Opposing Roles for CXCR3 Signaling in Central Nervous System Versus Ocular Inflammation Mediated by the Astrocyte-Targeted Production of IL-12

Krauthausen, Marius; Ellis, Sally L.; Zimmermann, Julian; Sarris, Maria; Wakefield, Denis; Heneka, Michael T.; Campbell, Iain L.; Müller, Marcus

doi:10.1016/j.ajpath.2011.07.041

Cited by 10 publications

(8 citation statements)

References 51 publications

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“…Tissue was homogenized using a Precellys 24 tissue homogenizer ( Bertin Technologies, Saint-Quentin-en-Yvelines Cedex, France ) in lysis buffer described elsewhere [65]. Samples were centrifuged at 12000 rpm / 13200 g for 15 min and supernatants were taken.…”

Section: Methodsmentioning

confidence: 99%

CNS-Targeted Production of IL-17A Induces Glial Activation, Microvascular Pathology and Enhances the Neuroinflammatory Response to Systemic Endotoxemia

et al. 2013

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Interleukin-17A (IL-17A) is a key cytokine modulating the course of inflammatory diseases. Whereas effector functions of IL-17A like induction of antimicrobial peptides and leukocyte infiltration could clearly be demonstrated for peripheral organs, CNS specific effects are not well defined and appear controversial. To further clarify the functional significance of IL-17A in the CNS, we generated a transgenic mouse line with astrocyte-restricted expression of the IL-17A gene. GFAP/IL-17A transgenic mice develop normally and do not show any signs of neurological dysfunction. However, histological characterization revealed astrocytosis and activation of microglia. Demyelination, neurodegeneration or prominent tissue damage was not observed but a vascular pathology mimicking microangiopathic features was evident. Histological and flow cytometric analysis demonstrated the absence of parenchymal infiltration of immune cells into the CNS of GFAP/IL-17A transgenic mice. In GFAP/IL-17A mice, LPS-induced endotoxemia led to a more pronounced microglial activation with expansion of a distinct CD45high/CD11b+ population and increased induction of proinflammatory cytokines compared with controls. Our data argues against a direct role of IL-17A in mediating tissue damage during neuroinflammation. More likely IL-17A acts as a modulating factor in the network of induced cytokines. This novel mouse model will be a very useful tool to further characterize the role of IL-17A in neuroinflammatory disease models.

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Section: Methodsmentioning

confidence: 99%

CNS-Targeted Production of IL-17A Induces Glial Activation, Microvascular Pathology and Enhances the Neuroinflammatory Response to Systemic Endotoxemia

et al. 2013

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“…Although CXCR3 antagonists have a plethora of conceivable clinical applications and a number of CXCR3 antagonists are available, none of these substances have yet passed clinical studies with success and approval (82). In addition, we know from recent experimental studies that manipulation of the CXCR3 chemokine system can result in very unexpected and potentially harmful effects (83). Finally, CXCR3 antagonists have to be tested and identified for their ability to cross the BBB, allowing a local inhibition of CXCR3 inside the CNS.…”

Section: Discussionmentioning

confidence: 99%

CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model

Krauthausen¹,

Kummer²,

Zimmermann³

et al. 2014

J. Clin. Invest.

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118

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“…Reactive astrocytes can be induced to adopt a proinflammatory phenotype not only by inhibiting an anti-inflammatory signaling pathway, but also by overexpressing proinflammatory cytokines. Thus, increasing astrocytic production of proinflammatory cytokines, including TNF-α, IL-12, IL-17, or the T lymphocyte chemoattractant CXCL10, exacerbates T lymphocyte and myeloid cell infiltration into the CNS at baseline and in EAE [67,[140][141][142][143][144]. Similarly, overexpressing astrocytic IL-6 increases immune cell infiltration in SCI and EAE and reduces pathogen burden during viral infection [59][60][61].…”

Section: Astrocytic Regulation Of the Adaptive Immune Responsementioning

confidence: 99%

Astrocytes: Integrative Regulators of Neuroinflammation in Stroke and Other Neurological Diseases

2016

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Astrocytes regulate neuroinflammatory responses after stroke and in other neurological diseases. Although not all astrocytic responses reduce inflammation, their predominant function is to protect the brain by driving the system back to homeostasis after injury. They receive multidimensional signals within the central nervous system and between the brain and the systemic circulation. Processing this information allows astrocytes to regulate synapse formation and maintenance, cerebral blood flow, and blood-brain barrier integrity. Similarly, in response to stroke and other central nervous system disorders, astrocytes detect and integrate signals of neuronal damage and inflammation to regulate the neuroinflammatory response. Two direct regulatory mechanisms in the astrocyte arsenal are the ability to form both physical and molecular barriers that seal the injury site and localize the neuroinflammatory response. Astrocytes also indirectly regulate the inflammatory response by affecting neuronal health during the acute injury and axonal regrowth. This ability to regulate the location and degree of neuroinflammation after injury, combined with the long time course of neuroinflammation, makes astrocytic signaling pathways promising targets for therapies.

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Opposing Roles for CXCR3 Signaling in Central Nervous System Versus Ocular Inflammation Mediated by the Astrocyte-Targeted Production of IL-12

Cited by 10 publications

References 51 publications

CNS-Targeted Production of IL-17A Induces Glial Activation, Microvascular Pathology and Enhances the Neuroinflammatory Response to Systemic Endotoxemia

CNS-Targeted Production of IL-17A Induces Glial Activation, Microvascular Pathology and Enhances the Neuroinflammatory Response to Systemic Endotoxemia

CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer’s disease model

Astrocytes: Integrative Regulators of Neuroinflammation in Stroke and Other Neurological Diseases

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