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Martin Lipp - One of the best experts on this subject based on the ideXlab platform.
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CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs reprinted from cell vol 99 pg 23 33 1999
Journal of Immunology, 2016Co-Authors: Reinhold Förster, Andreas Schubel, Dagmar Breitfeld, Elisabeth Kremmer, Eckhard Wolf, Ingrid Rennermuller, Martin LippAbstract:The proper function of immune surveillance requires well-coordinated mechanisms in order to guide the patrolling immune cells through peripheral tissues and into secondary lymphoid organs. Analyzing gene-targeted mice, we identified the Chemokine Receptor CCR7 as an important organizer of the primary immune response CCR7-deficient mice show severely delayed kinetics regarding the antibody response and lack contact sensitivity and defayed type hypersensitivity reactions. Due to the impaired migration of lymphocytes, these animals reveal profound morphological alterations in all secondary lymphoid organs, Upon activation, mature skin dendritic cells fad to migrate into the draining lymph nodes. Thus, in order to bring together lymphocytes and dendritic cells to form the characteristic microarchitecture of secondary lymphoid organs, CCR7 is required to rapidly initiate an adoptive immune response.
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ccl21 slc improves tumor protection by a dna vaccine in a her2 neu mouse tumor model
Cancer Gene Therapy, 2012Co-Authors: T Nguyenhoai, Martin Lipp, Gerd Baldenhofer, M Sayed S Ahmed, M Phamduc, Bernd DorkenAbstract:Secondary lymphoid-tissue Chemokine (SLC/CCL21) is a CC Chemokine that is constitutively expressed in various lymphoid tissues and binds to Chemokine Receptor CCR7 on mature dendritic cells (DCs) and distinct T-and B-cell sub-populations. In vivo, CCL21 regulates the encounters between DC and T cells and thus is a key regulator of adaptive immune responses. We asked whether CCL21 is able to augment immunogenicity of a DNA-based vaccine against Her2/neu in a Balb/c mouse model with syngeneic Her2/neu+ tumor cells (D2F2/E2). Mice were vaccinated intramuscularly with plasmid DNA (pDNA) on day 1 and boosted on day 15; tumor challenge was performed subcutaneously on day 25. Coexpression of CCL21 and Her-2/neu resulted in induction of a TH1-polarized immune response and substantial improvement of the protective effect of the DNA vaccine. Coexpression of tumor antigen pDNA(Her2/neu) with both pDNA(GM-CSF) and pDNA(CCL21) as adjuvants led to further improvement of protection by the vaccine (70% tumor-free mice on day 35 vs 40% with either adjuvant alone vs 5-10% with tumor antigen alone). Our results show that CCL21 is a potent adjuvant for DNA vaccination, particularly in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF). Clinical use of a pDNA(Her2/neu/CCL21/GM-CSF) vaccine might be particularly promising in minimal residual Her2/neu+ breast cancer.
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CCR7 regulates lymphocyte egress and recirculation through body cavities
Journal of Leukocyte Biology, 2010Co-Authors: Uta E. Höpken, Susann Winter, Ariel H. Achtman, Kerstin Kruger, Martin LippAbstract:T and B lymphocytes recirculate among blood, lymph, and extralymphoid tissues to ensure immune surveillance and the establishment of self-tolerance. The underlying mechanisms regulating homeostatic lymphocyte recirculation through body cavities are not fully understood. Here, we demonstrate that the homeostatic Chemokine Receptor CCR7 regulates homeostatic recirculation of lymphocytes through body cavities. CCR7 deficiency results in massive accumulation of CD4 and CD8 T cells and B-2 B cells in the peritoneal and pleural cavities. The increase in B-2 B and T lymphocytes is not associated with an altered maturation and/or activation status of these cells. Mechanistically, an increase in peritoneal lymphocyte numbers is caused by impaired egress of CCR7-deficient lymphocytes from body cavities. These results establish that CCR7 plays a crucial role in lymphocyte exit from the PerC. J. Leukoc. Biol. 87: 000–000; 2010.
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CCR7 regulates lymphocyte egress and recirculation through body cavities.
Journal of Leukocyte Biology, 2009Co-Authors: Uta E. Höpken, Susann Winter, Ariel H. Achtman, Kerstin Kruger, Martin LippAbstract:T and B lymphocytes recirculate among blood, lymph, and extralymphoid tissues to ensure immune surveillance and the establishment of self-tolerance. The underlying mechanisms regulating homeostatic lymphocyte recirculation through body cavities are not fully understood. Here, we demonstrate that the homeostatic Chemokine Receptor CCR7 regulates homeostatic recirculation of lymphocytes through body cavities. CCR7 deficiency results in massive accumulation of CD4(+) and CD8(+) T cells and B-2 B cells in the peritoneal and pleural cavities. The increase in B-2 B and T lymphocytes is not associated with an altered maturation and/or activation status of these cells. Mechanistically, an increase in peritoneal lymphocyte numbers is caused by impaired egress of CCR7-deficient lymphocytes from body cavities. These results establish that CCR7 plays a crucial role in lymphocyte exit from the PerC.
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Thymocyte-Dendritic Cell Interactions near Sources of CCR7 Ligands in the Thymic Cortex
The Journal of Immunology, 2008Co-Authors: Ena Ladi, Martin Lipp, Tanja A. Schwickert, Tatyana Chtanova, Ying Chen, Paul Herzmark, Xinye Yin, Holly L. Aaron, Shiao Wei Chan, Badrinath RoysamAbstract:Little is known about the dynamics of the interactions between thymocytes and other cell types, as well as the spatiotemporal distribution of thymocytes during positive selection in the microenvironment of the cortex. We used two-photon laser scanning microscopy of the mouse thymus to visualize thymocytes and dendritic cells (DCs) and to characterize their interactions in the cortex. We show that thymocytes make frequent contacts with DCs in the thymic cortex and that these associations increase when thymocytes express T cell Receptors that mediate positive selection. We also show that cortical DCs and the Chemokine CCL21 expression are closely associated with capillaries throughout the cortex. The overexpression of the Chemokine Receptor CCR7 in thymocytes results in an increase in DC-thymocyte interactions, while the loss of CCR7 in the background of a positive-selecting TCR reduces the extent of DC-thymocyte interactions. These observations identify a vasculature-associated microenvironment within the thymic cortex that promotes interactions between DCs and thymocytes that are receiving positive selection signals.
Reinhold Förster - One of the best experts on this subject based on the ideXlab platform.
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CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs reprinted from cell vol 99 pg 23 33 1999
Journal of Immunology, 2016Co-Authors: Reinhold Förster, Andreas Schubel, Dagmar Breitfeld, Elisabeth Kremmer, Eckhard Wolf, Ingrid Rennermuller, Martin LippAbstract:The proper function of immune surveillance requires well-coordinated mechanisms in order to guide the patrolling immune cells through peripheral tissues and into secondary lymphoid organs. Analyzing gene-targeted mice, we identified the Chemokine Receptor CCR7 as an important organizer of the primary immune response CCR7-deficient mice show severely delayed kinetics regarding the antibody response and lack contact sensitivity and defayed type hypersensitivity reactions. Due to the impaired migration of lymphocytes, these animals reveal profound morphological alterations in all secondary lymphoid organs, Upon activation, mature skin dendritic cells fad to migrate into the draining lymph nodes. Thus, in order to bring together lymphocytes and dendritic cells to form the characteristic microarchitecture of secondary lymphoid organs, CCR7 is required to rapidly initiate an adoptive immune response.
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afferent lymph derived t cells and dcs use different Chemokine Receptor CCR7 dependent routes for entry into the lymph node and intranodal migration
Nature Immunology, 2011Co-Authors: Asolina Braun, Tim Worbs, Leandros G Moschovakis, Stephan Halle, Katharina Hoffmann, Jasmin Bolter, Anika Munk, Reinhold FörsterAbstract:Lymphatic vessels provide conduits that channel leukocytes to draining lymph nodes. Forster and colleagues show that lymph-derived dendritic cells and T cells take different paths to enter draining lymph nodes.
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regulatory t cells interfere with the development of bronchus associated lymphoid tissue
Journal of Experimental Medicine, 2007Co-Authors: Jessica R Kocks, Gabriele Hintzen, Lars Ohl, Ana Clara Marques Davalosmisslitz, Reinhold FörsterAbstract:Presence and extent of bronchus-associated lymphoid tissue (BALT) is subject to considerable variations between species and is only occasionally observed in lungs of mice. Here we demonstrate that mice deficient for the Chemokine Receptor CCR7 regularly develop highly organized BALT. These structures were not present at birth but were detectable from day 5 onwards. Analyzing CCR7−/−/wild-type bone marrow chimeras, we demonstrate that the development of BALT is caused by alterations of the hematopoietic system in CCR7-deficient mice. These observations together with the finding that CCR7-deficient mice posses dramatically reduced numbers of regulatory T cells (T reg cells) in the lung-draining bronchial lymph node suggest that BALT formation might be caused by disabled in situ function of T reg cells. Indeed, although adoptive transfer of wild-type T reg cells to CCR7-deficient recipients resulted in a profound reduction of BALT formation, neither naive wild-type T cells nor T reg cells from CCR7−/− donors impair BALT generation. Furthermore, we provide evidence that CCR7-deficient T reg cells, although strongly impaired in homing to peripheral lymph nodes, are fully effective in vitro. Thus our data reveal a CCR7-dependent homing of T reg cells to peripheral lymph nodes in conjunction with a role for these cells in controlling BALT formation.
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adaptation of solitary intestinal lymphoid tissue in response to microbiota and Chemokine Receptor CCR7 signaling
Journal of Immunology, 2006Co-Authors: Oliver Pabst, Heike Herbrand, Michaela Friedrichsen, Sarvari Velaga, Martina Dorsch, Gunter Berhardt, Tim Worbs, Andrew J Macpherson, Reinhold FörsterAbstract:Besides Peyer's patches, solitary intestinal lymphoid tissue (SILT) provides a structural platform to efficiently initiate immune responses in the murine small intestine. SILT consists of dynamic lymphoid aggregates that are heterogeneous in size and composition, ranging from small clusters of mostly lineage-negative cells known as cryptopatches to larger isolated lymphoid follicles rich in B cells. In this study, we report that in Chemokine Receptor CCR7-deficient mice SILT is enlarged, although unchanged in frequency and cellular composition compared with wild-type mice. This phenotype is conferred by bone marrow-derived cells and is independent of the presence of intestinal bacteria. Remarkably, particularly small-sized SILT predominates in germfree wild-type mice. Colonization of wild-type mice with commensal bacteria provokes an adjustment of the spectrum of SILT to that observed under specific pathogen-free conditions by the conversion of pre-existing lymphoid structures into larger-sized SILT. In conclusion, our findings establish that intestinal microbes influence the manifestation of gut-associated lymphoid tissues and identify CCR7 signaling as an endogeneous factor that controls this process.
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CCR7 governs skin dendritic cell migration under inflammatory and steady state conditions
Immunity, 2004Co-Authors: Lars Ohl, Golo Henning, Mariette Mohaupt, Niklas Czeloth, Gabriele Hintzen, Ziba Kiafard, Jorg Zwirner, Thomas Blankenstein, Reinhold FörsterAbstract:The CC Chemokine Receptor CCR7 has been identified as a key regulator of homeostatic B and T cell trafficking to secondary lymphoid organs. Data presented here demonstrate that CCR7 is also an essential mediator for entry of both dermal and epidermal dendritic cells (DC) into the lymphatic vessels within the dermis while this Receptor is dispensable for the mobilization of Langerhans cells from the epidermis to the dermis. Moreover, a distinct population of CD11c(+)MHCII(high) DC showing low expression of the costimulatory molecules CD40, CD80, and CD86 in wild-type animals was virtually absent in skin-draining lymph nodes of CCR7-deficient mice under steady-state conditions. We provide evidence that these cells represent a semimature population of DC that is capable of initiating T cell proliferation under conditions known to induce tolerance. Thus, our data identify CCR7 as a key regulator that governs trafficking of skin DC under both inflammatory and steady-state conditions.
Daniel F Legler - One of the best experts on this subject based on the ideXlab platform.
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CAL-1 as Cellular Model System to Study CCR7-Guided Human Dendritic Cell Migration
'Frontiers Media SA', 2021Co-Authors: Edith Uetz-von Allmen, Daniel F Legler, Vladimir Purvanov, Guerric P. B. Samson, Takahiro MaedaAbstract:Dendritic cells (DCs) are potent and versatile professional antigen-presenting cells and central for the induction of adaptive immunity. The ability to migrate and transport peripherally acquired antigens to draining lymph nodes for subsequent cognate T cell priming is a key feature of DCs. Consequently, DC-based immunotherapies are used to elicit tumor-antigen specific T cell responses in cancer patients. Understanding Chemokine-guided DC migration is critical to explore DCs as cellular vaccines for immunotherapeutic approaches. Currently, research is hampered by the lack of appropriate human cellular model systems to effectively study spatio-temporal signaling and CCR7-driven migration of human DCs. Here, we report that the previously established human neoplastic cell line CAL-1 expresses the human DC surface antigens CD11c and HLA-DR together with co-stimulatory molecules. Importantly, if exposed for three days to GM-CSF, CAL-1 cells induce the endogenous expression of the Chemokine Receptor CCR7 upon encountering the clinically approved TLR7/8 agonist Resiquimod R848 and readily migrate along Chemokine gradients. Further, we demonstrate that CAL-1 cells can be genetically modified to express fluorescent (GFP)-tagged reporter proteins to study and visualize signaling or can be gene-edited using CRISPR/Cas9. Hence, we herein present the human CAL-1 cell line as versatile and valuable cellular model system to effectively study human DC migration and signaling
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CCR7 is recruited to the immunological synapse acts as co stimulatory molecule and drives lfa 1 clustering for efficient t cell adhesion through zap70
Frontiers in Immunology, 2019Co-Authors: Julia M Laufer, Ilona Kindinger, Marc Artinger, Andreas Pauli, Daniel F LeglerAbstract:The Chemokine Receptor CCR7 guides T cells and dendritic cells to and within lymph nodes to launch the onset of adaptive immunity. Here, we demonstrate that CCR7 in addition acts as a potent co-stimulatory molecule in T cell activation. We found that antigen recognition and engagement of the TCR results in CCR7 accumulation at the immunological synapse where CCR7 and the TCR co-localize within sub-synaptic vesicles. We demonstrate that CCR7 triggering alone is sufficient to recruit and activate ZAP70, a critical kinase for T cell activation, through Src kinase, whereas TCR CCR7 co-stimulation results in increased and prolonged ZAP70 kinase activity. Finally, we show that ZAP70, acting as adapter molecule, is critical for CCR7-mediated inside-out signaling to integrins, thereby modulating LFA-1 valency regulation to promote cell adhesion, a key step in immunological synapse formation and efficient T cell activation.
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Engineering of Nanobodies Recognizing the Human Chemokine Receptor CCR7
MDPI AG, 2019Co-Authors: Barbara D. Jakobs, Lisa Spannagel, Vladimir Purvanov, Edith Uetz-von Allmen, Christoph Matti, Daniel F LeglerAbstract:The Chemokine Receptor CCR7 plays a pivotal role in health and disease. In particular, CCR7 controls homing of antigen-bearing dendritic cells and T cells to lymph nodes, where adaptive immune responses are initiated. However, CCR7 also guides T cells to inflamed synovium and thereby contributes to rheumatoid arthritis and promotes cancer cell migration and metastasis formation. Nanobodies have recently emerged as versatile tools to study G-protein-coupled Receptor functions and are being tested in diagnostics and therapeutics. In this study, we designed a strategy to engineer novel nanobodies recognizing human CCR7. We generated a nanobody library based on a solved crystal structure of the nanobody Nb80 recognizing the β2-adrenergic Receptor (β2AR) and by specifically randomizing two segments within complementarity determining region 1 (CDR1) and CDR3 of Nb80 known to interact with β2AR. We fused the nanobody library to one half of split-YFP in order to identify individual nanobody clones interacting with CCR7 fused to the other half of split-YFP using bimolecular fluorescence complementation. We present three novel nanobodies, termed Nb1, Nb5, and Nb38, that recognize human CCR7 without interfering with G-protein-coupling and downstream signaling. Moreover, we were able to follow CCR7 trafficking upon CCL19 triggering using Nb1, Nb5, and Nb38
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Data_Sheet_1_CCR7 Is Recruited to the Immunological Synapse, Acts as Co-stimulatory Molecule and Drives LFA-1 Clustering for Efficient T Cell Adhesion Through ZAP70.PDF
2019Co-Authors: Julia M Laufer, Ilona Kindinger, Marc Artinger, Andreas Pauli, Daniel F LeglerAbstract:The Chemokine Receptor CCR7 guides T cells and dendritic cells to and within lymph nodes to launch the onset of adaptive immunity. Here, we demonstrate that CCR7 in addition acts as a potent co-stimulatory molecule in T cell activation. We found that antigen recognition and engagement of the TCR results in CCR7 accumulation at the immunological synapse where CCR7 and the TCR co-localize within sub-synaptic vesicles. We demonstrate that CCR7 triggering alone is sufficient to recruit and activate ZAP70, a critical kinase for T cell activation, through Src kinase, whereas TCR CCR7 co-stimulation results in increased and prolonged ZAP70 kinase activity. Finally, we show that ZAP70, acting as adapter molecule, is critical for CCR7-mediated inside-out signaling to integrins, thereby modulating LFA-1 valency regulation to promote cell adhesion, a key step in immunological synapse formation and efficient T cell activation.
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common and biased signaling pathways of the Chemokine Receptor CCR7 elicited by its ligands ccl19 and ccl21 in leukocytes
Journal of Leukocyte Biology, 2016Co-Authors: Mark A Hauser, Daniel F LeglerAbstract:Chemokines are pivotal regulators of cell migration during continuous immune surveillance, inflammation, homeostasis, and development. Chemokine binding to their 7-transmembrane domain, G-protein-coupled Receptors causes conformational changes that elicit intracellular signaling pathways to acquire and maintain an asymmetric architectural organization and a polarized distribution of signaling molecules necessary for directional cell migration. Leukocytes rely on the interplay of Chemokine-triggered migration modules to promote amoeboid-like locomotion. One of the most important Chemokine Receptors for adaptive immune cell migration is the CC-Chemokine Receptor CCR7. CCR7 and its ligands CCL19 and CCL21 control homing of T cells and dendritic cells to areas of the lymph nodes where T cell priming and the initiation of the adaptive immune response occur. Moreover, CCR7 signaling also contributes to T cell development in the thymus and to lymphorganogenesis. Although the CCR7-CCL19/CCL21 axis evolved to benefit the host, inappropriate regulation or use of these proteins can contribute or cause pathobiology of chronic inflammation, tumorigenesis, and metastasis, as well as autoimmune diseases. Therefore, it appears as the CCR7-CCL19/CCL21 axis is tightly regulated at numerous intersections. Here, we discuss the multiple regulatory mechanism of CCR7 signaling and its influence on CCR7 function. In particular, we focus on the functional diversity of the 2 CCR7 ligands, CCL19 and CCL21, as well as on their impact on biased signaling. The understanding of the molecular determinants of biased signaling and the multiple layers of CCR7 regulation holds the promise for potential future therapeutic intervention.
Ryosuke Hishimura - One of the best experts on this subject based on the ideXlab platform.
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CCL21/CCR7 axis regulating juvenile cartilage repair can enhance cartilage healing in adults.
Scientific reports, 2019Co-Authors: Zenta Joutoku, Masatake Matsuoka, Kentaro Homan, Daisuke Momma, Rikiya Baba, Kazutoshi Hontani, Shinji Matsubara, Tomohiro Onodera, Masanari Hamasaki, Ryosuke HishimuraAbstract:Juvenile tissue healing is capable of extensive scarless healing that is distinct from the scar-forming process of the adult healing response. Although many growth factors can be found in the juvenile healing process, the molecular mechanisms of juvenile tissue healing are poorly understood. Here we show that juvenile mice deficient in the Chemokine Receptor CCR7 exhibit diminished large-scale healing potential, whereas CCR7-depleted adult mice undergo normal scar-forming healing similar to wild type mice. In addition, the CCR7 ligand CCL21 was transiently expressed around damaged cartilage in juvenile mice, whereas it is rarely expressed in adults. Notably, exogenous CCL21 administration to adults decreased scar-forming healing and enhanced hyaline-cartilage repair in rabbit osteochondral defects. Our data indicate that the CCL21/CCR7 axis may play a role in the molecular control mechanism of juvenile cartilage repair, raising the possibility that agents modulating the production of CCL21 in vivo can improve the quality of cartilage repair in adults. Such a strategy may prevent post-traumatic arthritis by mimicking the self-repair in juvenile individuals.
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ccl21 CCR7 axis regulating juvenile cartilage repair can enhance cartilage healing in adults
Scientific Reports, 2019Co-Authors: Zenta Joutoku, Masatake Matsuoka, Kentaro Homan, Daisuke Momma, Rikiya Baba, Kazutoshi Hontani, Shinji Matsubara, Tomohiro Onodera, Masanari Hamasaki, Ryosuke HishimuraAbstract:Juvenile tissue healing is capable of extensive scarless healing that is distinct from the scar-forming process of the adult healing response. Although many growth factors can be found in the juvenile healing process, the molecular mechanisms of juvenile tissue healing are poorly understood. Here we show that juvenile mice deficient in the Chemokine Receptor CCR7 exhibit diminished large-scale healing potential, whereas CCR7-depleted adult mice undergo normal scar-forming healing similar to wild type mice. In addition, the CCR7 ligand CCL21 was transiently expressed around damaged cartilage in juvenile mice, whereas it is rarely expressed in adults. Notably, exogenous CCL21 administration to adults decreased scar-forming healing and enhanced hyaline-cartilage repair in rabbit osteochondral defects. Our data indicate that the CCL21/CCR7 axis may play a role in the molecular control mechanism of juvenile cartilage repair, raising the possibility that agents modulating the production of CCL21 in vivo can improve the quality of cartilage repair in adults. Such a strategy may prevent post-traumatic arthritis by mimicking the self-repair in juvenile individuals.
Zenta Joutoku - One of the best experts on this subject based on the ideXlab platform.
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CCL21/CCR7 axis regulating juvenile cartilage repair can enhance cartilage healing in adults.
Scientific reports, 2019Co-Authors: Zenta Joutoku, Masatake Matsuoka, Kentaro Homan, Daisuke Momma, Rikiya Baba, Kazutoshi Hontani, Shinji Matsubara, Tomohiro Onodera, Masanari Hamasaki, Ryosuke HishimuraAbstract:Juvenile tissue healing is capable of extensive scarless healing that is distinct from the scar-forming process of the adult healing response. Although many growth factors can be found in the juvenile healing process, the molecular mechanisms of juvenile tissue healing are poorly understood. Here we show that juvenile mice deficient in the Chemokine Receptor CCR7 exhibit diminished large-scale healing potential, whereas CCR7-depleted adult mice undergo normal scar-forming healing similar to wild type mice. In addition, the CCR7 ligand CCL21 was transiently expressed around damaged cartilage in juvenile mice, whereas it is rarely expressed in adults. Notably, exogenous CCL21 administration to adults decreased scar-forming healing and enhanced hyaline-cartilage repair in rabbit osteochondral defects. Our data indicate that the CCL21/CCR7 axis may play a role in the molecular control mechanism of juvenile cartilage repair, raising the possibility that agents modulating the production of CCL21 in vivo can improve the quality of cartilage repair in adults. Such a strategy may prevent post-traumatic arthritis by mimicking the self-repair in juvenile individuals.
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ccl21 CCR7 axis regulating juvenile cartilage repair can enhance cartilage healing in adults
Scientific Reports, 2019Co-Authors: Zenta Joutoku, Masatake Matsuoka, Kentaro Homan, Daisuke Momma, Rikiya Baba, Kazutoshi Hontani, Shinji Matsubara, Tomohiro Onodera, Masanari Hamasaki, Ryosuke HishimuraAbstract:Juvenile tissue healing is capable of extensive scarless healing that is distinct from the scar-forming process of the adult healing response. Although many growth factors can be found in the juvenile healing process, the molecular mechanisms of juvenile tissue healing are poorly understood. Here we show that juvenile mice deficient in the Chemokine Receptor CCR7 exhibit diminished large-scale healing potential, whereas CCR7-depleted adult mice undergo normal scar-forming healing similar to wild type mice. In addition, the CCR7 ligand CCL21 was transiently expressed around damaged cartilage in juvenile mice, whereas it is rarely expressed in adults. Notably, exogenous CCL21 administration to adults decreased scar-forming healing and enhanced hyaline-cartilage repair in rabbit osteochondral defects. Our data indicate that the CCL21/CCR7 axis may play a role in the molecular control mechanism of juvenile cartilage repair, raising the possibility that agents modulating the production of CCL21 in vivo can improve the quality of cartilage repair in adults. Such a strategy may prevent post-traumatic arthritis by mimicking the self-repair in juvenile individuals.