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MyD88 in T cells

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https://www.readbyqxmd.com/read/28099848/biophysical-attributes-of-cpg-presentation-control-tlr9-signaling-to-differentially-polarize-systemic-immune-responses
#1
Jardin A Leleux, Pallab Pradhan, Krishnendu Roy
It is currently unknown whether and how mammalian pathogen recognition receptors (PRRs) respond to biophysical patterns of pathogen-associated molecular danger signals. Using synthetic pathogen-like particles (PLPs) that mimic physical properties of bacteria or large viruses, we have discovered that the quality and quantity of Toll-like receptor 9 (TLR9) signaling by CpG in mouse dendritic cells (mDCs) are uniquely dependent on biophysical attributes; specifically, the surface density of CpG and size of the presenting PLP...
January 17, 2017: Cell Reports
https://www.readbyqxmd.com/read/28088065/methionine-enkephalin-menk-mounts-antitumor-effect-via-regulating-dendritic-cells-dcs
#2
Yiming Meng, Xinghua Gao, Wenna Chen, Nicolas P Plotnikoff, Noreen Griffin, Guirong Zhang, Fengping Shan
MENK, an endogenous opioid peptide has been reported to have many immunological and antitumor activities. So far the detailed mechanisms of antitumor through regulating DCs by MENK have not been elucidated yet. The aim of this work was to investigate the antitumor mechanisms of MENK via regulating DC. The monitoring methods, such as ELISA, MTS assay, CFSE, Real-time PCR and Western blot were included in our research. We found bone marrow derived dendritic cells (BMDCs) in 36 female C57BL/6 mice treated with MENK enhanced expression of key surface molecules, increased production of critical cytokines reduced endocytosis of FITC-dextran, upregulated TLR4 through MyD88/NF-κB signaling pathway and mounted higher antitumor activity...
January 11, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28076786/porphyromonas-gingivalis-promotes-unrestrained-type-i-interferon-production-by-dysregulating-tam-signaling-via-myd88-degradation
#3
Gabriel Mizraji, Maria Nassar, Hadas Segev, Hafiz Sharawi, Luba Eli-Berchoer, Tal Capucha, Tsipora Nir, Yaara Tabib, Avraham Maimon, Shira Dishon, Lior Shapira, Gabriel Nussbaum, Asaf Wilensky, Avi-Hai Hovav
Whereas type I interferons (IFNs-I) were proposed to be elevated in human periodontitis, their role in the disease remains elusive. Using a bacterial-induced model of murine periodontitis, we revealed a prolonged elevation in IFN-I expression. This was due to the downregulation of TAM signaling, a major negative regulator of IFN-I. Further examination revealed that the expression of certain TAM components was reduced as a result of prolonged degradation of MYD88 by the infection. As a result of such prolonged IFN-I production, innate immunological functions of the gingiva were disrupted, and CD4(+) T cells were constitutively primed by dendritic cells, leading to elevated RANKL expression and, subsequently, alveolar bone loss (ABL)...
January 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28069819/temporal-role-for-myd88-in-a-model-of-brucella-induced-arthritis-and-musculoskeletal-inflammation
#4
Carolyn A Lacey, William J Mitchell, Charles R Brown, Jerod A Skyberg
Brucella spp. are facultative intracellular Gram-negative bacteria that cause the zoonotic disease brucellosis, one of the most common global zoonoses. Osteomyelitis, arthritis and musculoskeletal inflammation are common focal complications of brucellosis in humans; however, wild-type (WT) mice infected systemically with conventional doses of Brucella do not develop these complications. Here we report WT C57BL/6 mice infected via the footpad with 10(3)-10(6) CFUs of Brucella spp. display neutrophil and monocyte infiltration to the joint space and surrounding musculoskeletal tissue...
January 9, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28056114/diagnosis-and-management-of-waldenstr%C3%A3-m-macroglobulinemia-mayo-stratification-of-macroglobulinemia-and-risk-adapted-therapy-msmart-guidelines-2016
#5
Prashant Kapoor, Stephen M Ansell, Rafael Fonseca, Asher Chanan-Khan, Robert A Kyle, Shaji K Kumar, Joseph R Mikhael, Thomas E Witzig, Michelle Mauermann, Angela Dispenzieri, Sikander Ailawadhi, A Keith Stewart, Martha Q Lacy, Carrie A Thompson, Francis K Buadi, David Dingli, William G Morice, Ronald S Go, Dragan Jevremovic, Taimur Sher, Rebecca L King, Esteban Braggio, Ann Novak, Vivek Roy, Rhett P Ketterling, Patricia T Greipp, Martha Grogan, Ivana N Micallef, P Leif Bergsagel, Joseph P Colgan, Nelson Leung, Wilson I Gonsalves, Yi Lin, David J Inwards, Suzanne R Hayman, Grzegorz S Nowakowski, Patrick B Johnston, Steven J Russell, Svetomir N Markovic, Steven R Zeldenrust, Yi L Hwa, John A Lust, Luis F Porrata, Thomas M Habermann, S Vincent Rajkumar, Morie A Gertz, Craig B Reeder
Importance: Waldenström macroglobulinemia (WM), an IgM-associated lymphoplasmacytic lymphoma, has witnessed several practice-altering advances in recent years. With availability of a wider array of therapies, the management strategies have become increasingly complex. Our multidisciplinary team appraised studies published or presented up to December 2015 to provide consensus recommendations for a risk-adapted approach to WM, using a grading system. Observations: Waldenström macroglobulinemia remains a rare, incurable cancer, with a heterogeneous disease course...
January 5, 2017: JAMA Oncology
https://www.readbyqxmd.com/read/28011934/exogenous-il-33-restores-dendritic-cell-activation-and-maturation-in-established-cancer
#6
Donye Dominguez, Cong Ye, Zhe Geng, Siqi Chen, Jie Fan, Lei Qin, Alan Long, Long Wang, Zhuoli Zhang, Yi Zhang, Deyu Fang, Timothy M Kuzel, Bin Zhang
The role of IL-33, particularly in tumor growth and tumor immunity, remains ill-defined. We show that exogenous IL-33 can induce robust antitumor effect through a CD8(+) T cell-dependent mechanism. Systemic administration of rIL-33 alone was sufficient to inhibit growth of established tumors in transplant and de novo melanoma tumorigenesis models. Notably, in addition to a direct action on CD8(+) T cell expansion and IFN-γ production, rIL-33 therapy activated myeloid dendritic cells (mDCs) in tumor-bearing mice, restored antitumor T cell activity, and increased Ag cross-presentation within the tumor microenvironment...
December 23, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28003376/selective-irak4-inhibition-attenuates-disease-in-murine-lupus-models-and-demonstrates-steroid-sparing-activity
#7
Shailesh Dudhgaonkar, Sourabh Ranade, Jignesh Nagar, Siva Subramani, Durga Shiv Prasad, Preethi Karunanithi, Ratika Srivastava, Kamala Venkatesh, Sabariya Selvam, Prasad Krishnamurthy, T Thanga Mariappan, Ajay Saxena, Li Fan, Dawn K Stetsko, Deborah A Holloway, Xin Li, Jun Zhu, Wen-Pin Yang, Stefan Ruepp, Satheesh Nair, Joseph Santella, John Duncia, John Hynes, Kim W McIntyre, Julie A Carman
The serine/threonine kinase IL-1R-associated kinase (IRAK)4 is a critical regulator of innate immunity. We have identified BMS-986126, a potent, highly selective inhibitor of IRAK4 kinase activity that demonstrates equipotent activity against multiple MyD88-dependent responses both in vitro and in vivo. BMS-986126 failed to inhibit assays downstream of MyD88-independent receptors, including the TNF receptor and TLR3. Very little activity was seen downstream of TLR4, which can also activate an MyD88-independent pathway...
December 21, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27997610/effective-respiratory-cd8-t-cell-immunity-to-influenza-virus-induced-by-intranasal-carbomer-lecithin-adjuvanted-non-replicating-vaccines
#8
David J Gasper, Brandon Neldner, Erin H Plisch, Hani Rustom, Emily Carrow, Hirotaka Imai, Yoshihiro Kawaoka, M Suresh
CD8+ cytotoxic T lymphocytes (CTLs) are critical for clearing many viral infections, and protective CTL memory can be induced by vaccination with attenuated viruses and vectors. Non-replicating vaccines are typically potentiated by the addition of adjuvants that enhance humoral responses, however few are capable of generating CTL responses. Adjuplex is a carbomer-lecithin-based adjuvant demonstrated to elicit robust humoral immunity to non-replicating antigens. We report that mice immunized with non-replicating Adjuplex-adjuvanted vaccines generated robust antigen-specific CTL responses...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27996000/central-role-of-cd169-lymph-node-resident-macrophages-in-the-adjuvanticity-of-the-qs-21-component-of-as01
#9
Sophie Detienne, Iain Welsby, Catherine Collignon, Sandrine Wouters, Margherita Coccia, Sophie Delhaye, Laurye Van Maele, Séverine Thomas, Maëlle Swertvaegher, Aurélie Detavernier, Abdelatif Elouahabi, Stanislas Goriely, Arnaud M Didierlaurent
Saponins represent a promising class of vaccine adjuvant. Together with the TLR4-ligand MPL, QS-21 is part of the Adjuvant System AS01, a key component of the malaria and zoster candidate vaccines that display demonstrated clinical efficacy. However, the mechanism of action of QS-21 in this liposomal formulation is poorly understood. Upon intra-muscular immunisation, we observed that QS-21 rapidly accumulated in CD169(+) resident macrophages of the draining lymph node where it elicited a local innate immune response...
December 20, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27966556/mv140-a-sublingual-polyvalent-bacterial-preparation-to-treat-recurrent-urinary-tract-infections-licenses-human-dendritic-cells-for-generating-th1-th17-and-il-10-responses-via-syk-and-myd88
#10
C Benito-Villalvilla, C Cirauqui, C M Diez-Rivero, M Casanovas, J L Subiza, O Palomares
Recurrent urinary tract infections (RUTIs) are one of the most common bacterial infectious diseases, especially in women. Antibiotics remain the mainstay of treatment, but their overuse is associated with antibiotic-resistant infections and deleterious effects in the microbiota. Therefore, alternative approaches are fully demanded. Sublingual immunization with MV140 (Uromune), a polyvalent bacterial preparation (PBP) of whole heat-inactivated bacteria, demonstrated clinical efficacy for the treatment of RUTIs, but the involved immunological mechanisms remain unknown...
December 14, 2016: Mucosal Immunology
https://www.readbyqxmd.com/read/27933064/systemic-expression-of-notch-ligand-delta-like-4-during-mycobacterial-infection-alters-the-t-cell-immune-response
#11
Matthew A Schaller, Ronald M Allen, Soichiro Kimura, Cheryl L Day, Steven L Kunkel
The Notch ligand delta-like 4 (DLL4) is known to fine-tune the CD4(+) T cell cytokine response. DLL4 is expressed on the surface of antigen-presenting cells (APCs) in a MyD88-dependent manner. We found that DLL4 expression was upregulated on bone marrow progenitor cells and APCs in mice infected with BCG Mycobacterium. Transfer of DLL4(+) progenitor cells from infected hosts resulted in an increase DLL4(+) myeloid cells in the spleen, indicating that expression of the dll4 gene is propagated throughout hematopoiesis...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27930350/toll-like-receptor-tlr-4-and-myd88-are-essential-for-atheroprotection-by-peritoneal-b1a-b-cells
#12
Hamid Hosseini, Yi Li, Peter Kanellakis, Christopher Tay, Anh Cao, Edgar Liu, Karlheinz Peter, Peter Tipping, Ban-Hock Toh, Alex Bobik, Tin Kyaw
BACKGROUND: We previously identified peritoneal B1a cells that secrete natural IgM as a key atheroprotective B cell subset. However, the molecules that activate atheroprotective B1a cells are unknown. Here, we investigated whether Toll-like receptors (TLRs) TLR2, TLR4, and TLR9 expressed by B1a cells are required for IgM-mediated atheroprotection. METHODS AND RESULTS: We adoptively transferred B1a cells from wild-type mice or from mice deficient in TLR2, TLR4, TLR9, or myeloid differentiation primary response 88 (MyD88) into ApoE(-/-) mice depleted of peritoneal B1a cells by splenectomy and fed a high-fat diet for 8 weeks...
November 14, 2016: Journal of the American Heart Association
https://www.readbyqxmd.com/read/27888719/treponema-pallidum-flagellin-flaa2-induces-il-6-secretion-in-thp-1-cells-via-the-toll-like-receptor-2-signaling-pathway
#13
Yafeng Xie, Man Xu, Yongjian Xiao, Zhuoran Liu, Chuanhao Jiang, Xingxing Kuang, Chuan Wang, Haiying Wu, Jing Peng, Chun Li, Yu Wang, Huaming Liu, Bin Liu, Xiaotuan Zhang, Feijun Zhao, Tiebing Zeng, Shuangquan Liu, Yimou Wu
Treponema pallidum subsp. pallidum membrane proteins are considered as potent inducers in the initiation and development of inflammation. In the present study, the mechanism that leads to the production of interleukin 6 (IL-6), one of the key proinflammatory cytokines, by human monocytic THP-1 cells when these cells are treated with T. pallidum flagellin FlaA2 was investigated. Stimulation with flagellin FlaA2 can induce IL-6 expression in human monocytes and augment the phosphorylation of ERK, p38, and NF-κB, but has no effect on the phosphorylation of JNK...
January 2017: Molecular Immunology
https://www.readbyqxmd.com/read/27872207/myeloid-specific-gene-deletion-of-protein-phosphatase-2a-magnifies-myd88-and-trif-dependent-inflammation-following-endotoxin-challenge
#14
Lei Sun, Tiffany T Pham, Timothy T Cornell, Kelli L McDonough, Walker M McHugh, Neal B Blatt, Mary K Dahmer, Thomas P Shanley
Protein phosphatase 2A (PP2A) is a member of the intracellular serine/threonine phosphatases. Innate immune cell activation triggered by pathogen-associated molecular patterns is mediated by various protein kinases, and PP2A plays a counter-regulatory role by deactivating these kinases. In this study, we generated a conditional knockout of the α isoform of the catalytic subunit of PP2A (PP2ACα). After crossing with myeloid-specific cre-expressing mice, effective gene knockout was achieved in various myeloid cells...
January 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27864347/human-pancreatic-cancer-cells-induce-a-myd88-dependent-stromal-response-to-promote-a-tumor-tolerant-immune-microenvironment
#15
Daniel Delitto, Andrea E Delitto, Bayli B DiVita, Kien Pham, Song Han, Emily R Hartlage, Brittney N Newby, Michael H Gerber, Kevin E Behrns, Lyle L Moldawer, Ryan M Thomas, Thomas George, Todd Brusko, Clayton E Mathews, Chen Liu, Jose G Trevino, Steven J Hughes, Shannon Wallet
Cancer cells exert mastery over the local tumor-associated stroma (TAS) to configure protective immunity within the tumor microenvironment. The immunomodulatory character of pancreatic lysates of patients with cancer differs from those with pancreatitis. In this study, we evaluated the crosstalk between pancreatic cancer (PC) and its TAS in primary human cell culture models. Upon exposure of TAS to PC cell-conditioned media, we documented robust secretion of IL-6 and IL-8. This TAS response was MyD88-dependent and sufficient to directly suppress both CD4+ and CD8+ T cell proliferation, inducing Th17 polarization at the expense of Th1...
November 18, 2016: Cancer Research
https://www.readbyqxmd.com/read/27856326/expression-pattern-analysis-of-irf4-and-its-related-genes-revealed-the-functional-differentiation-of-irf4-paralogues-in-teleost
#16
Kete Ai, Kai Luo, Youshen Li, Wei Hu, Weihua Gao, Liu Fang, Guangming Tian, Guoliang Ruan, Qiaoqing Xu
In mammals, interferon regulatory factor 4 (IRF4) plays an important role in the process of development and differentiation of B cells, T cells and dendritic cells. It can regulate immune pathway through IRF5, MyD88, IL21, PGC1α, and NOD2. In the present study, we investigated the expression pattern of IRF4 paralogues and these related genes for the first time in teleosts. The results showed that these genes were all expressed predominantly in known immune tissues while IRF5 was also relatively highly expressed in muscle...
November 14, 2016: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/27836955/ifn-%C3%AE-ifn-%C3%AE-responses-to-respiratory-viruses-in-paediatric-asthma
#17
Annika Bergauer, Nina Sopel, Bettina Kroß, Tytti Vuorinen, Paraskevi Xepapadaki, Scott T Weiss, Ashley Blau, Himanshu Sharma, Cornelia Kraus, Rebekka Springel, Manfred Rauh, Susanne Mittler, Anna Graser, Theodor Zimmermann, Volker O Melichar, Alexander Kiefer, Marek L Kowalski, Anna Sobanska, Tuomas Jartti, Heikki Lukkarinen, Nikolaos G Papadopoulos, Susetta Finotto
We analysed the influence of rhinovirus (RV) in nasopharyngeal fluid (NPF) on type I and III interferon (IFN) responses (e.g. IFN-α and IFN -: λ) and their signal transduction, at baseline and during disease exacerbation, in cohorts of pre-school children with and without asthma.At the time of recruitment into the Europe-wide study PreDicta, and during symptoms, NPF was collected and the local RV colonisation was analysed. Peripheral blood mononuclear cells (PBMCs) were challenged in vitro with RV or not...
November 11, 2016: European Respiratory Journal: Official Journal of the European Society for Clinical Respiratory Physiology
https://www.readbyqxmd.com/read/27825468/novel-therapeutic-targets-in-waldenstrom-macroglobulinemia
#18
REVIEW
Aneel Paulus, Sikander Ailawadhi, Asher Chanan-Khan
Understanding of molecular mechanisms that drive Waldenstrom macroglobulinemia (WM) cell survival are rapidly evolving. This review briefly highlights emerging "WM-relevant" targets; for which therapeutic strategies are currently being investigated in preclinical and clinical studies. With the discovery of MYD88L265P signaling and remarkable activity of ibrutinib in WM, other targets within the B-cell receptor pathway are now being focused on for therapeutic intervention. Additional targets which play a role in WM cell survival include TLR7, 8 and 9, proteasome-associated deubiquitinating enzymes (USP14 and UCHL5), XPO1/CRM1 and AURKA...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27813535/coinhibition-of-the-deubiquitinating-enzymes-usp14-and-uchl5-with-vlx1570-is-lethal-to-ibrutinib-or-bortezomib-resistant-waldenstrom-macroglobulinemia-tumor-cells
#19
A Paulus, S Akhtar, T R Caulfield, K Samuel, H Yousaf, Y Bashir, S M Paulus, D Tran, R Hudec, D Cogen, J Jiang, B Edenfield, A Novak, S M Ansell, T Witzig, P Martin, M Coleman, V Roy, S Ailawadhi, K Chitta, S Linder, A Chanan-Khan
The survival of Waldenstrom macroglobulinemia (WM) tumor cells hinges on aberrant B-cell receptor (BCR) and MYD88 signaling. WM cells upregulate the proteasome function to sustain the BCR-driven growth while maintaining homeostasis. Clinically, two treatment strategies are used to disrupt these complementary yet mutually exclusive WM survival pathways via ibrutinib (targets BTK/MYD88 node) and bortezomib (targets 20 S proteasome). Despite the success of both agents, WM patients eventually become refractory to treatment, highlighting the adaptive plasticity of WM cells and underscoring the need for development of new therapeutics...
November 4, 2016: Blood Cancer Journal
https://www.readbyqxmd.com/read/27798617/fibroblastic-reticular-cells-regulate-intestinal-inflammation-via-il-15-mediated-control-of-group-1-ilcs
#20
Cristina Gil-Cruz, Christian Perez-Shibayama, Lucas Onder, Qian Chai, Jovana Cupovic, Hung-Wei Cheng, Mario Novkovic, Philipp A Lang, Markus B Geuking, Kathy D McCoy, Shinya Abe, Guangwei Cui, Koichi Ikuta, Elke Scandella, Burkhard Ludewig
Fibroblastic reticular cells (FRCs) of secondary lymphoid organs form distinct niches for interaction with hematopoietic cells. We found here that production of the cytokine IL-15 by FRCs was essential for the maintenance of group 1 innate lymphoid cells (ILCs) in Peyer's patches and mesenteric lymph nodes. Moreover, FRC-specific ablation of the innate immunological sensing adaptor MyD88 unleashed IL-15 production by FRCs during infection with an enteropathogenic virus, which led to hyperactivation of group 1 ILCs and substantially altered the differentiation of helper T cells...
December 2016: Nature Immunology
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