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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 5

Identification of Cxcr3-expressing cells in Dhh-Cre Nf1fl/fl nerve/DRG and neurofibroma.

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Identification of Cxcr3-expressing cells in Dhh-Cre Nf1fl/fl nerve/DRG a...
(A) Cxcr3 expression colocalizes with CD3+ T cells and CD11c+ DCs in 2-month nerve/DRG (original magnification, ×60. Scale bar: 20 μm) and (B) in 7-month neurofibroma (original magnification, ×60. Scale bar: 20 μm). (C) Cxcr3-expressing cells are rare in WT nerves (n = 4) and are predominantly T cells and DCs in Dhh-Cre Nf1fl/fl nerve/DRG (n = 9) and neurofibroma (n = 7) (****P < 0.0001, 2-way ANOVA with Tukey’s MCT). The box plot depicts the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range. (D) T cells were rare in 2-month (n ≥ 4 all groups) sciatic nerves, but loss of Cxcr3 reduced T cell accumulation in 7-month Dhh-Cre Nf1fl/fl sciatic nerves (**P < 0.01, ***P < 0.001, 2-way ANOVA with Tukey’s MCT). Symbols represent individual mice; horizontal bars indicate the mean ± SD. (E) DC numbers in sciatic nerves were unaffected by loss of Cxcr3 (NS, 2-way ANOVA). (F and G) Colorimetric (DAB) staining of CD3+ T cells and CD11c+ DCs in human peripheral nerve and plexiform neurofibroma (original magnification, ×40. Scale bar: 50 μm). (F) T cells are absent in normal human peripheral nerves (n = 7) but numerous in human plexiform neurofibroma (n = 19). (G) DCs are absent in human peripheral nerves (n = 7) but detectable in some human plexiform neurofibromas (n = 15). Arrowhead points to CD11c+ (brown) cell. (H) Quantification of T cells (*P < 0.01, unpaired t test) and (I) quantification of CD11c+ cells (NS, P = 0.056, unpaired t test) in human tissue sections. (J) Box-and-whisker plot showing relative CXCR3 mRNA expression in human plexiform neurofibroma (pNF) versus normal human nerve. The box plot depicts the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range.

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