scholarly journals Multiple Roles of Myd88 in the Immune Response to the Plague F1-V Vaccine and in Protection against an Aerosol Challenge ofYersinia pestisCO92 in Mice

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Jennifer L. Dankmeyer ◽  
Randy L. Fast ◽  
Christopher K. Cote ◽  
Patricia L. Worsham ◽  
David Fritz ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune System ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Multiple Roles ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Lethal Challenge ◽  
V Protein ◽  
Deficient Mice

The current candidate vaccine againstYersinia pestisinfection consists of two subunit proteins: the capsule protein or F1 protein and the low calcium response V protein or V-antigen. Little is known of the recognition of the vaccine by the host’s innate immune system and how it affects the acquired immune response to the vaccine. Thus, we vaccinated Toll-like receptor (Tlr)2,4, and2/4-double deficient, as well as signal adaptor proteinMyd88-deficient mice. We found that Tlr4 and Myd88 appeared to be required for an optimal immune response to the F1-V vaccine but not Tlr2 when compared to wild-type mice. However, there was a difference between the requirement for Tlr4 and MyD88 in vaccinated animals. When F1-V vaccinatedTlr4mutant (lipopolysaccharide tolerant) andMyd88-deficient mice were challenged by aerosol withY. pestisCO92, all but oneTlr4mutant mice survived the challenge, but no vaccinatedMyd88-deficient mice survived the challenge. Spleens from these latter nonsurviving mice showed thatY. pestiswas not cleared from the infected mice. Our results suggest that MyD88 appears to be important for both an optimal immune response to F1-V and in protection against a lethal challenge ofY. pestisCO92 in F1-V vaccinated mice.

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.

Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis

2005 ◽  
Vol 288 (5) ◽  
pp. G1055-G1065 ◽  
Author(s):  
Masayuki Fukata ◽  
Kathrin S. Michelsen ◽  
Rajaraman Eri ◽  
Lisa S. Thomas ◽  
Bing Hu ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Bacterial Translocation ◽  
Innate Immune ◽  
Severe Bleeding ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Acute Colitis ◽  
Epithelial Injury ◽  
Adapter Molecule

Inflammatory bowel disease (IBD) arises from a dysregulated mucosal immune response to luminal bacteria. Toll-like receptor (TLR)4 recognizes LPS and transduces a proinflammatory signal through the adapter molecule myeloid differentiation marker 88 (MyD88). We hypothesized that TLR4 participates in the innate immune response to luminal bacteria and the development of colitis. TLR4−/− and MyD88−/− mice and littermate controls were given 2.5% dextran sodium sulfate (DSS) for 5 or 7 days followed by a 7-day recovery. Colitis was assessed by weight loss, rectal bleeding, and histopathology. Immunostaining was performed for macrophage markers, chemokine expression, and cell proliferation markers. DSS treatment of TLR4−/− mice was associated with striking reduction in acute inflammatory cells compared with wild-type mice despite similar degrees of epithelial injury. TLR4−/− mice experienced earlier and more severe bleeding than control mice. Similar results were seen with MyD88−/− mice, suggesting that this is the dominant downstream pathway. Mesenteric lymph nodes from TLR4−/− and MyD88−/− mice more frequently grew gram-negative bacteria. Altered neutrophil recruitment was due to diminished macrophage inflammatory protein-2 expression by lamina propria macrophages in TLR4−/− and MyD88−/− mice. The similarity in crypt epithelial damage between TLR4−/− or MyD88−/− and wild-type mice was seen despite decreased epithelial proliferation in knockout mice. TLR4 through the adapter molecule MyD88 is important in intestinal response to injury and in limiting bacterial translocation. Despite the diversity of luminal bacteria, other TLRs do not substitute for the role of TLR4 in this acute colitis model. A defective innate immune response may result in diminished bacterial clearance and ultimately dysregulated response to normal flora.

scholarly journals Pericentromeric hypomethylation elicits an interferon response in an animal model of ICF syndrome

2018 ◽  
Author(s):  
Srivarsha Rajshekar ◽  
Jun Yao ◽  
Paige K. Arnold ◽  
Sara G. Payne ◽  
Yinwen Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Animal Model ◽  
Innate Immune System ◽  
Innate Immune ◽  
Interferon Response ◽  
Wild Type ◽  
Icf Syndrome ◽  
Progressive Loss ◽  
Satellite Repeats ◽  
General Importance

AbstractPericentromeric satellite repeats are enriched in 5-methylcytosine (5mC). Loss of 5mC at these sequences is common in cancer and is a hallmark of Immunodeficiency, Centromere and Facial abnormalities (ICF) syndrome. While the general importance of 5mC is well-established, the specific functions of 5mC at pericentromeres are less clear. To address this deficiency, we generated a viable animal model of pericentromeric hypomethylation through mutation of the ICF-gene ZBTB24. Deletion of zebrafish zbtb24 caused a progressive loss of 5mC at pericentromeres and ICF-like phenotypes. Hypomethylation of these repeats triggered derepression of pericentromeric transcripts and activation of an interferon-based innate immune response. Injection of pericentromeric RNA is sufficient to elicit this response in wild-type embryos, and mutation of the MDA5-MAVS dsRNA-sensing machinery blocks the response in mutants. These findings identify activation of the innate immune system as an early consequence of pericentromeric hypomethylation, implicating derepression of pericentromeric transcripts as a trigger of autoimmunity.

scholarly journals Activation of the Innate Immune System by Treponema denticola Periplasmic Flagella through Toll-Like Receptor 2

2017 ◽  
Vol 86 (1) ◽  
Author(s):  
John Ruby ◽  
Michael Martin ◽  
Michael J. Passineau ◽  
Valentina Godovikova ◽  
J. Christopher Fenno ◽  
...  
Keyword(s):  
Immune System ◽  
Innate Immune System ◽  
Innate Immune ◽  
Treponema Denticola ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Content Type ◽  
Tnf Α ◽  
Toll Like Receptor 2 ◽  
Periplasmic Flagella

ABSTRACTTreponema denticolais an indigenous oral spirochete that inhabits the gingival sulcus or periodontal pocket. Increased numbers of oral treponemes within this environment are associated with localized periodontal inflammation, and they are also part of an anaerobic polymicrobial consortium responsible for endodontic infections. Previous studies have indicated thatT. denticolastimulates the innate immune system through Toll-like receptor 2 (TLR2); however, the pathogen-associated molecular patterns (PAMPs) responsible forT. denticolaactivation of the innate immune system are currently not well defined. In this study, we investigated the role played byT. denticolaperiplasmic flagella (PF), unique motility organelles of spirochetes, in stimulating an innate immune response. Wild-typeT. denticolastimulated the production of the cytokines tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), IL-6, IL-10, and IL-12 by monocytes from human peripheral blood mononuclear cells, while its isogenic nonmotile mutant lacking PF resulted in significantly diminished cytokine stimulation. In addition, highly purified PF were able to dose dependently stimulate cytokine TNF-α, IL-1β, IL-6, IL-10, and IL-12 production in human monocytes. Wild-typeT. denticolaand the purified PF triggered activation of NF-κB through TLR2, as determined using a variety of TLR-transfected human embryonic 293 cell lines, while the PF-deficient mutants lacked the ability to stimulate, and the complemented PF-positiveT. denticolastrain restored the activation. These findings suggest thatT. denticolastimulates the innate immune system in a TLR2-dependent fashion and that PF are a key bacterial component involved in this process.

scholarly journals Absence of GdX/UBL4A protects against inflammatory bowel diseases by regulating NF-κB signaling in DCs and macrophages

2018 ◽  
Author(s):  
Chunxiao Liu ◽  
Yifan Zhou ◽  
Mengdi Li ◽  
Ying Wang ◽  
Shigao Yang ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Diseases ◽  
Adaptor Protein ◽  
Endotoxin Shock ◽  
Innate Immune ◽  
Mucosal Inflammation ◽  
Innate Immune Responses ◽  
Bowel Diseases ◽  
Inflammatory Bowel ◽  
Deficient Mice

AbstractNuclear factor-kappa B (NF-κB) activation is critical for innate immune responses. Here we report that the UBL4A (Ubiquitin-like protein 4A, also named GdX) enhances dendritic cells (DCs) and macrophages (Mφ)-mediated innate immune defenses by positively regulating NF-κB signaling. GdX-deficient mice were resistant to LPS-induced endotoxin shock and DSS-induced colitis. DC- or Mφ-specific GdX-deficient mice displayed alleviated mucosal inflammation, and the production of pro-inflammatory cytokines by GdX-deficient DCs and Mφ was reduced. Mechanistically, we found that PTPN2 (TC45) and PP2A form a complex with RelA (p65) to mediate its dephosphorylation whereas GdX interrupts the TC45/PP2A/p65 complex formation and restrict p65 dephosphorylation by trapping TC45. Our study provides a mechanism by which NF-κB signaling is positively regulated by an adaptor protein GdX in DC or Mφ to maintain the innate immune response. Targeting GdX could be a strategy to reduce over-activated immune response in inflammatory diseases.

scholarly journals Urokinase receptor-deficient mice mount an innate immune response to and clarify respiratory viruses as efficiently as wild-type mice

Virulence ◽  
2015 ◽  
Vol 6 (7) ◽  
pp. 710-715 ◽  
Author(s):  
Manuel Ramos ◽  
Yolanda Lao ◽  
César Eguiluz ◽  
Margarita Del Val ◽  
Isidoro Martínez
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Respiratory Viruses ◽  
Urokinase Receptor ◽  
Innate Immune ◽  
Wild Type ◽  
Deficient Mice

scholarly journals Angiotensin II-induced hypertension and cardiac hypertrophy are differentially mediated by TLR3- and TLR4-dependent pathways

2019 ◽  
Vol 316 (5) ◽  
pp. H1027-H1038 ◽  
Author(s):  
Madhu V. Singh ◽  
Michael Z. Cicha ◽  
Sarah Nunez ◽  
David K. Meyerholz ◽  
Mark W. Chapleau ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Innate Immune System ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Ang Ii ◽  
Interferon Β ◽  
Induced Hypertension ◽  
Deficient Mice ◽  
Receptor Domain

Toll-like receptors (TLR) are key components of the innate immune system that elicit inflammatory responses through the adaptor proteins myeloid differentiation protein 88 (MyD88) and Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF). Previously, we demonstrated that TRIF mediates the signaling of angiotensin II (ANG II)- induced hypertension and cardiac hypertrophy. Since TRIF is activated selectively by TLR3 and TLR4, our goals in this study were to determine the roles of TLR3 and TLR4 in mediating ANG II-induced hypertension and cardiac hypertrophy, and associated changes in proinflammatory gene expression in heart and kidney. In wild-type (WT) mice, ANG II infusion (1,000 ng·kg−1·min−1 for 3 wk) increased systolic blood pressure and caused cardiac hypertrophy. In ANG II-infused TLR4-deficient mice ( Tlr4del), hypertrophy was significantly attenuated despite a preserved or enhanced hypertensive response. In contrast, in TLR3-deficient mice ( Tlr3−/−), both ANG II-induced hypertension and hypertrophy were abrogated. In WT mice, ANG II increased the expression of several proinflammatory genes in hearts and kidneys that were attenuated in both TLR4- and TLR3-deficient mice compared with WT. We conclude that ANG II activates both TLR4-TRIF and TLR3-TRIF pathways in a nonredundant manner whereby hypertension is dependent on activation of the TLR3-TRIF pathway and cardiac hypertrophy is dependent on both TLR3-TRIF and TLR4-TRIF pathways. NEW & NOTEWORTHY Angiotensin II (ANG II)-induced hypertension is dependent on the endosomal Toll-like receptor 3 (TLR3)-Toll-interleukin receptor domain-containing adaptor protein-inducing interferon-β (TRIF) pathway of the innate immune system but not on cell membrane localized TLR4. However, ANG II-induced cardiac hypertrophy is regulated by both TLR4-TRIF and TLR3-TRIF pathways. Thus, ANG II-induced rise in systolic blood pressure is independent of TLR4-TRIF effect on cardiac hypertrophy. The TLR3-TRIF pathway may be a potential target of therapeutic intervention.

Toll-like receptor 7 deficiency promotes survival and reduces adverse left ventricular remodelling after myocardial infarction

2019 ◽  
Vol 115 (12) ◽  
pp. 1791-1803 ◽  
Author(s):  
Dominique P V de Kleijn ◽  
Suet Yen Chong ◽  
Xiaoyuan Wang ◽  
Siti Maryam J M Yatim ◽  
Anna-Marie Fairhurst ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Immune System ◽  
Cardiac Function ◽  
Innate Immune System ◽  
Left Ventricular ◽  
Innate Immune ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Ventricular Remodelling ◽  
Left Ventricular Remodelling

Abstract Aims The Toll-like receptor 7 (TLR7) is an intracellular innate immune receptor activated by nucleic acids shed from dying cells leading to activation of the innate immune system. Since innate immune system activation is involved in the response to myocardial infarction (MI), this study aims to identify if TLR7 is involved in post-MI ischaemic injury and adverse remodelling after MI. Methods and results TLR7 involvement in MI was investigated in human tissue from patients with ischaemic heart failure, as well as in a mouse model of permanent left anterior descending artery occlusion in C57BL/6J wild type and TLR7 deficient (TLR7−/−) mice. TLR7 expression was up-regulated in human and mouse ischaemic myocardium after MI. Compared to wild type mice, TLR7−/− mice had less acute cardiac rupture associated with blunted activation of matrix metalloproteinase 2, increased expression of tissue inhibitor of metalloproteinase 1, recruitment of more myofibroblasts, and the formation of a myocardial scar with higher collagen fibre density. Furthermore, inflammatory cell influx and inflammatory cytokine expression post-MI were reduced in the TLR7−/− heart. During a 28-day follow-up after MI, TLR7 deficiency resulted in less chronic adverse left ventricular remodelling and better cardiac function. Bone marrow (BM) transplantation experiments showed that TLR7 deficiency in BM-derived cells preserved cardiac function after MI. Conclusions In acute MI, TLR7 mediates the response to acute cardiac injury and chronic remodelling probably via modulation of post-MI scar formation and BM-derived inflammatory infiltration of the myocardium.

scholarly journals Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy

2012 ◽  
Vol 117 (2) ◽  
pp. 329-338 ◽  
Author(s):  
Willem-Jan M. Schellekens ◽  
Hieronymus W. H. van Hees ◽  
Michiel Vaneker ◽  
Marianne Linkels ◽  
P. N. Richard Dekhuijzen ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Caspase 3 ◽  
Toll Like Receptor ◽  
Wild Type ◽  
Toll Like Receptor 4 ◽  
Ubiquitin Proteasome Pathway ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Diaphragm Atrophy ◽  
Deficient Mice

Background Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. Methods Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. Results Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. Conclusion Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

The dysfunctional innate immune response triggered by Toll-like receptor activation is restored by TLR7/TLR8 and TLR9 ligands in cutaneous lichen planus

2014 ◽  
Vol 172 (1) ◽  
pp. 48-55 ◽  
Author(s):  
R. Domingues ◽  
G. Costa de Carvalho ◽  
L.M. da Silva Oliveira ◽  
E. Futata Taniguchi ◽  
J.M. Zimbres ◽  
...  
Keyword(s):  
Immune Response ◽  
Lichen Planus ◽  
Innate Immune Response ◽  
Receptor Activation ◽  
Innate Immune ◽  
Toll Like Receptor
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