Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice

Abstract

macrophage subpopulations with distinct activities (24,25). Further characterization of these neurofibroma leukocytes and their contributions to tumor initiation and growth is necessary for the development of safe and effective immunomodulatory therapies.In the Dhh-Cre Nf1 fl/fl mouse neurofibroma model, biallelic deletion of Nf1 in the Schwann cell lineage mimics the biallelic loss of NF1 in human NF1 and sporadic plexiform neurofibroma (26). The peripheral nerves of these mice appear normal at 1 month of age, but pathological changes, including mast cell and macrophage infiltration and abnormal Schwann cell proliferation, are evident at 2 months of age (26,27). By 4 months of age, these mice invariably form MRI-detectable paraspinal neurofibromas that histologically and transcriptionally resemble human plexiform neurofibroma (26,28,29). Schwann cell-specific deletion of Nf1 using other drivers can also induce nerve pathology and neurofibroma development in mice (19,(30)(31)(32). In contrast, CNPase-human EGFR (CNPase-hEGFR) mice have increased Ras activity driven by overexpression of hEGFR and develop similar nerve pathology to Nf1 mouse models but have reduced myeloid cell infiltration, and only approximately 1 in 20 develop a neurofibroma (20,33).Here, we compare nerves from these mouse models transcriptionally and identify a chemokine, Cxcl10, that is uniquely overexpressed in 2-month Dhh-Cre Nf1 fl/fl nerves. CXCL10 and its receptor, CXCR3, are important modulators of neuroinflammation and tumor biology (34)(35)(36). In this study, we identify Cxcl10and Cxcr3-expressing cell populations in nerves and neurofibroma and demonstrate the necessity of Cxcr3 for neurofibroma development in Dhh-Cre Nf1 fl/fl mice. Results Differential gene expression analyses identify Cxcl10 as a potential modulator of plexiform neurofibroma development.Peripheral nerves from GEMMs of NF1 (GEMM-NF1) (P0-CreB Nf1 fl/fl , P0-CreB Nf1 fl/-, Dhh-Cre Nf1 fl/fl ) invariably develop neurofibromas (26,31). P0-CreB and Dhh-Cre are transgenic mouse strains that express Cre recombinase in peripheral nerve Schwann cells; when used to recombine Nf1 in mice, peripheral nerves show pathological mast cell recruitment, disruption of axon and nonmyelinating Schwann cell (axon/ Remak bundle) interactions, and collagen deposition (nerve disruption). This nerve disruption phenotype precedes plexiform neurofibroma development. Although several of these changes have been proposed to contribute to neurofibroma development, similar nerve pathology is also observed in CNPase-hEGFR/ + and CNPase-hEGFR/CNPase-hEGFR mice, which recruit fewer macrophages and rarely form neurofibromas (33,37). In contrast, this pathology is not observed in Npcis mice (Nf1 +/− Trp53 +/− deletions in cis) that progress directly to malignant peripheral nerve sheath tumor (ref. 38 and Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.98601DS1) or in CNPase-HRas12V mice that do not develop plexiform neurofibroma (39)....

Lymphocyte Subpopulations in Patients With Neurofibromatosis Type 1-associated Optic Pathway Gliomas and Plexiform Neurofibromas

“…In a few reports, immunological profiling of NF1-associated tumors was analyzed. These investigations potentially offer a way to guide the rational selection of immunotherapeutic treatments (19)(20)(21).…”

P2RY14 cAMP signaling regulates Schwann cell precursor self-renewal, proliferation, and nerve tumor initiation in a mouse model of neurofibromatosis

“…In the Nf1 fl/fl ;Dhh Cre neurofibroma mouse model, Cre recombinase is expressed from Desert Hedgehog (Dhh) regulatory sequences to effect recombination of the Nf1 fl/fl allele, resulting in loss of both Nf1 alleles in developing SCPs at E12.5 ( Wu et al, 2008 ). Nf1 fl/fl ;Dhh Cre mice develop paraspinal neurofibromas that have loss of axon-SC interaction in Remak bundles, mast cell and macrophage accumulation, and nerve fibrosis, all characteristics of human PNs ( Wu et al, 2008 ; Liao et al, 2018 ; Fletcher et al, 2019a ; Fletcher et al, 2019b ). In this setting, PNs are present by 4 months of age, and neurofibromas enlarge as the mice age, ultimately compressing the spinal cord causing paralysis and thus, necessitating sacrifice ( Wu et al, 2008 ).…”

Pharmacological Approaches in Neurofibromatosis Type 1-Associated Nervous System Tumors

“…Additionally, since macrophages are recruited via CXCL10-CXCR3, which are expressed in T cells and dendritic cells, the deletion of CXCR3 may prevent neurofibroma formation. However, studies revealed that anti-CXCR3 did not reduce the tumor size of the established tumor [58].…”

“…All genetically engineered models can be also modified by crossing them with mice that have specific genetic defects to assess the contribution of specific genes on the NF1related tumors in tumor cells or their microenvironments [58,76,91]. Apart from commonly used mice models, scientists also developed a minipig model for NF1 which may overcome some limitations in mouse models and better represent disease features in humans [158,159].…”