Krauthausen, Marius: The role of the chemokine receptor CXCR3 in mouse models for IL-12-driven CNS-inflammation and Morbus Alzheimer-like neurodegeneration. - Bonn, 2013. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
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author = {{Marius Krauthausen}},
title = {The role of the chemokine receptor CXCR3 in mouse models for IL-12-driven CNS-inflammation and Morbus Alzheimer-like neurodegeneration},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2013,
month = jan,

note = {The chemokine receptor CXCR3 and its corresponding ligands CXCL9, CXCL10 and CXCL11 are well known to be involved in the trafficking and migration of activated CD4+ Th1 T cells, CD8+ T cells and NK cells during inflammation. Because of the high levels of CXCR3 expression on Th1 and NK cells, this chemokine receptor is used as a prototypical marker for these cells. Functional existence of CXCR3 has also been demonstrated on resident cells of the CNS, although the relevance of CXCR3 for CNS immune and non-immune functions is only scarcely defined. The CXCR3 ligands CXCL9, CXCL10 and CXCL11 are induced in a vast variety of inflammatory CNS diseases with a variable degree of immune cell infiltration, but recently these ligands have also been shown to be induced in neurodegenerative diseases without significant infiltration of immune cells. Taken together, the available data argues for a diverse and complex role of CXCR3 in neuroinflammatory diseases, which is beyond simple immune cell attraction. Furthermore, the impact of CXCR3 in neurodegenerative diseases is almost undiscovered.
To further examine the functional role of CXCR3 in CNS disease models, we genetically deleted the CXCR3 receptor in specific CNS disease models. We first focused on the impact of CXCR3 on a highly inflammatory, Th1 cell-mediated immune response in the CNS induced by the CNS-specific production of IL-12 in transgenic mice (GF-IL12 model). Secondly and in contrast to the first model, we examined the role of CXCR3 signaling in a neurodegenerative disease using transgenic mice co-expressing two human Alzheimer’s disease (AD) mutations with only minor inflammatory features (APP/PS1 model).
GF-IL12 mice develop ataxia due to severe cerebellar inflammation, but have little overt ocular pathology. In GF-IL12 mice deficient for CXCR3 the incidence of ataxia was drastically reduced, but surprisingly all mice developed cataract and severe inflammatory destruction of the eyes. Histological examination revealed only minimal cerebellar inflammation in the majority of GF-IL12/CXCR3KO mice, but severe retinal disorganization, loss of photoreceptors and lens destruction of the eyes. The number of CD3+, CD11b+ and NK 1.1+ cells were reduced in the cerebellum, but highly increased in the eyes of GF-IL12/CXCR3KO compared to GF-IL12 mice. In addition, high levels of various transcripts of proinflammatory cytokines were found in the cerebellum of GF-IL12 and the eye of GF-IL12/CXCR3KO mice. These findings demonstrate key, but paradoxical functions for CXCR3 in IL-12-induced immune pathology in the CNS, promoting inflammation in the brain yet restricting it in the eye. From this experiment we conclude that CXCR3 can have both striking protective and harmful functions in CNS and ocular inflammation and that this effect does not only depend on the trigger as suggested by previous studies but likely also on the micro-milieu of the affected organ.
Early chemokine induction has been described in chronic neurodegenerative diseases such as AD. Descriptive studies in brain tissue from AD patients and the according animal models revealed high levels of the chemokine CXCL10, suggesting an important pathogenetic role of this chemokine and the corresponding receptor CXCR3. To further elucidate the role of CXCR3 in a less inflammatory CNS disease model, we analyzed CXCR3-competent APP/PS1 transgenic mice and APP/PS1/CXCR3-/- transgenic mice for Aβ-deposition, APP-processing and inflammatory gene transcription. Furthermore, microglial phagocytosis assays were used to analyze the impact of CXCR3 on the microglial phagocytosis of Aβ. We found a strongly reduced plaque burden and Aβ peptide-levels APP/PS1/CXCR3-/- compared to APP/PS1 mice. An alternative morphological activation and diminished accumulation of microglia was detected in APP/PS1/CXCR3-/- mice and after cortical injection of Aβ into CXCR3-/- mice. CXCR3 deficiency led to a reduction of proinflammatory cytokine RNA levels like TNF-α and IL-1β in APP/PS1 brain tissue. In vitro, CXCR3-/- and CXCR3 antagonist treated microglia showed enhanced phagocytosis of Aβ. Taken together, we identified CXCR3 as a critical factor modulating the development of the microglial response and thereby the progression of the Alzheimer’s like pathology observed in APP/PS1 mice.
The presented studies highlight the potent but also complex functional properties of CXCR3 in both, highly inflammatory and neurodegenerative CNS-disease models. CXCR3 appears to be a novel and promising therapeutic target for AD but our data further underline the functional complexity and unpredictability of this chemokine system in CNS diseases. Until then, therapeutic targeting of CXCR3 has to be proceeded with caution.},

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