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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 1

Gene expression reveals differential expression of Cxcl10 in neurofibroma development.

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Gene expression reveals differential expression of Cxcl10 in neurofibrom...
(A) Gene expression in control nerves compared with Nf1-mutant GEMM and related EGFR and HRas mouse models; 2,028 genes were differentially expressed (ANOVA, P < 0.05, Benjamini-Hochberg FDR), forming 6 distinct gene expression clusters. Relative levels of gene expression are shown as fold change (left); red means high and blue means low gene expression. Clusters were refined using K-means clustering (n = 6) for subsequent gene ontology (GO) analyses (the colored column to the right of the heatmap labeled C1–C6 represents K-means clusters). The pattern of gene expression in clusters C1 and C6 was associated with the presence of nerve disruption, a common pattern of axon-glial dissociation, fibrosis, and inflammation occurring in plexiform neurofibroma mouse models and CNPase-hEGFR nerves, which is designated by a green bar under the heatmap. (B) An independent analysis of 1-month and 2-month Nf1fl/fl (control), CNPase-hEGFR/ CNPase-hEGFR, and Dhh-Cre Nf1fl/fl nerves identified 1,339 genes as differentially expressed between these groups at the 2-month but not the 1-month time point (ANOVA, P < 0.05, Benjamini-Hochberg FDR; n = 4 for the 2-month Nf1fl/fl control, n = 3 other groups). CNPase-hEGFR/CNPase-hEGFR and Dhh-Cre Nf1fl/fl nerves at the 2-month time point shared a common pattern of gene regulation distinct from maturation-associated changes in 2-month controls. Consistent with the presence of the nerve disruption phenotype in these 2-month experimental nerves, many of these differentially expressed genes were associated with the nerve disruption phenotype identified in A (indicated by the column to the right of the heatmap in B). (C) Genes differentially expressed between Dhh-Cre Nf1fl/fl and CNPase-hEGFR/CNPase-hEGFR nerve/DRG. Only 38 genes were significantly upregulated or downregulated greater than 2-fold in 2-month Dhh-Cre Nf1fl/fl nerve/DRG relative to 2-month Nf1fl/fl controls that were not similarly upregulated or downregulated in CNPase-hEGFR/CNPase-hEGFR nerve/DRG (P < 0.05, Benjamini-Hochberg FDR) in Dhh-Cre Nf1fl/fl nerve/DRG but not CNPase-hEGFR nerve/DRG (relative to their respective controls). The 7 most upregulated genes are shown. Cxcl10 was the only cytokine uniquely upregulated in Dhh-Cre Nf1fl/fl nerve/DRG. (D) Cxcl10 upregulation in 2-month Dhh-Cre Nf1fl/fl (n = 3 all groups) nerve/DRG was validated by quantitative PCR (**P < 0.01, Dunnett’s multiple-comparisons test [MCT]). Cxcl10 was also upregulated in neurofibroma (****P < 0.0001, Dunnett’s MCT). (E–G) Its receptor, Cxcr3 (****P < 0.0001, Dunnett’s MCT), and its alternative ligands, Cxcl9 and Cxcl11 (**P < 0.01, Dunnett’s MCT), were overexpressed in neurofibroma but not in 2-month Dhh-Cre Nf1fl/fl nerve/DRG (n = 3 all groups). Symbols represent individual mice; horizontal bars indicate the mean ± SD.

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