scholarly journals Dectin-3 recognizes cryptococcal glucuronoxylomannan to initiate host defense against cryptococcosis

2018 ◽  
Author(s):  
Hua-Rong Huang ◽  
Fan Li ◽  
Hua Han ◽  
Quan-Zhen Lv ◽  
Xia Xu ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Inflammatory Cytokine Production ◽  
Lectin Receptor ◽  
Structural Differences ◽  
Life Threatening ◽  
Serotype B ◽  
Deficient Mice ◽  
Macrophage Accumulation

AbstractCryptococcus neoformansandCryptococcus gattiicause life-threatening meningoencephalitis and pneumonia in immunosuppressed and immunocompetent individuals. Given the structural differences of major polysaccharide glucuronoxylomannan (GXM) betweenC. neoformansandC. gattii, it remains unclear that how innate immune system recognizes GXM. Here, we report that C-type lectin receptor Dectin-3 (MCL encoded by Clec4d) is a direct receptor for GXMs fromC. neoformansserotype AD (C.n-AD) andC. gattiiserotype B (C.g-B). GXMs fromC.n-AD andC.g-B activated both NF-κB and ERK pathways to induce the pro-inflammatory cytokine production, whereas it was completely abolished due to deficiency of Dectin-3 or its downstream adaptor protein CARD9. Upon pulmonaryC.n-AD andC.g-B infection, Dectin-3- and CARD9-deficient mice were highly susceptible and showed augmented lung injury due to impairment of alveolar macrophage accumulation and killing activities. These results demonstrate that Dectin-3 contributes to host immunity againstCryptococcusinfection through selectively recognizingGXM.

scholarly journals C4b binding protein negatively regulates TLR1/2 response

2016 ◽  
Vol 23 (1) ◽  
pp. 11-19 ◽  
Author(s):  
Naoko Morita ◽  
Ikuko Yamai ◽  
Koichiro Takahashi ◽  
Yutaka Kusumoto ◽  
Takuma Shibata ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Binding Protein ◽  
Negative Regulation ◽  
Negative Regulator ◽  
Wild Type ◽  
Inflammatory Cytokine Production ◽  
Inflammatory Signals ◽  
Deficient Mice

TLR2 associates with TLR1 and recognizes microbial lipoproteins. Pam3CSK4, a triacylated lipoprotein, is anchored to the extracellular domain of TLR1 and TLR2 and induces pro-inflammatory signals. Here we show that C4b binding protein (C4BP), which is a complement pathway inhibitor, is a TLR2-associated molecule. Immunoprecipitation assay using anti-TLR2 mAb shows that C4BP binds to TLR2. In C4BP-deficient mice, Pam3CSK4-induced IL-6 levels were increased compared with wild type mice. In C4BP-expressing cells, Pam3CSK4-induced IL-8 production was reduced depending on the C4BP expression levels. These results reveal the important role of C4BP in negative regulation of TLR1/2-dependent pro-inflammatory cytokine production. Furthermore, using a fluorescent conjugated Pam3CSK4, we show that C4BP blocks the binding of Pam3CSK4 to TLR1/2. Finally, we show that exogenous C4BP also inhibits Pam3CSK4-induced signaling leading to IL-8 production. Our results indicate C4BP binding to TLR2 and consequent neutralization of its activity otherwise inducing pro-inflammatory cytokine production. C4BP is a negative regulator of TLR1/2 activity.

scholarly journals MyD88-Dependent Signaling Drives Host Survival and Early Cytokine Production during Histoplasma capsulatum Infection

2015 ◽  
Vol 83 (4) ◽  
pp. 1265-1275 ◽  
Author(s):  
Alison Coady ◽  
Anita Sil
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Alveolar Macrophages ◽  
Fungal Pathogen ◽  
Histoplasma Capsulatum ◽  
Cytokine Production ◽  
Adaptor Protein ◽  
Cell Types ◽  
Innate Immune ◽  
Content Type

The ability of the innate immune system to trigger an adaptive T cell response is critical to resolution of infection with the fungal pathogenHistoplasma capsulatum. However, the signaling pathways and cell types involved in the recognition of and response to this respiratory pathogen remain poorly defined. Here, we show that MyD88, an adaptor protein vital to multiple innate immune pathways, is critically required for the host response toHistoplasma. MyD88-deficient (MyD88−/−) mice are unable to control the fungal burden and are more sensitive toHistoplasmainfection than wild-type, Dectin-1−/−, or interleukin 1 receptor-deficient (IL-1R−/−) mice. We found that MyD88 is necessary for the production of key early inflammatory cytokines and the subsequent recruitment of inflammatory monocytes to the lung. In both ourin vitroandex vivoanalyses, MyD88 was intrinsically required in dendritic cells and alveolar macrophages for initial cytokine production. Additionally, MyD88-deficient bone marrow-derived dendritic cells fail to efficiently control fungal growth when cocultured with primed splenic T cells. Surprisingly, mice that lack MyD88 only in dendritic cells and alveolar macrophages are competent for early cytokine production and normal survival, indicating the presence of compensatory and redundant MyD88 signaling in other cell types during infection. Ultimately, global MyD88 deficiency prevents proper T cell activation and gamma interferon (IFN-γ) production, which are critical for infection resolution. Collectively, this work reveals a central role for MyD88 in coordinating the innate and adaptive immune responses to infection with this ubiquitous fungal pathogen of humans.

scholarly journals Innate immunity against Francisella tularensis is dependent on the ASC/caspase-1 axis

2005 ◽  
Vol 202 (8) ◽  
pp. 1043-1049 ◽  
Author(s):  
Sanjeev Mariathasan ◽  
David S. Weiss ◽  
Vishva M. Dixit ◽  
Denise M. Monack
Keyword(s):  
Francisella Tularensis ◽  
Bacterial Pathogen ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Wild Type ◽  
Innate Defense ◽  
Caspase 1 ◽  
Host Cell Death ◽  
Host Defense Response ◽  
Deficient Mice

Francisella tularensis is a highly infectious gram-negative coccobacillus that causes the zoonosis tularemia. This bacterial pathogen causes a plague-like disease in humans after exposure to as few as 10 cells. Many of the mechanisms by which the innate immune system fights Francisella are unknown. Here we show that wild-type Francisella, which reach the cytosol, but not Francisella mutants that remain localized to the vacuole, induced a host defense response in macrophages, which is dependent on caspase-1 and the death-fold containing adaptor protein ASC. Caspase-1 and ASC signaling resulted in host cell death and the release of the proinflammatory cytokines interleukin (IL)-1β and IL-18. F. tularensis–infected caspase-1– and ASC-deficient mice showed markedly increased bacterial burdens and mortality as compared with wild-type mice, demonstrating a key role for caspase-1 and ASC in innate defense against infection by this pathogen.

scholarly journals The Role of JAK-3 in Regulating TLR-Mediated Inflammatory Cytokine Production in Innate Immune Cells

2013 ◽  
Vol 191 (3) ◽  
pp. 1164-1174 ◽  
Author(s):  
Huizhi Wang ◽  
Jonathan Brown ◽  
Shegan Gao ◽  
Shuang Liang ◽  
Ravi Jotwani ◽  
...  
Keyword(s):  
Immune Cells ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Inflammatory Cytokine Production

scholarly journals MicroRNA expression in maturing murine megakaryocytes

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. e128-e138 ◽  
Author(s):  
Joanna B. Opalinska ◽  
Alexey Bersenev ◽  
Zhe Zhang ◽  
Alec A. Schmaier ◽  
John Choi ◽  
...  
Keyword(s):  
Cytokine Production ◽  
Microrna Expression ◽  
Innate Immune ◽  
Mouse Bone Marrow ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Progenitor ◽  
Inflammatory Cytokine Production ◽  
Small Noncoding Rnas ◽  
Cast Doubt

Abstract MicroRNAs are small noncoding RNAs that regulate cellular development by interfering with mRNA stability and translation. We examined global microRNA expression during the differentiation of murine hematopoietic progenitors into megakaryocytes. Of 435 miRNAs analyzed, 13 were up-regulated and 81 were down-regulated. Many of these changes are consistent with miRNA profiling studies of human megakaryocytes and platelets, although new patterns also emerged. Among 7 conserved miRNAs that were up-regulated most strongly in murine megakaryocytes, 6 were also induced in the related erythroid lineage. MiR-146a was strongly up-regulated during mouse and human megakaryopoiesis but not erythropoiesis. However, overexpression of miR-146a in mouse bone marrow hematopoietic progenitor populations produced no detectable alterations in megakaryocyte development or platelet production in vivo or in colony assays. Our findings extend the repertoire of differentially regulated miRNAs during murine megakaryopoiesis and provide a useful new dataset for hematopoiesis research. In addition, we show that enforced hematopoietic expression of miR-146a has minimal effects on megakaryopoiesis. These results are compatible with prior studies indicating that miR-146a inhibits megakaryocyte production indirectly by suppressing inflammatory cytokine production from innate immune cells, but cast doubt on a different study, which suggests that this miRNA inhibits megakaryopoiesis cell-autonomously.

scholarly journals Critical Role for MyD88-Mediated Neutrophil Recruitment during Clostridium difficile Colitis

2012 ◽  
Vol 80 (9) ◽  
pp. 2989-2996 ◽  
Author(s):  
Irene Jarchum ◽  
Mingyu Liu ◽  
Chao Shi ◽  
Michele Equinda ◽  
Eric G. Pamer
Keyword(s):  
Clostridium Difficile ◽  
Inflammatory Responses ◽  
Adaptor Protein ◽  
Neutrophil Recruitment ◽  
Innate Immune ◽  
Antibiotic Administration ◽  
Immune Signaling ◽  
Content Type ◽  
Innate Immune Signaling ◽  
Deficient Mice

ABSTRACTClostridium difficilecan infect the large intestine and cause colitis when the normal intestinal microbiota is altered by antibiotic administration. Little is known about the innate immune signaling pathways that marshal inflammatory responses toC. difficileinfection and whether protective and pathogenic inflammatory responses can be dissociated. Toll-like receptors predominantly signal via the MyD88 adaptor protein and are important mediators of innate immune signaling in the intestinal mucosa. Here, we demonstrate that MyD88-mediated signals trigger neutrophil and CCR2-dependent Ly6Chimonocyte recruitment to the colonic lamina propria (cLP) during infection, which prevent dissemination of bystander bacteria to deeper tissues. Mortality is markedly increased in MyD88-deficient mice followingC. difficileinfection, as are parameters of mucosal tissue damage and inflammation. Antibody-mediated depletion of neutrophils markedly increases mortality, while attenuated recruitment of Ly6Chimonocytes in CCR2-deficient mice does not alter the course ofC. difficileinfection. Expression of CXCL1, a neutrophil-recruiting chemokine, is impaired in the cLP of MyD88−/−mice. Our studies suggest that MyD88-mediated signals promote neutrophil recruitment by inducing expression of CXCL1, thereby providing critical early defense againstC. difficile-mediated colitis.

scholarly journals Positive and Negative Regulation of FcεRI-Mediated Signaling by the Adaptor Protein LAB/NTAL

2004 ◽  
Vol 200 (8) ◽  
pp. 991-1000 ◽  
Author(s):  
Minghua Zhu ◽  
Yan Liu ◽  
Surapong Koonpaew ◽  
Olivia Granillo ◽  
Weiguo Zhang
Keyword(s):  
B Cells ◽  
Mast Cells ◽  
Cytokine Production ◽  
Cell Function ◽  
Adaptor Protein ◽  
Thymocyte Development ◽  
Positive Role ◽  
Erk Activation ◽  
Deficient Mice

Linker for activation of B cells (LAB, also called NTAL; a product of wbscr5 gene) is a newly identified transmembrane adaptor protein that is expressed in B cells, NK cells, and mast cells. Upon BCR activation, LAB is phosphorylated and interacts with Grb2. LAB is capable of rescuing thymocyte development in LAT-deficient mice. To study the in vivo function of LAB, LAB-deficient mice were generated. Although disruption of the Lab gene did not affect lymphocyte development, it caused mast cells to be hyperresponsive to stimulation via the FcεRI, evidenced by enhanced Erk activation, calcium mobilization, degranulation, and cytokine production. These data suggested that LAB negatively regulates mast cell function. However, mast cells that lacked both linker for activation of T cells (LAT) and LAB proteins had a more severe block in FcεRI-mediated signaling than LAT−/− mast cells, demonstrating that LAB also shares a redundant function with LAT to play a positive role in FcεRI-mediated signaling.

scholarly journals IRF5 Promotes Influenza Virus-Induced Inflammatory Responses in Human Induced Pluripotent Stem Cell-Derived Myeloid Cells and Murine Models

2020 ◽  
Vol 94 (9) ◽  
Author(s):  
Jessica L. Forbester ◽  
Mathew Clement ◽  
Dannielle Wellington ◽  
Amy Yeung ◽  
Sandra Dimonte ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Virus Replication ◽  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Inflammatory Responses ◽  
Myeloid Cells ◽  
Innate Immune ◽  
Inflammatory Cytokine Production ◽  
Induced Pluripotent

ABSTRACT Recognition of influenza A virus (IAV) by the innate immune system triggers pathways that restrict viral replication, activate innate immune cells, and regulate adaptive immunity. However, excessive innate immune activation can exaggerate disease. The pathways promoting excessive activation are incompletely understood, with limited experimental models to investigate the mechanisms driving influenza virus-induced inflammation in humans. Interferon regulatory factor 5 (IRF5) is a transcription factor that plays important roles in the induction of cytokines after viral sensing. In an in vivo model of IAV infection, IRF5 deficiency reduced IAV-driven immune pathology and associated inflammatory cytokine production, specifically reducing cytokine-producing myeloid cell populations in Irf5−/− mice but not impacting type 1 interferon (IFN) production or virus replication. Using cytometry by time of flight (CyTOF), we identified that human lung IRF5 expression was highest in cells of the myeloid lineage. To investigate the role of IRF5 in mediating human inflammatory responses by myeloid cells to IAV, we employed human-induced pluripotent stem cells (hIPSCs) with biallelic mutations in IRF5, demonstrating for the first time that induced pluripotent stem cell-derived dendritic cells (iPS-DCs) with biallelic mutations can be used to investigate the regulation of human virus-induced immune responses. Using this technology, we reveal that IRF5 deficiency in human DCs, or macrophages, corresponded with reduced virus-induced inflammatory cytokine production, with IRF5 acting downstream of Toll-like receptor 7 (TLR7) and, possibly, retinoic acid-inducible gene I (RIG-I) after viral sensing. Thus, IRF5 acts as a regulator of myeloid cell inflammatory cytokine production during IAV infection in mice and humans and drives immune-mediated viral pathogenesis independently of type 1 IFN and virus replication. IMPORTANCE The inflammatory response to influenza A virus (IAV) participates in infection control but contributes to disease severity. After viral detection, intracellular pathways are activated, initiating cytokine production, but these pathways are incompletely understood. We show that interferon regulatory factor 5 (IRF5) mediates IAV-induced inflammation and, in mice, drives pathology. This was independent of antiviral type 1 IFN and virus replication, implying that IRF5 could be specifically targeted to treat influenza virus-induced inflammation. We show for the first time that human iPSC technology can be exploited in genetic studies of virus-induced immune responses. Using this technology, we deleted IRF5 in human myeloid cells. These IRF5-deficient cells exhibited impaired influenza virus-induced cytokine production and revealed that IRF5 acts downstream of Toll-like receptor 7 and possibly retinoic acid-inducible gene I. Our data demonstrate the importance of IRF5 in influenza virus-induced inflammation, suggesting that genetic variation in the IRF5 gene may influence host susceptibility to viral diseases.

scholarly journals Glutathione Metabolism Contributes to the Induction of Trained Immunity

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 971
Author(s):  
Anaisa V. Ferreira ◽  
Valerie A.C.M. Koeken ◽  
Vasiliki Matzaraki ◽  
Sarantos Kostidis ◽  
Juan Carlos Alarcon-Barrera ◽  
...  
Keyword(s):  
Inflammatory Cytokine ◽  
Cytokine Production ◽  
Ex Vivo ◽  
Production Capacity ◽  
Innate Immune ◽  
Glutathione Metabolism ◽  
Nucleotide Polymorphisms ◽  
Inflammatory Cytokine Production ◽  
Trained Immunity

The innate immune system displays heterologous memory characteristics, which are characterized by stronger responses to a secondary challenge. This phenomenon termed trained immunity relies on epigenetic and metabolic rewiring of innate immune cells. As reactive oxygen species (ROS) production has been associated with the trained immunity phenotype, we hypothesized that the increased ROS levels and the main intracellular redox molecule glutathione play a role in the induction of trained immunity. Here we show that pharmacological inhibition of ROS in an in vitro model of trained immunity did not influence cell responsiveness; the modulation of glutathione levels reduced pro-inflammatory cytokine production in human monocytes. Single nucleotide polymorphisms (SNPs) in genes involved in glutathione metabolism were found to be associated with changes in pro-inflammatory cytokine production capacity upon trained immunity. Also, plasma glutathione concentrations were positively associated with ex vivo IL-1β production, a biomarker of trained immunity, produced by monocytes of BCG-vaccinated individuals. In conclusion, glutathione metabolism is involved in the induction of trained immunity, and future studies are warranted to explore its functional consequences in human diseases.

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