{"id":{"repo_id":"freiburg-diss","oai_identifier":"oai:freidok.uni-freiburg.de:1791"},"canonical_url":"https://search.dev.ndltd.org/etd/freiburg-diss/oai:freidok.uni-freiburg.de:1791","repository":{"repo_id":"freiburg-diss","name":"University of Freiburg","base_url":"https://freidok.uni-freiburg.de/oai/oai2.php"},"display":{"title":"Neuropathological characterization of transgenic mice with astrocyte-directed production of the CXC chemokine ligand 10","abstract":"Chemokines constitute a large family of chemotactic cytokines which regulate leukocyte trafficking to different target organs during physiological and pathological states. The CXC chemokine ligand (CXCL) 10 (formerly known as IP-10) is induced locally in the central nervous system (CNS) during diverse neuroinflammatory disorders. In the present study, the impact of CXCL10 production in the CNS was examined in transgenic mice with astrocyte-directed production of this chemokine. <br>These glial fibrillary acidic protein (GFAP)-CXCL10 transgenic mice developed spontaneous, transgene dose- and age-related leukocyte infiltrates in perivascular, meningeal and ventricular areas of the brain that were composed of, surprisingly, predominantly neutrophils, and lower numbers of T cells and cells of the monocytic lineage. <br>No phenotypical abnormalities or histological signs of neurodegeneration were evident in the GFAP-CXCL10 mice. In addition, the expression level of a number of inflammation-related genes, including proinflammatory cytokines and chemokines, was not significantly altered in the CNS of the transgenic mice. <br>The recruitment of leukocytes to the CNS of GFAP-CXCL10 mice could be markedly enhanced by peripheral immunization with Complete Freund's Adjuvant (CFA) and pertussis toxin in the absence of CNS-specific autoantigen. This response was accompanied by a transient, moderate increase in the expression level of several proinflammatory chemokine (CCL6 and CCL2), cytokine (TNF-alpha IL-1-alpha and IL-1-betaand other host response genes which are typically upregulated during neuroinflammatory processes (GFAP, EB22/5, ICAM-1 and Mac-1). <br>Flow cytometric expression analysis of the CXCL10 receptor, CXCR3, on <br>brain-infiltrating leukocytes from GFAP-CXCL10 mice indicated that there was significant enrichment for CXCR3-positive cells in the CNS of these mice compared with spleen. The majority of CXCR3-positive cells co-expressed the T cell marker CD3, whereas Gr1-positive granulocytes were negative for CXCR3 expression. <br>In conclusion, astrocyte production of CXCL10 can promote spontaneous and potentiate immune-induced leukocyte recruitment to the CNS, but is not sufficient on its own to promote a degenerative immune pathology. The accumulation of neutrophils in the CNS of GFAP-CXCL10 mice is independent of CXCR3 and hence involves an as yet undefined mechanism.","abstract_html":"Chemokines constitute a large family of chemotactic cytokines which regulate leukocyte trafficking to different target organs during physiological and pathological states. The CXC chemokine ligand (CXCL) 10 (formerly known as IP-10) is induced locally in the central nervous system (CNS) during diverse neuroinflammatory disorders. In the present study, the impact of CXCL10 production in the CNS was examined in transgenic mice with astrocyte-directed production of this chemokine. &lt;br&gt;These glial fibrillary acidic protein (GFAP)-CXCL10 transgenic mice developed spontaneous, transgene dose- and age-related leukocyte infiltrates in perivascular, meningeal and ventricular areas of the brain that were composed of, surprisingly, predominantly neutrophils, and lower numbers of T cells and cells of the monocytic lineage. &lt;br&gt;No phenotypical abnormalities or histological signs of neurodegeneration were evident in the GFAP-CXCL10 mice. In addition, the expression level of a number of inflammation-related genes, including proinflammatory cytokines and chemokines, was not significantly altered in the CNS of the transgenic mice. &lt;br&gt;The recruitment of leukocytes to the CNS of GFAP-CXCL10 mice could be markedly enhanced by peripheral immunization with Complete Freund&#x27;s Adjuvant (CFA) and pertussis toxin in the absence of CNS-specific autoantigen. This response was accompanied by a transient, moderate increase in the expression level of several proinflammatory chemokine (CCL6 and CCL2), cytokine (TNF-alpha IL-1-alpha and IL-1-betaand other host response genes which are typically upregulated during neuroinflammatory processes (GFAP, EB22/5, ICAM-1 and Mac-1). &lt;br&gt;Flow cytometric expression analysis of the CXCL10 receptor, CXCR3, on &lt;br&gt;brain-infiltrating leukocytes from GFAP-CXCL10 mice indicated that there was significant enrichment for CXCR3-positive cells in the CNS of these mice compared with spleen. The majority of CXCR3-positive cells co-expressed the T cell marker CD3, whereas Gr1-positive granulocytes were negative for CXCR3 expression. &lt;br&gt;In conclusion, astrocyte production of CXCL10 can promote spontaneous and potentiate immune-induced leukocyte recruitment to the CNS, but is not sufficient on its own to promote a degenerative immune pathology. The accumulation of neutrophils in the CNS of GFAP-CXCL10 mice is independent of CXCR3 and hence involves an as yet undefined mechanism.","abstract_has_math":false,"creators":["Boztug, Kaan"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Volk, Benedikt"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":null,"date_issued":"","date_published":null,"updated_at":"2026-07-24T02:22:28Z","subjects":["CXCL10","IP-10","CXCR3","GFAP","Complete Freund's Adjuvans"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://freidok.uni-freiburg.de/data/1791","outbound_label":"Repository record","outbound_source":"source_url"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Volk, Benedikt"]},{"key":"dc:creator","label":"Author","values":["Boztug, Kaan"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:type","label":"Dc Type","values":["DoctoralThesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["CXCL10","IP-10","CXCR3","GFAP","Complete Freund's Adjuvans"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Chemokines constitute a large family of chemotactic cytokines which regulate leukocyte trafficking to different target organs during physiological and pathological states. The CXC chemokine ligand (CXCL) 10 (formerly known as IP-10) is induced locally in the central nervous system (CNS) during diverse neuroinflammatory disorders. In the present study, the impact of CXCL10 production in the CNS was examined in transgenic mice with astrocyte-directed production of this chemokine. <br>These glial fibrillary acidic protein (GFAP)-CXCL10 transgenic mice developed spontaneous, transgene dose- and age-related leukocyte infiltrates in perivascular, meningeal and ventricular areas of the brain that were composed of, surprisingly, predominantly neutrophils, and lower numbers of T cells and cells of the monocytic lineage. <br>No phenotypical abnormalities or histological signs of neurodegeneration were evident in the GFAP-CXCL10 mice. In addition, the expression level of a number of inflammation-related genes, including proinflammatory cytokines and chemokines, was not significantly altered in the CNS of the transgenic mice. <br>The recruitment of leukocytes to the CNS of GFAP-CXCL10 mice could be markedly enhanced by peripheral immunization with Complete Freund's Adjuvant (CFA) and pertussis toxin in the absence of CNS-specific autoantigen. This response was accompanied by a transient, moderate increase in the expression level of several proinflammatory chemokine (CCL6 and CCL2), cytokine (TNF-alpha IL-1-alpha and IL-1-betaand other host response genes which are typically upregulated during neuroinflammatory processes (GFAP, EB22/5, ICAM-1 and Mac-1). <br>Flow cytometric expression analysis of the CXCL10 receptor, CXCR3, on <br>brain-infiltrating leukocytes from GFAP-CXCL10 mice indicated that there was significant enrichment for CXCR3-positive cells in the CNS of these mice compared with spleen. The majority of CXCR3-positive cells co-expressed the T cell marker CD3, whereas Gr1-positive granulocytes were negative for CXCR3 expression. <br>In conclusion, astrocyte production of CXCL10 can promote spontaneous and potentiate immune-induced leukocyte recruitment to the CNS, but is not sufficient on its own to promote a degenerative immune pathology. The accumulation of neutrophils in the CNS of GFAP-CXCL10 mice is independent of CXCR3 and hence involves an as yet undefined mechanism.","Chemokine sind eine Familie von chemotaktischen Zytokinen, die die Migration von Leukozyten in verschiedene Zielorgane während physiologischer und pathologischer Zustände des Organismus steuern. Im Rahmen diverser entzündlicher Erkrankungen des Zentralnervensystems (ZNS) wird die Expression des CXC Chemokinliganden CXCL10 in intrinsischen Zellen des ZNS induziert. In der vorliegenden Studie wurden die Auswirkungen der Produktion von CXCL10 im ZNS in einem transgenen Mausmodell mit konstitutiver Expression dieses Chemokins in Astrozyten untersucht. <br>Diese saure Gliafaserprotein (GFAP)-CXCL10 transgenen Mäuse entwickelten spontan leukozytäre Infiltrate in perivaskulären, meningealen und ventrikulären Arealen des Gehirns, deren Anzahl und Ausmaß vom Alter der Tiere und vom Expressionslevel des Transgens abhängig waren. Überraschenderweise fanden sich unter den ZNS-infiltrierenden Leukozyten vor allem neutrophile Granulozyten, und eine kleinere Zahl von T-Zellen und Monozyten/Makrophagen. <br>In den GFAP-CXCL10 Mäusen wurden keine phänotypischen Veränderungen festgestellt, und die routinehistologische Analyse ergab keinen Hinweis auf einen neurodegenerativen Prozess. Die Genexpression verschiedener Entzündungsmoleküle war in den transgenen Mäusen unverändert im Vergleich zu Wildtyp-Kontrollmäusen. <br>Durch eine periphere Immunstimulation mittels vollständigem Freundschen Adjuvans (CFA) und Pertussistoxin ohne spezifisches Neuroantigen konnte die Rekrutierung von Leukozyten in das ZNS der GFAP-CXCL10 Mäuse deutlich verstärkt werden. Diese Reaktion wurde begleitet von einer vorübergehenden, moderaten Erhöhung des Expressionslevels verschiedener inflammatorischer Gene. <br>Die durchflusszytometrische Analyse der Expression des Rezeptors für CXCL10, CXCR3, auf ZNS-infiltrierenden Leukozyten in den transgenen Mäusen zeigte eine signifikante Anreicherung von CXCR3-positiven Zellen im Vergleich zur Milz. Die Mehrzahl der CXCR3-positiven Zellen im ZNS der transgenen Mäuse exprimierte den T-Zell-Marker CD3, während auf Gr1-positiven Granulozyten keine Expression von CXCR3 gefunden wurde. <br>Die Ergebnisse dieser Studie zeigen, dass die Produktion von CXCL10 in Astrozyten die spontane Rekrutierung von Leukozyten in das ZNS bewirken kann und dass dieser Effekt verstärkt wird durch periphere, unspezifische Immunstimulation. Die Leukozytenakkumulation im ZNS von GFAP-CXCL10 Mäusen ist nicht mit einer degenerativen Immunpathologie verbunden. Die Akkumulation von neutrophilen Granulozyten im ZNS von GFAP-CXCL10 transgenen Mäusen ist unabhängig von CXCR3 und involviert somit einen bisher nicht definierten Mechanismus."]},{"key":"dc:format.medium","label":"Dc Format Medium","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Neuropathological characterization of transgenic mice with astrocyte-directed production of the CXC chemokine ligand 10","Neuropathologische Charakterisierung eines transgenen Mausmodells mit Produktion des CXC Chemokinliganden 10 durch Astrozyten"]}]}],"canonical_facts":{"dc:contributor":["Volk, Benedikt"],"dc:creator":["Boztug, Kaan"],"dc:description.abstract":["Chemokines constitute a large family of chemotactic cytokines which regulate leukocyte trafficking to different target organs during physiological and pathological states. The CXC chemokine ligand (CXCL) 10 (formerly known as IP-10) is induced locally in the central nervous system (CNS) during diverse neuroinflammatory disorders. In the present study, the impact of CXCL10 production in the CNS was examined in transgenic mice with astrocyte-directed production of this chemokine. <br>These glial fibrillary acidic protein (GFAP)-CXCL10 transgenic mice developed spontaneous, transgene dose- and age-related leukocyte infiltrates in perivascular, meningeal and ventricular areas of the brain that were composed of, surprisingly, predominantly neutrophils, and lower numbers of T cells and cells of the monocytic lineage. <br>No phenotypical abnormalities or histological signs of neurodegeneration were evident in the GFAP-CXCL10 mice. In addition, the expression level of a number of inflammation-related genes, including proinflammatory cytokines and chemokines, was not significantly altered in the CNS of the transgenic mice. <br>The recruitment of leukocytes to the CNS of GFAP-CXCL10 mice could be markedly enhanced by peripheral immunization with Complete Freund's Adjuvant (CFA) and pertussis toxin in the absence of CNS-specific autoantigen. This response was accompanied by a transient, moderate increase in the expression level of several proinflammatory chemokine (CCL6 and CCL2), cytokine (TNF-alpha IL-1-alpha and IL-1-betaand other host response genes which are typically upregulated during neuroinflammatory processes (GFAP, EB22/5, ICAM-1 and Mac-1). <br>Flow cytometric expression analysis of the CXCL10 receptor, CXCR3, on <br>brain-infiltrating leukocytes from GFAP-CXCL10 mice indicated that there was significant enrichment for CXCR3-positive cells in the CNS of these mice compared with spleen. The majority of CXCR3-positive cells co-expressed the T cell marker CD3, whereas Gr1-positive granulocytes were negative for CXCR3 expression. <br>In conclusion, astrocyte production of CXCL10 can promote spontaneous and potentiate immune-induced leukocyte recruitment to the CNS, but is not sufficient on its own to promote a degenerative immune pathology. The accumulation of neutrophils in the CNS of GFAP-CXCL10 mice is independent of CXCR3 and hence involves an as yet undefined mechanism.","Chemokine sind eine Familie von chemotaktischen Zytokinen, die die Migration von Leukozyten in verschiedene Zielorgane während physiologischer und pathologischer Zustände des Organismus steuern. Im Rahmen diverser entzündlicher Erkrankungen des Zentralnervensystems (ZNS) wird die Expression des CXC Chemokinliganden CXCL10 in intrinsischen Zellen des ZNS induziert. In der vorliegenden Studie wurden die Auswirkungen der Produktion von CXCL10 im ZNS in einem transgenen Mausmodell mit konstitutiver Expression dieses Chemokins in Astrozyten untersucht. <br>Diese saure Gliafaserprotein (GFAP)-CXCL10 transgenen Mäuse entwickelten spontan leukozytäre Infiltrate in perivaskulären, meningealen und ventrikulären Arealen des Gehirns, deren Anzahl und Ausmaß vom Alter der Tiere und vom Expressionslevel des Transgens abhängig waren. Überraschenderweise fanden sich unter den ZNS-infiltrierenden Leukozyten vor allem neutrophile Granulozyten, und eine kleinere Zahl von T-Zellen und Monozyten/Makrophagen. <br>In den GFAP-CXCL10 Mäusen wurden keine phänotypischen Veränderungen festgestellt, und die routinehistologische Analyse ergab keinen Hinweis auf einen neurodegenerativen Prozess. Die Genexpression verschiedener Entzündungsmoleküle war in den transgenen Mäusen unverändert im Vergleich zu Wildtyp-Kontrollmäusen. <br>Durch eine periphere Immunstimulation mittels vollständigem Freundschen Adjuvans (CFA) und Pertussistoxin ohne spezifisches Neuroantigen konnte die Rekrutierung von Leukozyten in das ZNS der GFAP-CXCL10 Mäuse deutlich verstärkt werden. Diese Reaktion wurde begleitet von einer vorübergehenden, moderaten Erhöhung des Expressionslevels verschiedener inflammatorischer Gene. <br>Die durchflusszytometrische Analyse der Expression des Rezeptors für CXCL10, CXCR3, auf ZNS-infiltrierenden Leukozyten in den transgenen Mäusen zeigte eine signifikante Anreicherung von CXCR3-positiven Zellen im Vergleich zur Milz. Die Mehrzahl der CXCR3-positiven Zellen im ZNS der transgenen Mäuse exprimierte den T-Zell-Marker CD3, während auf Gr1-positiven Granulozyten keine Expression von CXCR3 gefunden wurde. <br>Die Ergebnisse dieser Studie zeigen, dass die Produktion von CXCL10 in Astrozyten die spontane Rekrutierung von Leukozyten in das ZNS bewirken kann und dass dieser Effekt verstärkt wird durch periphere, unspezifische Immunstimulation. Die Leukozytenakkumulation im ZNS von GFAP-CXCL10 Mäusen ist nicht mit einer degenerativen Immunpathologie verbunden. Die Akkumulation von neutrophilen Granulozyten im ZNS von GFAP-CXCL10 transgenen Mäusen ist unabhängig von CXCR3 und involviert somit einen bisher nicht definierten Mechanismus."],"dc:format.medium":["application/pdf"],"dc:subject":["CXCL10","IP-10","CXCR3","GFAP","Complete Freund's Adjuvans"],"dc:title":["Neuropathological characterization of transgenic mice with astrocyte-directed production of the CXC chemokine ligand 10","Neuropathologische Charakterisierung eines transgenen Mausmodells mit Produktion des CXC Chemokinliganden 10 durch Astrozyten"],"dc:type":["DoctoralThesis"]},"updated_at":"2026-07-24T02:22:28Z"}