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Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice
Jonathan S. Fletcher, … , Nathan Salomonis, Nancy Ratner
Jonathan S. Fletcher, … , Nathan Salomonis, Nancy Ratner
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(3):e98601. https://doi.org/10.1172/jci.insight.98601.
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Research Article Inflammation Neuroscience

Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice

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Abstract

Plexiform neurofibroma is a major contributor to morbidity in patients with neurofibromatosis type I (NF1). Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Antiinflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in Nf1-mutant nerves, which invariably form neurofibroma, and show disruption of neuron–glial cell interactions and immune cell infiltration to mouse models, which rarely progresses to neurofibroma with or without disruption of neuron–glial cell interactions. We find that the chemokine Cxcl10 is uniquely upregulated in NF1 mice that invariably develop neurofibroma. Global deletion of the CXCL10 receptor Cxcr3 prevented neurofibroma development in these neurofibroma-prone mice, and an anti–Cxcr3 antibody somewhat reduced tumor numbers. Cxcr3 expression localized to T cells and DCs in both inflamed nerves and neurofibromas, and Cxcr3 expression was necessary to sustain elevated macrophage numbers in Nf1-mutant nerves. To our knowledge, these data support a heretofore-unappreciated role for T cells and DCs in neurofibroma initiation.

Authors

Jonathan S. Fletcher, Jianqiang Wu, Walter J. Jessen, Jay Pundavela, Jacob A. Miller, Eva Dombi, Mi-Ok Kim, Tilat A. Rizvi, Kashish Chetal, Nathan Salomonis, Nancy Ratner

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Figure 3

Global deletion of Cxcr3 prevents plexiform neurofibroma and reduces nerve pathology in Dhh-Cre Nf1fl/fl mice.

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Global deletion of Cxcr3 prevents plexiform neurofibroma and reduces ner...
(A) Dhh-Cre Nf1fl/fl Cxcr3-null (n = 25) mice survived significantly longer than Dhh-Cre Nf1fl/fl (n = 11) mice (****P < 0.0001, log-rank test). All of the Dhh-Cre Nf1fl/fl and none of the Dhh-Cre Nf1fl/fl Cxcr3-null mice developed neurofibromas. Censored data points represent Dhh-Cre Nf1fl/fl Cxcr3-null mice collected at 18 to 20 months of age for dissection, pathological analyses, and histological analyses. (B) Loss of Cxcr3 did not prevent Nf1 recombination in Dhh-Cre Nf1fl/fl Cxcr3-null sciatic nerve. (C–E) Representative images of age-matched (10-month) spinal cords and associated spinal nerve/DRG are shown; such dissections were performed on all study mice (n > 10 each group). White arrows indicate plexiform neurofibromas. (F–H) Close-up of C–E; white arrows indicate bilateral plexiform neurofibromas compressing the spinal cord. (I–K) Representative electron micrographs from saphenous nerves (n = 3 examined for each genotype). (I) Electron micrograph of a normal 7-month saphenous nerve. (J) Black arrowhead indicates a disrupted Remak bundle in Dhh-Cre Nf1fl/fl saphenous nerve. Dark gray particulate (black asterisks) indicates deposited collagen. (K) Remak bundle disruption and collagen deposition were absent in 7-month Dhh-Cre Nf1fl/fl Cxcr3-null saphenous nerves. Original magnification, 4000× (I, J, and K).

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