The Experts below are selected from a list of 306 Experts worldwide ranked by ideXlab platform
Sophie E. Acton - One of the best experts on this subject based on the ideXlab platform.
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Podoplanin function is switched by partner proteins on fibroblastic reticular cells
bioRxiv, 2019Co-Authors: Charlotte M. De Winde, Spyridon Makris, Lindsey J. Millward, Agnesska C. Benjamin, Giulia Cazzagon, Víctor G. Martínez, Sophie E. ActonAbstract:Lymph Node Expansion is pivotal during immune activation. It is controlled by interactions between CLEC-2hi migratory den-dritic cells and podoplanin+ fibroblastic reticular cells (FRCs) resulting in rapid loss of actomyosin contractility permitting FRC spreading. Podoplanin is an inflammatory marker in many pathologies, reported to facilitate both contractility and cell pro-trusions. However, how podoplanin expression is regulated, and how this one membrane protein can elicit these opposing phenotypes is unknown. We report that CLEC-2 binding to FRCs induces transcriptional upregulation of podoplanin, increasing surface protein expression. Further, we find that tetraspanin CD82 is required for trafficking of podoplanin to the plasma membrane. At the cell surface, podoplanin elicits multiple functions, balanced by its membrane binding partners hyaluronan receptor CD44 and tetraspanin CD9. FRCs lacking expression of both CD44 and CD9 are hypercontractile, and upon binding to CLEC-2hi dendritic cells, both CD44 KO and CD9 KO FRCs exhibit defective protrusion formation and fail to spread. Podoplanin co-localises with CD44 or CD9 in distinct membrane domains, and both CD44 and CD9 are required for FRCs to spread in response to dendritic cells, however they control formation of cell protrusions via different and complimentary mechanisms. In vivo, surface expression levels of podoplanin, CD44 and CD9 are upregulated on T-cell zone FRCs in the early phase of lymph Node Expansion. Our data support a model whereby podoplanin resides in distinct plasma membrane domains, and that CLEC-2 binding serves as a molecular switch to change podoplanin function.
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Lymph Node fibroblastic reticular cells in health and disease
Nature Reviews Immunology, 2015Co-Authors: Anne L. Fletcher, Sophie E. Acton, Konstantin KnoblichAbstract:Fibroblastic reticular cells — which are immunologically specialized myofibroblasts of mesenchymal origin — create a network within lymph Nodes that is essential for immunological health through interactions with B cells, T cells, dendritic cells and high endothelial venules. Fibroblastic reticular cells (FRCs) are heterogeneous stromal cells. Subsets of FRCs include: T cell zone reticular cells that produce interleukin-7 (IL-7) to support naive T cells; resident and inducible B cell zone reticular cells that support naive B cells and follicle integrity; pericytic FRCs that support high endothelial venule (HEV) barrier function; follicular dendritic cells (FDCs) that support germinal centre function; and marginal reticular cells that can differentiate into FDCs. Crucial checkpoints in mesenchymal stromal cell development are retinoic acid signalling to mesenchymal progenitor cells, which creates the lymph Node anlage, followed by the attraction of lymphotoxin ligand-bearing group 3 innate lymphoid cells (usually mediated by CXC-chemokine ligand 13 (CXCL13)). Lymphotoxin-β receptor (LTβR) signalling to mesenchymal precursor cells results in the development of CC-chemokine ligand 19 (CCL19)^+CCL21^+CXCL13^+ receptor activator of NF-κB ligand (RANKL)^+LTβR^+ mucosal vascular addressin cell adhesion molecule 1 (MADCAM1)^+ lymphoid tissue organizer cells (LTo cells). Although it is still unclear precisely how LTo cells relate to mature FRCs, an immature FRC subset has been identified that requires LTβR signalling for the acquisition of an immunologically mature phenotype. FRCs give lymph Nodes the flexibility to stretch and to contract to accommodate the trapping of naive lymphocytes during an active immune response. Podoplanin (PDPN) maintains tension in the FRC network during homeostatic conditions, and this function is inhibited during an immune response when an influx of dendritic cells expressing C-type lectin domain family 1 member B (commonly known as CLEC2) inhibits PDPN-mediated FRC contractility. During a chronic infection such as with HIV-1, regulatory T cells upregulate transforming growth factor-β1 (TGFβ1) production, which signals to FRCs to markedly increase their extracellular matrix production. Naive T cells can no longer physically contact FRCs and lose access to IL-7, which results in widespread T cell death and prolonged immuNodeficiency. Therapeutic advances seeking to mimic or target FRC function include antifibrotic drugs to reverse lymph Node fibrosis, the administration of recombinant IL-7 to support T cell recovery after immuNodepletion, and the use of FRCs as a putative anti-inflammatory cell therapy. Over the past decade, a series of discoveries relating to fibroblastic reticular cells (FRCs) — immunologically specialized myofibroblasts found in lymphoid tissue — has promoted these cells from benign bystanders to major players in the immune response. In this Review, we focus on recent advances regarding the immunobiology of lymph Node-derived FRCs, presenting an updated view of crucial checkpoints during their development and their dynamic control of lymph Node Expansion and contraction during infection. We highlight the robust effects of FRCs on systemic B cell and T cell responses, and we present an emerging view of FRCs as drivers of pathology following acute and chronic viral infections. Lastly, we review emerging therapeutic advances that harness the immunoregulatory properties of FRCs.
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Lymph Node fibroblastic reticular cells in health and disease
Nature reviews. Immunology, 2015Co-Authors: Anne L. Fletcher, Sophie E. Acton, Konstantin KnoblichAbstract:Over the past decade, a series of discoveries relating to fibroblastic reticular cells (FRCs) — immunologically specialized myofibroblasts found in lymphoid tissue — has promoted these cells from benign bystanders to major players in the immune response. In this Review, we focus on recent advances regarding the immunobiology of lymph Node-derived FRCs, presenting an updated view of crucial checkpoints during their development and their dynamic control of lymph Node Expansion and contraction during infection. We highlight the robust effects of FRCs on systemic B cell and T cell responses, and we present an emerging view of FRCs as drivers of pathology following acute and chronic viral infections. Lastly, we review emerging therapeutic advances that harness the immunoregulatory properties of FRCs.
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dendritic cells control fibroblastic reticular network tension and lymph Node Expansion
Nature, 2014Co-Authors: Sophie E. Acton, Aaron J Farrugia, Jillian L Astarita, Diego Mouraosa, Robert P Jenkins, Emma Nye, Steven Hooper, Janneke Van Blijswijk, Neil C Rogers, Kathryn J SnelgroveAbstract:After immunogenic challenge, infiltrating and dividing lymphocytes markedly increase lymph Node cellularity, leading to organ Expansion. Here we report that the physical elasticity of lymph Nodes is maintained in part by podoplanin (PDPN) signalling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC-2 expressed on dendritic cells. We show in mouse cells that PDPN induces actomyosin contractility in FRCs via activation of RhoA/C and downstream Rho-associated protein kinase (ROCK). Engagement by CLEC-2 causes PDPN clustering and rapidly uncouples PDPN from RhoA/C activation, relaxing the actomyosin cytoskeleton and permitting FRC stretching. Notably, administration of CLEC-2 protein to immunized mice augments lymph Node Expansion. In contrast, lymph Node Expansion is significantly constrained in mice selectively lacking CLEC-2 expression in dendritic cells. Thus, the same dendritic cells that initiate immunity by presenting antigens to T lymphocytes also initiate remodelling of lymph Nodes by delivering CLEC-2 to FRCs. CLEC-2 modulation of PDPN signalling permits FRC network stretching and allows for the rapid lymph Node Expansion--driven by lymphocyte influx and proliferation--that is the critical hallmark of adaptive immunity.
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Dendritic cells control fibroblastic reticular network tension and lymph Node Expansion
Nature, 2014Co-Authors: Sophie E. Acton, Aaron J Farrugia, Jillian L Astarita, Robert P Jenkins, Emma Nye, Steven Hooper, Janneke Van Blijswijk, Neil C Rogers, Diego Mourão-sá, Kathryn J SnelgroveAbstract:During inflammation, the lymph Node stromal compartment is shown to accommodate high numbers of infiltrating lymphocytes by relaxing the cytoskeleton of fibroblastic reticular cells, allowing the latter to stretch and the lymph Node to expand. Lymph Nodes are dynamic structures that must respond rapidly to large cellular influxes provoked by local inflammation. However, how the lymph Node stromal compartment reacts to accommodate lymph Node Expansion remains unclear. This study shows that the lymph Node stromal compartment can accommodate large numbers of infiltrating lymphocytes by relaxing the cytoskeleton of fibroblastic reticular cells, allowing the cells to stretch and the lymph Node to expand. This lymph Node remodelling reaction is driven by the interaction of CLEC-2 protein on incoming antigen-presenting dendritic cells with podoplanin on fibroblastic reticular cells. After immunogenic challenge, infiltrating and dividing lymphocytes markedly increase lymph Node cellularity, leading to organ Expansion^ 1 , 2 . Here we report that the physical elasticity of lymph Nodes is maintained in part by podoplanin (PDPN) signalling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC-2 expressed on dendritic cells. We show in mouse cells that PDPN induces actomyosin contractility in FRCs via activation of RhoA/C and downstream Rho-associated protein kinase (ROCK). Engagement by CLEC-2 causes PDPN clustering and rapidly uncouples PDPN from RhoA/C activation, relaxing the actomyosin cytoskeleton and permitting FRC stretching. Notably, administration of CLEC-2 protein to immunized mice augments lymph Node Expansion. In contrast, lymph Node Expansion is significantly constrained in mice selectively lacking CLEC-2 expression in dendritic cells. Thus, the same dendritic cells that initiate immunity by presenting antigens to T lymphocytes^ 3 also initiate remodelling of lymph Nodes by delivering CLEC-2 to FRCs. CLEC-2 modulation of PDPN signalling permits FRC network stretching and allows for the rapid lymph Node Expansion—driven by lymphocyte influx and proliferation—that is the critical hallmark of adaptive immunity.
Kathryn J Snelgrove - One of the best experts on this subject based on the ideXlab platform.
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dendritic cells control fibroblastic reticular network tension and lymph Node Expansion
Nature, 2014Co-Authors: Sophie E. Acton, Aaron J Farrugia, Jillian L Astarita, Diego Mouraosa, Robert P Jenkins, Emma Nye, Steven Hooper, Janneke Van Blijswijk, Neil C Rogers, Kathryn J SnelgroveAbstract:After immunogenic challenge, infiltrating and dividing lymphocytes markedly increase lymph Node cellularity, leading to organ Expansion. Here we report that the physical elasticity of lymph Nodes is maintained in part by podoplanin (PDPN) signalling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC-2 expressed on dendritic cells. We show in mouse cells that PDPN induces actomyosin contractility in FRCs via activation of RhoA/C and downstream Rho-associated protein kinase (ROCK). Engagement by CLEC-2 causes PDPN clustering and rapidly uncouples PDPN from RhoA/C activation, relaxing the actomyosin cytoskeleton and permitting FRC stretching. Notably, administration of CLEC-2 protein to immunized mice augments lymph Node Expansion. In contrast, lymph Node Expansion is significantly constrained in mice selectively lacking CLEC-2 expression in dendritic cells. Thus, the same dendritic cells that initiate immunity by presenting antigens to T lymphocytes also initiate remodelling of lymph Nodes by delivering CLEC-2 to FRCs. CLEC-2 modulation of PDPN signalling permits FRC network stretching and allows for the rapid lymph Node Expansion--driven by lymphocyte influx and proliferation--that is the critical hallmark of adaptive immunity.
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Dendritic cells control fibroblastic reticular network tension and lymph Node Expansion
Nature, 2014Co-Authors: Sophie E. Acton, Aaron J Farrugia, Jillian L Astarita, Robert P Jenkins, Emma Nye, Steven Hooper, Janneke Van Blijswijk, Neil C Rogers, Diego Mourão-sá, Kathryn J SnelgroveAbstract:During inflammation, the lymph Node stromal compartment is shown to accommodate high numbers of infiltrating lymphocytes by relaxing the cytoskeleton of fibroblastic reticular cells, allowing the latter to stretch and the lymph Node to expand. Lymph Nodes are dynamic structures that must respond rapidly to large cellular influxes provoked by local inflammation. However, how the lymph Node stromal compartment reacts to accommodate lymph Node Expansion remains unclear. This study shows that the lymph Node stromal compartment can accommodate large numbers of infiltrating lymphocytes by relaxing the cytoskeleton of fibroblastic reticular cells, allowing the cells to stretch and the lymph Node to expand. This lymph Node remodelling reaction is driven by the interaction of CLEC-2 protein on incoming antigen-presenting dendritic cells with podoplanin on fibroblastic reticular cells. After immunogenic challenge, infiltrating and dividing lymphocytes markedly increase lymph Node cellularity, leading to organ Expansion^ 1 , 2 . Here we report that the physical elasticity of lymph Nodes is maintained in part by podoplanin (PDPN) signalling in stromal fibroblastic reticular cells (FRCs) and its modulation by CLEC-2 expressed on dendritic cells. We show in mouse cells that PDPN induces actomyosin contractility in FRCs via activation of RhoA/C and downstream Rho-associated protein kinase (ROCK). Engagement by CLEC-2 causes PDPN clustering and rapidly uncouples PDPN from RhoA/C activation, relaxing the actomyosin cytoskeleton and permitting FRC stretching. Notably, administration of CLEC-2 protein to immunized mice augments lymph Node Expansion. In contrast, lymph Node Expansion is significantly constrained in mice selectively lacking CLEC-2 expression in dendritic cells. Thus, the same dendritic cells that initiate immunity by presenting antigens to T lymphocytes^ 3 also initiate remodelling of lymph Nodes by delivering CLEC-2 to FRCs. CLEC-2 modulation of PDPN signalling permits FRC network stretching and allows for the rapid lymph Node Expansion—driven by lymphocyte influx and proliferation—that is the critical hallmark of adaptive immunity.
Peter Aronhime - One of the best experts on this subject based on the ideXlab platform.
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Current-mode synthesis using Node Expansion techniques
Analog Integrated Circuits and Signal Processing, 1994Co-Authors: M. Desai, Peter AronhimeAbstract:This paper derives Node Expansion methods by which a given passive network and its nodal admittance matrix are modified by expanding a Node into two Nodes and introducing a nullor or a dependent source between the newly created Nodes. Node Expansion provides a systematic method to introduce active elements in a network. The elements of the admitance matrix are modified, but the dimensions of the matrix are unchanged. These methods, which can be applied repetitively, are used to derive filters and oscillators from parental passive networks in a systematic manner.
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a Node Expansion method for current mode synthesis
International Symposium on Circuits and Systems, 1993Co-Authors: M. Desai, Peter AronhimeAbstract:A Node Expansion method for current-mode synthesis is presented. This method introduces an active element in a network to control the entries of the nodal admittance matrix without changing the dimensions of the matrix. It lends itself readily to the design of continuous-time signal processing circuits including filters. It is also an effective tool for comparing active circuits. >
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ISCAS - A Node Expansion method for current-mode synthesis
1993 IEEE International Symposium on Circuits and Systems, 1Co-Authors: M. Desai, Peter AronhimeAbstract:A Node Expansion method for current-mode synthesis is presented. This method introduces an active element in a network to control the entries of the nodal admittance matrix without changing the dimensions of the matrix. It lends itself readily to the design of continuous-time signal processing circuits including filters. It is also an effective tool for comparing active circuits. >
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Node addition procedures for network design
Proceedings of 1994 37th Midwest Symposium on Circuits and Systems, 1Co-Authors: Peichu Sheng, Peter AronhimeAbstract:A new method for introducing active devices directly into a given network is presented. The purpose of this method is to modify in a systematic manner the elements of the nodal admittance matrix of a given network in order to realize filters, oscillators, and other circuits useful for signal processing. Two examples of the application of this method are provided. In addition, this method is compared with a Node Expansion process previously developed.
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Node Expansion theorem for controlled sources
Proceedings of 36th Midwest Symposium on Circuits and Systems, 1Co-Authors: M. Desai, Peter AronhimeAbstract:A Node Expansion theorem is presented wherein dependent sources are introduced into a passive or active network to modify systematically the Node admittance matrix. An example of the use of the theorem is provided. >
Christopher T Ritchlin - One of the best experts on this subject based on the ideXlab platform.
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inos dependent and independent phases of lymph Node Expansion in mice with tnf induced inflammatory erosive arthritis
Arthritis Research & Therapy, 2019Co-Authors: Richard D Bell, Pamelia N Slattery, Emily Wu, Lianping Xing, Christopher T RitchlinAbstract:Introduction A pivotal effect of lymphatic vessel (LV) function in joint homeostasis was identified in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA). Specifically, loss of LV contractions is associated with progressive synovitis and erosions. Furthermore, draining lymph Node Expansion is a biomarker of arthritic progression, and both macrophages and lymphatic endothelial cells express inducible nitric oxide synthase (iNOS), which disrupts LV contraction and transport of immune cells to the draining lymph Nodes. Therefore, to directly assess these relationships, we tested the hypothesis that TNF-Tg mice with global genetic ablation of iNOS (iNOS−/−) will show delayed draining lymph Node Expansion, maintained LV contractions, and decreased synovitis and erosions.
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iNOS dependent and independent phases of lymph Node Expansion in mice with TNF-induced inflammatory-erosive arthritis
Arthritis Research & Therapy, 2019Co-Authors: Richard D Bell, Pamelia N Slattery, Lianping Xing, Christopher T Ritchlin, Edward M. SchwarzAbstract:Introduction A pivotal effect of lymphatic vessel (LV) function in joint homeostasis was identified in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA). Specifically, loss of LV contractions is associated with progressive synovitis and erosions. Furthermore, draining lymph Node Expansion is a biomarker of arthritic progression, and both macrophages and lymphatic endothelial cells express inducible nitric oxide synthase (iNOS), which disrupts LV contraction and transport of immune cells to the draining lymph Nodes. Therefore, to directly assess these relationships, we tested the hypothesis that TNF-Tg mice with global genetic ablation of iNOS (iNOS^−/−) will show delayed draining lymph Node Expansion, maintained LV contractions, and decreased synovitis and erosions. Method iNOS^−/−× TNF-Tg female and male mice, and control littermates (iNOS^−/−, TNF-Tg, and WT), were examined with (1) ultrasound to determine popliteal lymph Node (PLN) volume and (2) near-infrared imaging (NIR) to assess popliteal LV contraction frequency, and differences between genotypes were assessed at 3, 4, 5, and 6 months of age. Knees and PLN were harvested at 4 months in females and 6 months in males, to assess synovitis, bone erosions, and cellular accumulation in PLN sinuses via histology. Results Initially, an increase in PLN volume was observed for both female and male iNOS^−/−× TNF-Tg and TNF-Tg compared to their WT and iNOS^−/− counterparts at 2 and 3 months, respectively. Subsequently, TNF-Tg PLNs continue to increase in volume, while iNOS^−/−× TNF-Tg did not increase in volume from the initial timepoints. WT and iNOS^−/− PLN volume was unchanged throughout the experiment. LV contraction frequency was increased at 4 months in females and 5 months in males, in the iNOS^−/−× TNF-Tg mice compared to the TNF-Tg. Synovitis and erosions were moderately reduced in iNOS^−/−× TNF-Tg versus TNF-Tg knees in females, while no differences in knee pathology were observed in males. Conclusions Genetic iNOS ablation maintains draining lymph Node volume and LV function during TNF-induced inflammatory arthritis and is associated with moderately decreased joint inflammation and damage.
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inos dependent and independent phases of lymph Node Expansion in mice with tnf induced inflammatory erosive arthritis
Arthritis Research & Therapy, 2019Co-Authors: Richard D Bell, Pamelia N Slattery, Lianping Xing, Christopher T Ritchlin, Edward M. SchwarzAbstract:A pivotal effect of lymphatic vessel (LV) function in joint homeostasis was identified in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA). Specifically, loss of LV contractions is associated with progressive synovitis and erosions. Furthermore, draining lymph Node Expansion is a biomarker of arthritic progression, and both macrophages and lymphatic endothelial cells express inducible nitric oxide synthase (iNOS), which disrupts LV contraction and transport of immune cells to the draining lymph Nodes. Therefore, to directly assess these relationships, we tested the hypothesis that TNF-Tg mice with global genetic ablation of iNOS (iNOS−/−) will show delayed draining lymph Node Expansion, maintained LV contractions, and decreased synovitis and erosions. iNOS−/−× TNF-Tg female and male mice, and control littermates (iNOS−/−, TNF-Tg, and WT), were examined with (1) ultrasound to determine popliteal lymph Node (PLN) volume and (2) near-infrared imaging (NIR) to assess popliteal LV contraction frequency, and differences between genotypes were assessed at 3, 4, 5, and 6 months of age. Knees and PLN were harvested at 4 months in females and 6 months in males, to assess synovitis, bone erosions, and cellular accumulation in PLN sinuses via histology. Initially, an increase in PLN volume was observed for both female and male iNOS−/−× TNF-Tg and TNF-Tg compared to their WT and iNOS−/− counterparts at 2 and 3 months, respectively. Subsequently, TNF-Tg PLNs continue to increase in volume, while iNOS−/−× TNF-Tg did not increase in volume from the initial timepoints. WT and iNOS−/− PLN volume was unchanged throughout the experiment. LV contraction frequency was increased at 4 months in females and 5 months in males, in the iNOS−/−× TNF-Tg mice compared to the TNF-Tg. Synovitis and erosions were moderately reduced in iNOS−/−× TNF-Tg versus TNF-Tg knees in females, while no differences in knee pathology were observed in males. Genetic iNOS ablation maintains draining lymph Node volume and LV function during TNF-induced inflammatory arthritis and is associated with moderately decreased joint inflammation and damage.
Richard D Bell - One of the best experts on this subject based on the ideXlab platform.
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inos dependent and independent phases of lymph Node Expansion in mice with tnf induced inflammatory erosive arthritis
Arthritis Research & Therapy, 2019Co-Authors: Richard D Bell, Pamelia N Slattery, Emily Wu, Lianping Xing, Christopher T RitchlinAbstract:Introduction A pivotal effect of lymphatic vessel (LV) function in joint homeostasis was identified in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA). Specifically, loss of LV contractions is associated with progressive synovitis and erosions. Furthermore, draining lymph Node Expansion is a biomarker of arthritic progression, and both macrophages and lymphatic endothelial cells express inducible nitric oxide synthase (iNOS), which disrupts LV contraction and transport of immune cells to the draining lymph Nodes. Therefore, to directly assess these relationships, we tested the hypothesis that TNF-Tg mice with global genetic ablation of iNOS (iNOS−/−) will show delayed draining lymph Node Expansion, maintained LV contractions, and decreased synovitis and erosions.
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iNOS dependent and independent phases of lymph Node Expansion in mice with TNF-induced inflammatory-erosive arthritis
Arthritis Research & Therapy, 2019Co-Authors: Richard D Bell, Pamelia N Slattery, Lianping Xing, Christopher T Ritchlin, Edward M. SchwarzAbstract:Introduction A pivotal effect of lymphatic vessel (LV) function in joint homeostasis was identified in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA). Specifically, loss of LV contractions is associated with progressive synovitis and erosions. Furthermore, draining lymph Node Expansion is a biomarker of arthritic progression, and both macrophages and lymphatic endothelial cells express inducible nitric oxide synthase (iNOS), which disrupts LV contraction and transport of immune cells to the draining lymph Nodes. Therefore, to directly assess these relationships, we tested the hypothesis that TNF-Tg mice with global genetic ablation of iNOS (iNOS^−/−) will show delayed draining lymph Node Expansion, maintained LV contractions, and decreased synovitis and erosions. Method iNOS^−/−× TNF-Tg female and male mice, and control littermates (iNOS^−/−, TNF-Tg, and WT), were examined with (1) ultrasound to determine popliteal lymph Node (PLN) volume and (2) near-infrared imaging (NIR) to assess popliteal LV contraction frequency, and differences between genotypes were assessed at 3, 4, 5, and 6 months of age. Knees and PLN were harvested at 4 months in females and 6 months in males, to assess synovitis, bone erosions, and cellular accumulation in PLN sinuses via histology. Results Initially, an increase in PLN volume was observed for both female and male iNOS^−/−× TNF-Tg and TNF-Tg compared to their WT and iNOS^−/− counterparts at 2 and 3 months, respectively. Subsequently, TNF-Tg PLNs continue to increase in volume, while iNOS^−/−× TNF-Tg did not increase in volume from the initial timepoints. WT and iNOS^−/− PLN volume was unchanged throughout the experiment. LV contraction frequency was increased at 4 months in females and 5 months in males, in the iNOS^−/−× TNF-Tg mice compared to the TNF-Tg. Synovitis and erosions were moderately reduced in iNOS^−/−× TNF-Tg versus TNF-Tg knees in females, while no differences in knee pathology were observed in males. Conclusions Genetic iNOS ablation maintains draining lymph Node volume and LV function during TNF-induced inflammatory arthritis and is associated with moderately decreased joint inflammation and damage.
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inos dependent and independent phases of lymph Node Expansion in mice with tnf induced inflammatory erosive arthritis
Arthritis Research & Therapy, 2019Co-Authors: Richard D Bell, Pamelia N Slattery, Lianping Xing, Christopher T Ritchlin, Edward M. SchwarzAbstract:A pivotal effect of lymphatic vessel (LV) function in joint homeostasis was identified in the tumor necrosis factor-transgenic (TNF-Tg) mouse model of rheumatoid arthritis (RA). Specifically, loss of LV contractions is associated with progressive synovitis and erosions. Furthermore, draining lymph Node Expansion is a biomarker of arthritic progression, and both macrophages and lymphatic endothelial cells express inducible nitric oxide synthase (iNOS), which disrupts LV contraction and transport of immune cells to the draining lymph Nodes. Therefore, to directly assess these relationships, we tested the hypothesis that TNF-Tg mice with global genetic ablation of iNOS (iNOS−/−) will show delayed draining lymph Node Expansion, maintained LV contractions, and decreased synovitis and erosions. iNOS−/−× TNF-Tg female and male mice, and control littermates (iNOS−/−, TNF-Tg, and WT), were examined with (1) ultrasound to determine popliteal lymph Node (PLN) volume and (2) near-infrared imaging (NIR) to assess popliteal LV contraction frequency, and differences between genotypes were assessed at 3, 4, 5, and 6 months of age. Knees and PLN were harvested at 4 months in females and 6 months in males, to assess synovitis, bone erosions, and cellular accumulation in PLN sinuses via histology. Initially, an increase in PLN volume was observed for both female and male iNOS−/−× TNF-Tg and TNF-Tg compared to their WT and iNOS−/− counterparts at 2 and 3 months, respectively. Subsequently, TNF-Tg PLNs continue to increase in volume, while iNOS−/−× TNF-Tg did not increase in volume from the initial timepoints. WT and iNOS−/− PLN volume was unchanged throughout the experiment. LV contraction frequency was increased at 4 months in females and 5 months in males, in the iNOS−/−× TNF-Tg mice compared to the TNF-Tg. Synovitis and erosions were moderately reduced in iNOS−/−× TNF-Tg versus TNF-Tg knees in females, while no differences in knee pathology were observed in males. Genetic iNOS ablation maintains draining lymph Node volume and LV function during TNF-induced inflammatory arthritis and is associated with moderately decreased joint inflammation and damage.