathogen. To address this question, siRNA was used to silence a panel of IFNγ-induced genes in HeLa cells to identify genes required for restriction of C. burnetii intracellular replication. This screen demonstrated that Indoleamine 2,3-dioxygenase 1 (IDO1) contributes to IFNγ-mediated restriction of C. burnetii. IDO1 is an enzyme that catabolizes cellular tryptophan to kynurenine metabolites thereby reducing tryptophan availability in cells. Cells deficient in IDO1 function were more permissive for C. burnetii replication when treated with IFNγ, and supplementing IFNγ-treated cells with tryptophan enhanced intracellular replication. Additionally, ectopic expression of IDO1 in host cells was sufficient to restrict replication of C. burnetii in the absence of IFNγ signaling. Using differentiated THP1 macrophage-like cells it was determined that IFNγ-activation resulted in IDO1 production, and that supplementation of IFNγ-activated THP1 cells with tryptophan enhanced C. burnetii replication. Thus, this study identifies IDO1 production as a key cell-autonomous defense mechanism that limits infection by C. burnetii, which suggests that peptides derived from hydrolysis of proteins in the CCV do not provide an adequate supply of tryptophan for bacterial replication.
    MeSH term(s) Coxiella burnetii/drug effects ; Coxiella burnetii/pathogenicity ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors ; Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Interferon-gamma/pharmacology ; Lysosomes/virology ; Macrophages/metabolism ; Macrophages/pathology ; Macrophages/virology ; Q Fever/genetics ; Q Fever/prevention & control ; Q Fever/virology ; RNA, Small Interfering/genetics ; Tryptophan/metabolism ; Virus Replication/genetics
    Chemical Substances IDO1 protein, human ; Indoleamine-Pyrrole 2,3,-Dioxygenase ; RNA, Small Interfering ; Interferon-gamma (82115-62-6) ; Tryptophan (8DUH1N11BX)
    Language English
    Publishing date 2019-08-28
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7366
    ISSN (online) 1553-7374
    ISSN 1553-7366
    DOI 10.1371/journal.ppat.1007955
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Syntaxin 11 Contributes to the Interferon-Inducible Restriction of Coxiella burnetii Intracellular Infection.

    Ganesan, Sandhya / Alvarez, Natalie N / Steiner, Samuel / Fowler, Karen M / Corona, Abigail K / Roy, Craig R

    mBio

    2023  Volume 14, Issue 1, Page(s) e0354522

    Abstract: There is a limited understanding of host defense mechanisms targeting intracellular pathogens that proliferate in a lysosome. Coxiella burnetii is a model bacterial pathogen capable of replicating in the hydrolytic and acidic environment of the lysosome. ...

    Abstract There is a limited understanding of host defense mechanisms targeting intracellular pathogens that proliferate in a lysosome. Coxiella burnetii is a model bacterial pathogen capable of replicating in the hydrolytic and acidic environment of the lysosome. It has been shown that gamma interferon (IFNγ)-stimulated host cells restrict C. burnetii replication by a mechanism that involves host IDO1 depletion of tryptophan. Host cells deficient in IDO1 activity, however, retain the ability to restrict C. burnetii replication when stimulated with IFNγ, which suggests additional mechanisms of host defense. This study identified syntaxin 11 (STX11) as a host protein that contributes to IFNγ-mediated suppression of C. burnetii replication. STX11 is a SNARE protein; SNARE proteins are proteins that mediate fusion of host vesicles with specific subcellular organelles. Depletion of STX11 using either small interfering RNA (siRNA)- or CRISPR-based approaches enhanced C. burnetii replication intracellularly. Stable expression of STX11 reduced C. burnetii replication in epithelial cells and macrophages, which indicates that this STX11-dependent cell-autonomous response is operational in multiple cell types and can function independently of other IFNγ-induced factors. Fluorescently tagged STX11 localized to the
    MeSH term(s) Humans ; Coxiella burnetii ; Host-Pathogen Interactions/physiology ; Interferon-gamma/metabolism ; Interferons/metabolism ; Q Fever/metabolism ; Qa-SNARE Proteins/genetics ; Qa-SNARE Proteins/metabolism ; RNA, Small Interfering/metabolism ; Vacuoles/metabolism
    Chemical Substances Interferon-gamma (82115-62-6) ; Interferons (9008-11-1) ; Qa-SNARE Proteins ; RNA, Small Interfering ; STX11 protein, human
    Language English
    Publishing date 2023-02-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2557172-2
    ISSN 2150-7511 ; 2161-2129
    ISSN (online) 2150-7511
    ISSN 2161-2129
    DOI 10.1128/mbio.03545-22
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Measures of Bone Mineral Carbonate Content and Mineral Maturity/Crystallinity for FT-IR and Raman Spectroscopic Imaging Differentially Relate to Physical-Chemical Properties of Carbonate-Substituted Hydroxyapatite.

    Taylor, Erik A / Mileti, Cassidy J / Ganesan, Sandhya / Kim, Joo Ho / Donnelly, Eve

    Calcified tissue international

    2021  Volume 109, Issue 1, Page(s) 77–91

    Abstract: Bone mineral carbonate content assessed by vibrational spectroscopy relates to fracture incidence, and mineral maturity/ crystallinity (MMC) relates to tissue age. As FT-IR and Raman spectroscopy become more widely used to characterize the chemical ... ...

    Abstract Bone mineral carbonate content assessed by vibrational spectroscopy relates to fracture incidence, and mineral maturity/ crystallinity (MMC) relates to tissue age. As FT-IR and Raman spectroscopy become more widely used to characterize the chemical composition of bone in pre-clinical and translational studies, their bone mineral outcomes require improved validation to inform interpretation of spectroscopic data. In this study, our objectives were (1) to relate Raman and FT-IR carbonate:phosphate ratios calculated through direct integration of peaks to gold-standard analytical measures of carbonate content and underlying subband ratios; (2) to relate Raman and FT-IR MMC measures to gold-standard analytical measures of crystal size in chemical standards and native bone powders. Raman and FT-IR direct integration carbonate:phosphate ratios increased with carbonate content (Raman: p < 0.01, R
    MeSH term(s) Carbonates ; Durapatite ; Hydroxyapatites ; Spectroscopy, Fourier Transform Infrared ; Spectrum Analysis, Raman
    Chemical Substances Carbonates ; Hydroxyapatites ; Durapatite (91D9GV0Z28)
    Language English
    Publishing date 2021-03-12
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 304266-2
    ISSN 1432-0827 ; 0944-0747 ; 0008-0594 ; 0171-967X
    ISSN (online) 1432-0827
    ISSN 0944-0747 ; 0008-0594 ; 0171-967X
    DOI 10.1007/s00223-021-00825-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Potentiation of Cytokine-Mediated Restriction of

    Ngwaga, Tshegofatso / Hydock, Alex J / Ganesan, Sandhya / Shames, Stephanie R

    Journal of bacteriology

    2019  Volume 201, Issue 14

    Abstract: Legionella ... ...

    Abstract Legionella pneumophila
    MeSH term(s) Animals ; Bacterial Proteins/physiology ; Cells, Cultured ; Cytokines/immunology ; Cytoplasm/metabolism ; Host-Pathogen Interactions ; Immunity, Innate ; Legionella/physiology ; Macrophages/immunology ; Macrophages/microbiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Protein Transport ; Signal Transduction
    Chemical Substances Bacterial Proteins ; Cytokines
    Language English
    Publishing date 2019-06-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2968-3
    ISSN 1098-5530 ; 0021-9193
    ISSN (online) 1098-5530
    ISSN 0021-9193
    DOI 10.1128/JB.00755-18
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Peripheral cortical bone density predicts vertebral bone mineral properties in spine fusion surgery patients.

    Heilbronner, Alison K / Dash, Alexander / Straight, Beth E / Snyder, Leah J / Ganesan, Sandhya / Adu, Kobby B / Jae, Andy / Clare, Shannon / Billings, Emma / Kim, Han Jo / Cunningham, Matthew / Lebl, Darren R / Donnelly, Eve / Stein, Emily M

    Bone

    2023  Volume 169, Page(s) 116678

    Abstract: Spine fusion surgery is one of the most common orthopedic procedures, with over 400,000 performed annually to correct deformities and pain. However, complications occur in approximately one third of cases. While many of these complications may be related ...

    Abstract Spine fusion surgery is one of the most common orthopedic procedures, with over 400,000 performed annually to correct deformities and pain. However, complications occur in approximately one third of cases. While many of these complications may be related to poor bone quality, it is difficult to detect bone abnormalities prior to surgery. Areal BMD (aBMD) assessed by DXA may be artifactually high in patients with spine pathology, leading to missed diagnosis of deficits. In this study, we related preoperative imaging characteristics of both central and peripheral sites to direct measurements of bone quality in vertebral biopsies. We hypothesized that pre-operative imaging outcomes would relate to vertebral bone mineralization and collagen properties. Pre-operative assessments included DXA measurements of aBMD of the spine, hip, and forearm, central quantitative computed tomography (QCT) of volumetric BMD (vBMD) at the lumbar spine, and high resolution peripheral quantitative computed tomography (HRpQCT; Xtreme CT2) measurements of vBMD and microarchitecture at the distal radius and tibia. Bone samples were collected intraoperatively from the lumbar vertebrae and analyzed using Fourier-transform Infrared (FTIR) spectroscopy. Bone samples were obtained from 23 postmenopausal women (mean age 67 ± 7 years, BMI 28 ± 8 kg/m
    MeSH term(s) Humans ; Female ; Middle Aged ; Aged ; Absorptiometry, Photon/methods ; Bone Density ; Bone and Bones ; Cortical Bone ; Lumbar Vertebrae ; Radius
    Language English
    Publishing date 2023-01-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 632515-4
    ISSN 1873-2763 ; 8756-3282
    ISSN (online) 1873-2763
    ISSN 8756-3282
    DOI 10.1016/j.bone.2023.116678
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: NF-κB/Rel proteins and the humoral immune responses of Drosophila melanogaster.

    Ganesan, Sandhya / Aggarwal, Kamna / Paquette, Nicholas / Silverman, Neal

    Current topics in microbiology and immunology

    2010  Volume 349, Page(s) 25–60

    Abstract: Nuclear Factor-κB (NF-κB)/Rel transcription factors form an integral part of innate immune defenses and are conserved throughout the animal kingdom. Studying the function, mechanism of activation and regulation of these factors is crucial for ... ...

    Abstract Nuclear Factor-κB (NF-κB)/Rel transcription factors form an integral part of innate immune defenses and are conserved throughout the animal kingdom. Studying the function, mechanism of activation and regulation of these factors is crucial for understanding host responses to microbial infections. The fruit fly Drosophila melanogaster has proved to be a valuable model system to study these evolutionarily conserved NF-κB mediated immune responses. Drosophila combats pathogens through humoral and cellular immune responses. These humoral responses are well characterized and are marked by the robust production of a battery of anti-microbial peptides. Two NF-κB signaling pathways, the Toll and the IMD pathways, are responsible for the induction of these antimicrobial peptides. Signal transduction in these pathways is strikingly similar to that in mammalian TLR pathways. In this chapter, we discuss in detail the molecular mechanisms of microbial recognition, signal transduction and NF-κB regulation, in both the Toll and the IMD pathways. Similarities and differences relative to their mammalian counterparts are discussed, and recent advances in our understanding of the intricate regulatory networks in these NF-κB signaling pathways are also highlighted.
    MeSH term(s) Adaptive Immunity ; Animals ; Drosophila Proteins/physiology ; Drosophila melanogaster/immunology ; Immunity, Humoral ; NF-kappa B/physiology ; Signal Transduction ; Toll-Like Receptors/physiology ; Transcription Factors/physiology
    Chemical Substances Drosophila Proteins ; NF-kappa B ; Rel protein, Drosophila ; Tl protein, Drosophila ; Toll-Like Receptors ; Transcription Factors ; imd protein, Drosophila
    Language English
    Publishing date 2010-09-18
    Publishing country Germany
    Document type Journal Article ; Review
    ISSN 0070-217X
    ISSN 0070-217X
    DOI 10.1007/82_2010_107
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article: 87 : Caspase-8 regulates β-glucan induced IL-1β production and cell death

    Ganesan, Sandhya / K. Rathinam, Vijay A / Bossaller, Lukas / Kaiser, William J / Mocarski, Edward S / Green, Douglas R / Silverman, Neal S / Fitzgerald, Katherine A

    Cytokine. 2013 Sept., v. 63, no. 3

    2013  

    Abstract: Inflammasomes play a crucial role in host defense against a variety of microbial infections through regulating the maturation of the IL-1 family of cytokines as well as pyroptotic cell death. We have previously identified an essential role for the NLRP3- ... ...

    Abstract Inflammasomes play a crucial role in host defense against a variety of microbial infections through regulating the maturation of the IL-1 family of cytokines as well as pyroptotic cell death. We have previously identified an essential role for the NLRP3-ASC-Caspase-1 inflammasome in IL-1β production triggered by the fungal pathogen, C. albicans and the importance of this pathway in the clearance of C. albicans in an in vivo mouse model of Oropharyngeal Candidiasis (OPC). Here, we uncovered an important role for the pro-apoptotic caspase, Caspase-8 in IL-1β production induced by β-glucan, a potent immunostimulatory component of fungal cell walls. We found that β-glucan induced IL-1β production requires Caspase-8, in addition to the NLRP3-ASC-Caspase-1 inflammasome. We treated bone marrow derived macrophages and dendritic cells from RIP3⁻/⁻Caspase-8⁻/⁻ mice with various β-glucan related molecules, such as curdlan, fungal whole glucan particles or heat killed C. albicans, and found that Caspase-8 was required for IL-1β production with these stimuli but not with canonical inflammasome activators such as silica, nigericin or poly (dA:dT). Of note, Caspase-8 deficiency did not affect β-glucan induced synthesis of pro-IL1β. In addition, RIP3⁻/⁻Caspase-8⁻/⁻cells were protected from β-glucan induced cell death, whereas RIP3⁻/⁻ deficiency did not affect β-glucan induced IL-1β production or cell death. In contrast to these observations, we found that IL-1β production and cell death in response to live C. albicans infection was not Caspase-8 dependent, raising the possibility that β-glucan may not be exposed by C. albicans to engage this pathway. This study establishes a key link between Caspase-8 and Caspase-1 in coordinating cytokine secretion and cell death in response to fungal pathogenic patterns, and provides evidence for how pathways leading to inflammation and cell death are intertwined for an effective host immune response.
    Keywords animal models ; apoptosis ; bone marrow ; candidiasis ; caspase-1 ; caspase-8 ; cell walls ; curdlan ; dendritic cells ; fungi ; heat ; immune response ; inflammation ; interleukin-1 ; macrophages ; mice ; nigericin ; pathogens ; secretion ; silica
    Language English
    Dates of publication 2013-09
    Size p. 263-264.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 1018055-2
    ISSN 1096-0023 ; 1043-4666
    ISSN (online) 1096-0023
    ISSN 1043-4666
    DOI 10.1016/j.cyto.2013.06.087
    Database NAL-Catalogue (AGRICOLA)

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  9. Article ; Online: A novel role for the NLRC4 inflammasome in mucosal defenses against the fungal pathogen Candida albicans.

    Tomalka, Jeffrey / Ganesan, Sandhya / Azodi, Elaheh / Patel, Krupen / Majmudar, Parth / Hall, Brian A / Fitzgerald, Katherine A / Hise, Amy G

    PLoS pathogens

    2011  Volume 7, Issue 12, Page(s) e1002379

    Abstract: Candida sp. are opportunistic fungal pathogens that colonize the skin and oral cavity and, when overgrown under permissive conditions, cause inflammation and disease. Previously, we identified a central role for the NLRP3 inflammasome in regulating IL-1β ...

    Abstract Candida sp. are opportunistic fungal pathogens that colonize the skin and oral cavity and, when overgrown under permissive conditions, cause inflammation and disease. Previously, we identified a central role for the NLRP3 inflammasome in regulating IL-1β production and resistance to dissemination from oral infection with Candida albicans. Here we show that mucosal expression of NLRP3 and NLRC4 is induced by Candida infection, and up-regulation of these molecules is impaired in NLRP3 and NLRC4 deficient mice. Additionally, we reveal a role for the NLRC4 inflammasome in anti-fungal defenses. NLRC4 is important for control of mucosal Candida infection and impacts inflammatory cell recruitment to infected tissues, as well as protects against systemic dissemination of infection. Deficiency in either NLRC4 or NLRP3 results in severely attenuated pro-inflammatory and antimicrobial peptide responses in the oral cavity. Using bone marrow chimeric mouse models, we show that, in contrast to NLRP3 which limits the severity of infection when present in either the hematopoietic or stromal compartments, NLRC4 plays an important role in limiting mucosal candidiasis when functioning at the level of the mucosal stroma. Collectively, these studies reveal the tissue specific roles of the NLRP3 and NLRC4 inflammasome in innate immune responses against mucosal Candida infection.
    MeSH term(s) Animals ; Apoptosis Regulatory Proteins/immunology ; Apoptosis Regulatory Proteins/metabolism ; Calcium-Binding Proteins/immunology ; Calcium-Binding Proteins/metabolism ; Candida albicans/immunology ; Candidiasis/immunology ; Candidiasis/metabolism ; Carrier Proteins/immunology ; Carrier Proteins/metabolism ; Enzyme-Linked Immunosorbent Assay ; Fluorescent Antibody Technique ; Immunity, Innate/immunology ; Immunity, Mucosal ; Inflammasomes/immunology ; Inflammasomes/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mouth Mucosa/immunology ; Mouth Mucosa/metabolism ; Mouth Mucosa/microbiology ; NLR Family, Pyrin Domain-Containing 3 Protein ; Real-Time Polymerase Chain Reaction
    Chemical Substances Apoptosis Regulatory Proteins ; Calcium-Binding Proteins ; Carrier Proteins ; Inflammasomes ; Ipaf protein, mouse ; NLR Family, Pyrin Domain-Containing 3 Protein ; Nlrp3 protein, mouse
    Language English
    Publishing date 2011-12-08
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2205412-1
    ISSN 1553-7374 ; 1553-7366
    ISSN (online) 1553-7374
    ISSN 1553-7366
    DOI 10.1371/journal.ppat.1002379
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1β production in response to β-glucans and the fungal pathogen, Candida albicans.

    Ganesan, Sandhya / Rathinam, Vijay A K / Bossaller, Lukas / Army, Kelly / Kaiser, William J / Mocarski, Edward S / Dillon, Christopher P / Green, Douglas R / Mayadas, Tanya N / Levitz, Stuart M / Hise, Amy G / Silverman, Neal / Fitzgerald, Katherine A

    Journal of immunology (Baltimore, Md. : 1950)

    2014  Volume 193, Issue 5, Page(s) 2519–2530

    Abstract: Inflammasomes are central mediators of host defense to a wide range of microbial pathogens. The nucleotide-binding domain and leucine-rich repeat containing family (NLR), pyrin domain-containing 3 (NLRP3) inflammasome plays a key role in triggering ... ...

    Abstract Inflammasomes are central mediators of host defense to a wide range of microbial pathogens. The nucleotide-binding domain and leucine-rich repeat containing family (NLR), pyrin domain-containing 3 (NLRP3) inflammasome plays a key role in triggering caspase-1-dependent IL-1β maturation and resistance to fungal dissemination in Candida albicans infection. β-Glucans are major components of fungal cell walls that trigger IL-1β secretion in both murine and human immune cells. In this study, we sought to determine the contribution of β-glucans to C. albicans-induced inflammasome responses in mouse dendritic cells. We show that the NLRP3-apoptosis-associated speck-like protein containing caspase recruitment domain protein-caspase-1 inflammasome is absolutely critical for IL-1β production in response to β-glucans. Interestingly, we also found that both complement receptor 3 (CR3) and dectin-1 play a crucial role in coordinating β-glucan-induced IL-1β processing as well as a cell death response. In addition to the essential role of caspase-1, we identify an important role for the proapoptotic protease caspase-8 in promoting β-glucan-induced cell death and NLRP3 inflammasome-dependent IL-1β maturation. A strong requirement for CR3 and caspase-8 also was found for NLRP3-dependent IL-1β production in response to heat-killed C. albicans. Taken together, these results define the importance of dectin-1, CR3, and caspase-8, in addition to the canonical NLRP3 inflammasome, in mediating β-glucan- and C. albicans-induced innate responses in dendritic cells. Collectively, these findings establish a novel link between β-glucan recognition receptors and the inflammatory proteases caspase-8 and caspase-1 in coordinating cytokine secretion and cell death in response to immunostimulatory fungal components.
    MeSH term(s) Animals ; Candida albicans/genetics ; Candida albicans/immunology ; Candidiasis/genetics ; Candidiasis/immunology ; Candidiasis/pathology ; Carrier Proteins/genetics ; Carrier Proteins/immunology ; Caspase 8/genetics ; Caspase 8/immunology ; Cell Death/genetics ; Cell Death/immunology ; Dendritic Cells/immunology ; Dendritic Cells/pathology ; Fungal Polysaccharides/genetics ; Fungal Polysaccharides/immunology ; Humans ; Interleukin-1beta/genetics ; Interleukin-1beta/immunology ; Lectins, C-Type/genetics ; Lectins, C-Type/immunology ; Macrophage-1 Antigen/genetics ; Macrophage-1 Antigen/immunology ; Mice ; Mice, Knockout ; NLR Family, Pyrin Domain-Containing 3 Protein ; beta-Glucans/immunology
    Chemical Substances Carrier Proteins ; Fungal Polysaccharides ; IL1B protein, mouse ; Interleukin-1beta ; Lectins, C-Type ; Macrophage-1 Antigen ; NLR Family, Pyrin Domain-Containing 3 Protein ; Nlrp3 protein, mouse ; beta-Glucans ; dectin 1 ; Casp8 protein, mouse (EC 3.4.22.-) ; Caspase 8 (EC 3.4.22.-)
    Language English
    Publishing date 2014-07-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1400276
    Database MEDical Literature Analysis and Retrieval System OnLINE

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