The Experts below are selected from a list of 1290 Experts worldwide ranked by ideXlab platform
Mathias Heikenwalder - One of the best experts on this subject based on the ideXlab platform.
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the unexpected role of Lymphotoxin Beta receptor signaling in carcinogenesis from lymphoid tissue formation to liver and prostate cancer development
Oncogene, 2010Co-Authors: M Wolf, Mathias Heikenwalder, Nicolas Zeller, Gitta SeleznikAbstract:The cytokines Lymphotoxin (LT) alpha, Beta and their receptor (LTBetaR) belong to the tumor necrosis factor (TNF) superfamily, whose founder-TNFalpha-was initially discovered due to its tumor necrotizing activity. LTBetaR signaling serves pleiotropic functions including the control of lymphoid organ development, support of efficient immune responses against pathogens due to maintenance of intact lymphoid structures, induction of tertiary lymphoid organs, liver regeneration or control of lipid homeostasis. Signaling through LTBetaR comprises the noncanonical/canonical nuclear factor-kappaB (NF-kappaB) pathways thus inducing chemokine, cytokine or adhesion molecule expression, cell proliferation and cell survival. Blocking LTBetaR signaling or Fcgamma-receptor mediated immunoablation of LT-expressing cells was demonstrated to be beneficial in various infectious or noninfectious inflammatory or autoimmune disorders. Only recently, LTBetaR signaling was shown to initiate inflammation-induced carcinogenesis, to influence primary tumorigenesis and to control reemergence of carcinoma in various cancer models through distinct mechanisms. Indeed, LTBetaR signaling inhibition has already been used as efficient anti-inflammatory, anti-cancer therapy in some experimental models. Here, we review the pleiotropic functions attributed to LT, the effects of its deregulation and extensively discuss the recent literature on LT's link to carcinogenesis.
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the unexpected role of Lymphotoxin Beta receptor signaling in carcinogenesis from lymphoid tissue formation to liver and prostate cancer development
Oncogene, 2010Co-Authors: M Wolf, Mathias Heikenwalder, Nicolas Zeller, Gitta SeleznikAbstract:The cytokines Lymphotoxin (LT) α, β and their receptor (LTβR) belong to the tumor necrosis factor (TNF) superfamily, whose founder—TNFα—was initially discovered due to its tumor necrotizing activity. LTβR signaling serves pleiotropic functions including the control of lymphoid organ development, support of efficient immune responses against pathogens due to maintenance of intact lymphoid structures, induction of tertiary lymphoid organs, liver regeneration or control of lipid homeostasis. Signaling through LTβR comprises the noncanonical/canonical nuclear factor-κB (NF-κB) pathways thus inducing chemokine, cytokine or adhesion molecule expression, cell proliferation and cell survival. Blocking LTβR signaling or Fcγ-receptor mediated immunoablation of LT-expressing cells was demonstrated to be beneficial in various infectious or noninfectious inflammatory or autoimmune disorders. Only recently, LTβR signaling was shown to initiate inflammation-induced carcinogenesis, to influence primary tumorigenesis and to control reemergence of carcinoma in various cancer models through distinct mechanisms. Indeed, LTβR signaling inhibition has already been used as efficient anti-inflammatory, anti-cancer therapy in some experimental models. Here, we review the pleiotropic functions attributed to LT, the effects of its deregulation and extensively discuss the recent literature on LT's link to carcinogenesis.
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expression of Lymphotoxin Beta governs immunity at two distinct levels
European Journal of Immunology, 2006Co-Authors: Tobias Junt, Burkhard Ludewig, Nicola L Harris, Alexei V. Tumanov, Adriano Aguzzi, Sergei A Nedospasov, Dmitry V Kuprash, Mathias Heikenwalder, Nicolas Zeller, Rolf M ZinkernagelAbstract:Interaction of Lymphotoxin alpha(1)Beta(2) (LTalpha(1)Beta(2)) with its receptor is key for the generation and maintenance of secondary lymphoid organ microstructure. We used mice conditionally deficient for LTBeta on different lymphocyte subsets to determine how the LTBeta-dependent lymphoid structure influences immune reactivity. All conditionally LTBeta-deficient mice mounted normal immune responses against vesicular stomatitis virus (VSV), and were protected against lymphocytic choriomeningitis virus (LCMV). In contrast, they exhibited reduced immune responses against non-replicating antigens. Completely LTBeta-deficient mice failed to retain VSV in the marginal zone and died from VSV infections, and they became virus carriers following infection with the non-cytopathic LCMV, which was correlated with defective virus replication in dendritic cells. It was ruled out that LTBeta expression on lymphocytes influenced their activation, homing capacity, or maturation. We therefore conclude that LTBeta expression influences immune reactivity at two distinct levels: (i) Expression of LTBeta on lymphocytes enhances the induction of immune responses against limiting amounts of antigen. (ii) Expression of LTBeta on non-lymphocytes governs antiviral immunity by enhancing antigen presentation on antigen-presenting cells. This prevents cytotoxic T lymphocytes exhaustion or death of the host by uncontrolled virus spread.
Nicola L Harris - One of the best experts on this subject based on the ideXlab platform.
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Interactions between fibroblastic reticular cells and B cells promote mesenteric lymph node lymphangiogenesis.
Nature Communications, 2017Co-Authors: Lalit Kumar Dubey, Praneeth Karempudi, Burkhard Ludewig, Sanjiv A Luther, Nicola L HarrisAbstract:Lymphatic growth (lymphangiogenesis) within lymph nodes functions to promote dendritic cell entry and effector lymphocyte egress in response to infection or inflammation. Here we demonstrate a crucial role for Lymphotoxin-Beta receptor (LTβR) signaling to fibroblastic reticular cells (FRCs) by Lymphotoxin-expressing B cells in driving mesenteric lymph node lymphangiogenesis following helminth infection. LTβR ligation on fibroblastic reticular cells leads to the production of B-cell-activating factor (BAFF), which synergized with interleukin-4 (IL-4) to promote the production of the lymphangiogenic factors, vascular endothelial growth factors (VEGF)-A and VEGF-C, by B cells. In addition, the BAFF-IL-4 synergy augments expression of Lymphotoxin by antigen-activated B cells, promoting further B cell–fibroblastic reticular cell interactions. These results underlie the importance of Lymphotoxin-dependent B cell–FRC cross talk in driving the expansion of lymphatic networks that function to promote and maintain immune responsiveness. The growth of lymph nodes in response to infection requires lymphangiogenesis. Dubey et al. show that the mesenteric lymph node lymphangiogenesis upon helminth infection depends on the signaling loop between the B and fibroblastic reticular cells (FRCs), whereby the FRCs respond to Lymphotoxin secreted by B cells by releasing B cell activating factor.
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expression of Lymphotoxin Beta governs immunity at two distinct levels
European Journal of Immunology, 2006Co-Authors: Tobias Junt, Burkhard Ludewig, Nicola L Harris, Alexei V. Tumanov, Adriano Aguzzi, Sergei A Nedospasov, Dmitry V Kuprash, Mathias Heikenwalder, Nicolas Zeller, Rolf M ZinkernagelAbstract:Interaction of Lymphotoxin alpha(1)Beta(2) (LTalpha(1)Beta(2)) with its receptor is key for the generation and maintenance of secondary lymphoid organ microstructure. We used mice conditionally deficient for LTBeta on different lymphocyte subsets to determine how the LTBeta-dependent lymphoid structure influences immune reactivity. All conditionally LTBeta-deficient mice mounted normal immune responses against vesicular stomatitis virus (VSV), and were protected against lymphocytic choriomeningitis virus (LCMV). In contrast, they exhibited reduced immune responses against non-replicating antigens. Completely LTBeta-deficient mice failed to retain VSV in the marginal zone and died from VSV infections, and they became virus carriers following infection with the non-cytopathic LCMV, which was correlated with defective virus replication in dendritic cells. It was ruled out that LTBeta expression on lymphocytes influenced their activation, homing capacity, or maturation. We therefore conclude that LTBeta expression influences immune reactivity at two distinct levels: (i) Expression of LTBeta on lymphocytes enhances the induction of immune responses against limiting amounts of antigen. (ii) Expression of LTBeta on non-lymphocytes governs antiviral immunity by enhancing antigen presentation on antigen-presenting cells. This prevents cytotoxic T lymphocytes exhaustion or death of the host by uncontrolled virus spread.
Jeffrey L. Browning - One of the best experts on this subject based on the ideXlab platform.
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TRAF3 Controls Activation of the Canonical and Alternative NFκB by the Lymphotoxin Beta Receptor
The Journal of biological chemistry, 2010Co-Authors: Pradeep Bista, Weike Zeng, Sarah Ryan, Veronique Bailly, Jeffrey L. Browning, Matvey E. LukashevAbstract:Components of Lymphotoxin Beta receptor (LTBR)-associated signaling complexes, including TRAF2, TRAF3, NIK, IKK1, and IKK2 have been shown to participate in the coupling of LTBR to NFκB. Here, we report that TRAF3 functions as a negative regulator of LTBR signaling via both canonical and non-canonical NFκB pathways by two distinct mechanisms. Analysis of NFκB signaling in cell lines with functionally intact NFκB pathway but lacking LTBR-mediated induction of NFκB target genes revealed an inverse association of cellular TRAF3 levels with LTBR-specific defect in canonical NFκB activation. Increased expression of TRAF3 correlated with its increased recruitment to LTBR-induced signaling complexes, decreased recruitment of TRAF2, and attenuated phosphorylation of IκBα and RelA. In contrast, activation of NFκB by TNF did not depend on TRAF3 levels. siRNA-mediated depletion of TRAF3 promoted recruitment of TRAF2 and IKK1 to activated LTBR, enabling LTBR-inducible canonical NFκB signaling and NFκB target gene expression. TRAF3 knock-down also increased mRNA and protein expression of several non-canonical NFκB components, including NFκB2/p100, RelB, and NIK, accompanied by processing of NFκB2/p100 into p52. These effects of TRAF3 depletion did not require LTBR signaling and were consistent with autonomous activation of the non-canonical NFκB pathway. Our data illustrate the function of TRAF3 as a dual-mode repressor of LTBR signaling that controls activation of canonical NFκB, and de-repression of the intrinsic activity of non-canonical NFκB. Modulation of cellular TRAF3 levels may thus contribute to regulation of NFκB-dependent gene expression by LTBR by affecting the balance of LTBR-dependent activation of canonical and non-canonical NFκB pathways.
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blockade of Lymphotoxin Beta receptor signaling reduces aspects of sjogren s syndrome in salivary glands of non obese diabetic mice
Arthritis Research & Therapy, 2009Co-Authors: Margaret Karimi Gatumu, Jeffrey L. Browning, Roy A Fava, Adrian Papandile, Kathrine Skarstein, Anne Isine BolstadAbstract:The Lymphotoxin-Beta receptor (LTβR) pathway is important in the development and maintenance of lymphoid structures. Blocking this pathway has proven beneficial in murine models of autoimmune diseases such as diabetes and rheumatoid arthritis. The aim of this study was to determine the effects of LTβR pathway blockade on Sjogren syndrome (SS)-like salivary gland disease in non-obese diabetic (NOD) mice. The course of SS-like disease was followed in NOD mice that were given Lymphotoxin-Beta receptor-immunoglobulin fusion protein (LTβR-Ig) starting at 9 weeks of age. Treatment was given as a single weekly dose for 3, 7, or 10 weeks. Age-matched NOD mice treated with mouse monoclonal IgG1, or not treated at all, were used as controls. The severity of inflammation, cellular composition, and lymphoid neogenesis in the submandibular glands were determined by immunohistochemistry. Mandibular lymph nodes were also studied. Saliva flow rates were measured, and saliva was analyzed by a multiplex cytokine assay. The salivary glands were analyzed for CXCL13, CCL19, and CCL21 gene expression by quantitative polymerase chain reaction. Treatment with LTβR-Ig prevented the increase in size and number of focal infiltrates normally observed in this SS-like disease. Compared with the controls, the submandibular glands of LTβR-Ig-treated mice had fewer and smaller T- and B-cell zones and fewer high endothelial venules per given salivary gland area. Follicular dendritic cell networks were lost in LTβR-Ig-treated mice. CCL19 expression was also dramatically inhibited in the salivary gland infiltrates. Draining lymph nodes showed more gradual changes after LTβR-Ig treatment. Saliva flow was partially restored in mice treated with 10 LTβR-Ig weekly injections, and the saliva cytokine profile of these mice resembled that of mice in the pre-disease state. Our findings show that blocking the LTβR pathway results in ablation of the lymphoid organization in the NOD salivary glands and thus an improvement in salivary gland function.
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visualization of Lymphotoxin Beta and Lymphotoxin Beta receptor expression in mouse embryos
Journal of Immunology, 2002Co-Authors: Jeffrey L. Browning, Lars E FrenchAbstract:The heteromeric Lymphotoxin αβ ligand (LT) binds to the LTβ receptor (LTβR) and provides an essential trigger for lymph node (LN) development. LTβR signaling is also critical for the emergence of pathological ectopic lymph node-like structures and the maintenance of an organized splenic white pulp. To better understand the role of LT in development, the expression patterns of LTβ and LTβR mRNA were examined by in situ hybridization in the developing mouse embryo. Images of LTβ ligand expression in developing peripheral LN in the E18.5 embryo revealed a relatively early phase structure and allowed for comparative staging with LN development in rat and humans. The LTβR is expressed from E16.5 onward in respiratory, salivary, bronchial, and gastric epithelium, which may be consistent with early communication events between lymphoid elements and epithelial specialization over emerging mucosal LN. Direct comparison of mouse fetal and adult tissues by FACS analysis confirmed the elevated expression of LTBR in some embryonic epithelial layers. Therefore, surface LTBR expression may be elevated during fetal development in some epithelial layers.
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a role for Lymphotoxin Beta receptor in host defense against mycobacterium bovis bcg infection
European Journal of Immunology, 1999Co-Authors: Rudolf Lucas, Jeffrey L. Browning, Fabienne Tacchinicottier, Reto Guler, Dominique Vesin, Stephane Jemelin, Maria L Olleros, G Marchal, Pierre Vassalli, Irene GarciaAbstract:To investigate the role of membrane Lymphotoxin (LT)alpha1 / Beta2 and its LTBeta receptor (LTBetaR) in the protective immune response to Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection, we have used a soluble fusion molecule (LTBetaR-IgG1). LTBetaR-Ig treatment interferes with granuloma formation mainly in the spleen by inhibiting macrophage activation and nitric oxide synthase activity. In addition, a large accumulation of eosinophils was observed in the spleen of LTBetaR-Ig-treated infected mice. Decreased blood levels of IFN-gamma and increased IL-4 were also observed, suggesting that the LTBetaR pathway is important in BCG infection to favor a Th1 type of immune response. The treatment of transgenic mice expressing high blood levels of a soluble TNFR1-IgG3 fusion protein with LTBetaR-Ig resulted in a still higher sensitivity to BCG infection, and extensive necrosis in the spleen. In conclusion, these results suggest that the LTBetaR and the TNFR pathways are not redundant in the course of BCG infection and protective granuloma formation: the LTBetaR pathway appears to be important in spleen granuloma formation, whereas the TNFR pathway has a predominant role in other tissues.
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expression of the Lymphotoxin Beta receptor on follicular stromal cells in human lymphoid tissues
Cell Death & Differentiation, 1998Co-Authors: Jeffrey L. Browning, Carl F Ware, Barbara N Walter, Marianne Murphy, Larry Pikenobile, Neil A Fanger, Paul M Guyre, Lois B EpsteinAbstract:The Lymphotoxin β receptor (LTβR), and its ligand, LTα1β2, have been proposed to play a key role in the development and organization of lymphoid tissues. The LTβR is expressed on a variety of human primary and transformed cells, but strikingly absent on T or B lymphocytes and primary monocytes or peripheral dendritic cells, although LTβR is detected on some myeloid leukemic lines. In the developing thymus LTβR is prominent along the trabeculae and into the medulla upto corticomedullary junction. In the spleen, LTβR is prominently expressed by cells in the red pulp and along the borders of red and white pulp which colocalizes with reticular stromal cells. The LTβR is expressed on a human follicular dendritic cell line, FDC-1, and signals expression of CD54 when ligated with the LTα1β2 complex. These results support the concept that directional interactions between LTα1β2 bearing lymphocytes and LTβR bearing stromal cells are involved in the organization of lymphoid tissue.
Carl F Ware - One of the best experts on this subject based on the ideXlab platform.
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vascular endothelial growth factor promotes macrophage apoptosis through stimulation of tumor necrosis factor superfamily member 14 tnfsf14 light
Wound Repair and Regeneration, 2008Co-Authors: Melissa Petreaca, Carl F Ware, Manuela MartinsgreenAbstract:: Resolution of inflammation is critical for normal wound healing. Inflammation is prolonged and fails to resolve properly in chronic wounds. We used in vivo and in vitro approaches to show that vascular endothelial growth factor (VEGF) induces macrophage apoptosis and to delineate mechanisms involved in this process. VEGF inhibition during wound healing leads to an increased number of macrophages remaining in wounds, suggesting the involvement of VEGF in removal of these cells from the wound. If this effect has physiological relevance, it likely occurs via apoptosis. We show that VEGF increases apoptosis of macrophages in vitro using Annexin V-FITC staining and caspase activation. Microarray analysis, reverse transcription-polymerase chain reaction, and immunoblotting showed that VEGF increases the expression of tumor necrosis factor superfamily member 14 (TNFSF14/LIGHT) in macrophages. We also show that in macrophages LIGHT promotes apoptosis through the Lymphotoxin Beta receptor. Moreover, inhibition of LIGHT prevents VEGF-induced death, suggesting that LIGHT mediates VEGF-induced macrophage apoptosis. Taken together, our results identify a novel role for VEGF and for LIGHT in macrophage apoptosis during wound healing, an event critical in the resolution of inflammation. This finding may lead to the development of new strategies to improve resolution of inflammation in problematic wounds.
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the Lymphotoxin β receptor induces different patterns of gene expression via two nf κb pathways
Immunity, 2002Co-Authors: Emmanuel Dejardin, Carl F Ware, Nathalie Droin, Mireille Delhase, Elvira Haas, Yixue Cao, Constantin Makris, Michael Karin, Douglas R GreenAbstract:The Lymphotoxin-Beta receptor (LTBetaR) plays critical roles in inflammation and lymphoid organogenesis through activation of NF-kappaB. In addition to activation of the classical NF-kappaB, ligation of this receptor induces the processing of the cytosolic NF-kappaB2/p100 precursor to yield the mature p52 subunit, followed by translocation of p52 to the nucleus. This activation of NF-kappaB2 requires NIK and IKKalpha, while NEMO/IKKgamma is dispensable for p100 processing. IKKBeta-dependent activation of canonical NF-kappaB is required for the expression but not processing of p100 and for the expression of proinflammatory molecules including VCAM-1, MIP-1Beta, and MIP-2 in response to LTBetaR ligation. In contrast, IKKalpha controls the induction by LTBetaR ligation of chemokines and cytokines involved in lymphoid organogenesis, including SLC, BLC, ELC, SDF1, and BAFF.
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expression of the Lymphotoxin Beta receptor on follicular stromal cells in human lymphoid tissues
Cell Death & Differentiation, 1998Co-Authors: Jeffrey L. Browning, Carl F Ware, Barbara N Walter, Marianne Murphy, Larry Pikenobile, Neil A Fanger, Paul M Guyre, Lois B EpsteinAbstract:The Lymphotoxin β receptor (LTβR), and its ligand, LTα1β2, have been proposed to play a key role in the development and organization of lymphoid tissues. The LTβR is expressed on a variety of human primary and transformed cells, but strikingly absent on T or B lymphocytes and primary monocytes or peripheral dendritic cells, although LTβR is detected on some myeloid leukemic lines. In the developing thymus LTβR is prominent along the trabeculae and into the medulla upto corticomedullary junction. In the spleen, LTβR is prominently expressed by cells in the red pulp and along the borders of red and white pulp which colocalizes with reticular stromal cells. The LTβR is expressed on a human follicular dendritic cell line, FDC-1, and signals expression of CD54 when ligated with the LTα1β2 complex. These results support the concept that directional interactions between LTα1β2 bearing lymphocytes and LTβR bearing stromal cells are involved in the organization of lymphoid tissue.
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hepatitis c virus core protein interacts with the cytoplasmic tail of Lymphotoxin Beta receptor
Journal of Virology, 1997Co-Authors: Masayuki Matsumoto, Tsaiyuan Hsieh, Nongliao Zhu, T Vanarsdale, Soon B Hwang, Kingsong Jeng, Alexander E Gorbalenya, Carl F Ware, Michael M C LaiAbstract:Hepatitis C virus (HCV) core protein is a multifunctional protein. We examined whether it can interact with cellular proteins, thus contributing to viral pathogenesis. Using the HCV core protein as a bait to screen a human liver cDNA library in a yeast two-hybrid screening system, we have isolated several positive clones encoding cellular proteins that interact with the HCV core protein. Interestingly, more than half of these clones encode the cytoplasmic domain of Lymphotoxin-Beta receptor (LT BetaR), which is a member of the tumor necrosis factor receptor family. Their binding was confirmed by in vitro glutathione S-transferase fusion protein binding assay and protein-protein blotting assay to be direct and specific. The binding sites were mapped within a 58-amino-acid region of the cytoplasmic tail of LT BetaR. The binding site in the HCV core protein was localized within amino acid residues 36 to 91 from the N terminus, corresponding to the hydrophilic region of the protein. In mammalian cells, the core protein was found to be associated with the membrane-bound LT BetaR. Since the LT BetaR is involved in germinal center formation and developmental regulation of peripheral lymphoid organs, lymph node development, and apoptotic signaling, the binding of HCV core protein to LT BetaR suggests the possibility that this viral protein has an immunomodulating function and may explain the mechanism of viral persistence and pathogenesis of HCV.
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mouse Lymphotoxin Beta receptor molecular genetics ligand binding and expression
Journal of Immunology, 1995Co-Authors: Walker R Force, Jeffrey L. Browning, R Tizard, Barbara N Walter, Catherine Hession, C A Kozak, Carl F WareAbstract:Lymphotoxin (LT) -alpha Beta heterotrimer is a membrane-anchored ligand expressed by activated T cells which binds specifically to the LT Beta receptor (LT Beta R), a member of the TNFR family. The LT Beta R is implicated as a critical element in controlling lymph node development and cellular immune reactions. To address this hypothesis we have isolated a mouse cDNA encoding a single transmembrane protein of 415 amino acids with 76% identity to human LT Beta R. The receptor function of this molecule was demonstrated by the ability of the extracellular domain, constructed as a chimera with the Fc region of IgG7, to bind to LT alpha Beta complexes expressed on the surface of activated T cells or insect cells infected with baculoviruses containing LT alpha and LT Beta cDNAs. The gene encoding mouse LT Beta R, Ltbr, contains 10 exons spanning 6.9 kb and maps to mouse chromosome 6, which is closely linked to Tnfr1, consistent with the tight linkage of the human homologue of these genes on chromosome 12p13. Mouse LT Beta R mRNA is expressed by cell lines of monocytic and epithelial origin but not by a CTL line, and in vivo it is constitutively expressed in visceral and lymphoid tissues. The delineation of the structure of the mouse LT Beta R will aid investigations into the role of this cytokine-receptor system in immune function and development.
Sergei A Nedospasov - One of the best experts on this subject based on the ideXlab platform.
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Lymphotoxin Beta receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection
Immunity, 2010Co-Authors: Yugang Wang, Ekaterina P. Koroleva, Sergei A Nedospasov, Dmitry V Kuprash, Andrei A Kruglov, Alexei V. TumanovAbstract:Summary Epithelial cells provide the first line of defense against mucosal pathogens; however, their coordination with innate and adaptive immune cells is not well understood. Using mice with conditional gene deficiencies, we found that Lymphotoxin (LT) from innate cells expressing transcription factor RORγt, but not from adaptive T and B cells, was essential for the control of mucosal C. rodentium infection. We demonstrate that the LTβR signaling was required for the regulation of the early innate response against infection. Furthermore, we have revealed that LTβR signals in gut epithelial cells and hematopoietic-derived cells coordinate to protect the host from infection. We further determined that LTβR signaling in intestinal epithelial cells was required for recruitment of neutrophils to the infection site early during infection via production of CXCL1 and CXCL2 chemokines. These results support a model wherein LT from RORγt + cells orchestrates the innate immune response against mucosal microbial infection.
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blocking Lymphotoxin Beta receptor signalling exacerbates acute dss induced intestinal inflammation opposite functions for surface Lymphotoxin expressed by t and b lymphocytes
Molecular Immunology, 2008Co-Authors: Michaela Jungbeck, Peter Stopfer, Frauke Bataille, Sergei A Nedospasov, Daniela N Mannel, Thomas HehlgansAbstract:The Lymphotoxin Beta receptor (LTBetaR) signalling pathway is involved in the development of secondary lymphoid organs and the maintenance of organized lymphoid tissues. Additionally, previous studies clearly demonstrated the involvement of the LTBetaR interaction with its ligands in promoting intestinal inflammation. In order to dissect the role of LTBetaR activation in the mouse model of acute DSS-induced colitis we treated mice with a functional inhibitor of LTBetaR activation (LTBetaR:Ig) and compared it to disease in LTBetaR-deficient and LTalphaBeta-deficient mice. All these modes of LTBetaR signalling ablation resulted in significant aggravation of the disease and in release of inflammatory cytokines such as TNF, IL-6, and IFNgamma. Finally, using mice with conditionally ablated expression of membrane bound LTBeta on T or B cells, respectively, distinct and opposite contributions of surface LTBeta expressed on T or B cells was found. Thus, activation of LTBetaR by LTalphaBeta mainly expressed on T lymphocytes is crucial for the down regulation of the inflammatory response in this experimental model.
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expression of Lymphotoxin Beta governs immunity at two distinct levels
European Journal of Immunology, 2006Co-Authors: Tobias Junt, Burkhard Ludewig, Nicola L Harris, Alexei V. Tumanov, Adriano Aguzzi, Sergei A Nedospasov, Dmitry V Kuprash, Mathias Heikenwalder, Nicolas Zeller, Rolf M ZinkernagelAbstract:Interaction of Lymphotoxin alpha(1)Beta(2) (LTalpha(1)Beta(2)) with its receptor is key for the generation and maintenance of secondary lymphoid organ microstructure. We used mice conditionally deficient for LTBeta on different lymphocyte subsets to determine how the LTBeta-dependent lymphoid structure influences immune reactivity. All conditionally LTBeta-deficient mice mounted normal immune responses against vesicular stomatitis virus (VSV), and were protected against lymphocytic choriomeningitis virus (LCMV). In contrast, they exhibited reduced immune responses against non-replicating antigens. Completely LTBeta-deficient mice failed to retain VSV in the marginal zone and died from VSV infections, and they became virus carriers following infection with the non-cytopathic LCMV, which was correlated with defective virus replication in dendritic cells. It was ruled out that LTBeta expression on lymphocytes influenced their activation, homing capacity, or maturation. We therefore conclude that LTBeta expression influences immune reactivity at two distinct levels: (i) Expression of LTBeta on lymphocytes enhances the induction of immune responses against limiting amounts of antigen. (ii) Expression of LTBeta on non-lymphocytes governs antiviral immunity by enhancing antigen presentation on antigen-presenting cells. This prevents cytotoxic T lymphocytes exhaustion or death of the host by uncontrolled virus spread.
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ectodysplasin regulates the Lymphotoxin Beta pathway for hair differentiation
Proceedings of the National Academy of Sciences of the United States of America, 2006Co-Authors: Changyi Cui, Sergei A Nedospasov, Tsuyoshi Hashimoto, Sergei I Grivennikov, Yulan Piao, David SchlessingerAbstract:Mutations in the EDA gene cause anhidrotic/hypohidrotic ectodermal dysplasia, a disorder characterized by defective formation of hair, sweat glands, and teeth in humans and in a mouse model, “Tabby” (Ta). The gene encodes ectodysplasin, a TNF ligand family member that activates the NF-κB-signaling pathway, but downstream targets and the mechanism of skin appendage formation have been only partially analyzed. Comparative transcription profiling of embryonic skin during hair follicle development in WT and Ta mice identified critical anhidrotic/hypohidrotic ectodermal dysplasia (EDA) effectors in four pathways, three already implicated in follicle formation. They included Shh and its effectors, as well as antagonists for the Wnt (Dkk4) and BMP (Sostdc1) pathways. The fourth pathway was unexpected, a variant NF-κB-signaling cascade based on Lymphotoxin-β (LTβ)/RelB. Previously known to participate only in lymphoid organogenesis, LTβ was enriched in developing hair follicles of WT but not in Ta mice. Furthermore, in mice lacking LTβ, all three types of mouse hair were still formed, but all were structurally abnormal. Guard hairs became wavy and irregular, zigzag/auchen hairs lost their kinks, and in a phenocopy of features of Ta animals, the awl hairs doubled in number and were characteristically distorted and pinched. LTβ-null mice that received WT bone marrow transplants maintained mutant hair phenotypes, consistent with autonomous LTβ action in skin independent of its expression in lymphoid cells. Thus, as an EDA target, LTβ regulates the form of hair in developing hair follicles; and when EDA is defective, failure of LTβ activation can account for part of the Ta phenotype.
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Lymphotoxin Beta receptor immune interaction promotes tumor growth by inducing angiogenesis
Cancer Research, 2002Co-Authors: Thomas Hehlgans, Klaus Pfeffer, Peter Stopfer, Sergei A Nedospasov, Peter Muller, Benjamin Stoelcker, Grigore Cernaianu, Markus Guba, M Steinbauer, Daniela N MannelAbstract:Growth of solid fibrosarcoma tumors in mice was inhibited by the release of a solubleLymphotoxin-β receptor inhibitor (LTβR-immunoglobulin fusion protein) from the tumor cells. Tumor growth arrest in mice deficient in the ligand LTα1β2 demonstrated the requirement for activation of the LTβR on the tumor cells by host cell-derived LTα1β2. Activation of the LTβR resulted in enhanced release of macrophage inflammatory protein-2. Blocked angiogenesis was revealed in LTβR inhibitor-producing tumor nodules by immunohistochemistry and in vivo microscopy. The growth arrest of LTβR inhibitor-producing fibrosarcomas was overcome by forced MIP-2 expression in the tumor cells. Thus, LTβR activation on tumor cells by activated host lymphocytes can initiate a novel proangiogenic pathway leading to organized tumor tissue development.
