Abstract
To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4–6 weeks of age (WOA), Nf1OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFκB inhibitor treatment of Nf1OPG mice at 4–6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma.
Highlights
To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1OPG) mice, human and mouse RNAseq data, and two different experimental asthma models
To determine whether experimental asthma induction reduces murine glioma formation and growth in vivo, Nf1OPG mice were initially treated with ovalbumin (OVA) or house dust mite (HDM) between 4 and 6 weeks of age and euthanized at 12 weeks of age when optic gliomas are evident in >95% of mice (Fig. 1a)
Experimental asthma induction was confirmed by H&E staining of lung tissue, demonstrating infiltration of immune cells in peribronchiolar locations, consistent with submucosal inflammation after OVA or HDM challenge conditions compared to PBS controls (Supplementary Fig. 1a)
Summary
To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. OVA- and HDM-mediated asthma induction reduces optic nerve volumes and proliferation to levels comparable to Nf1+/− mice (Supplementary Fig. 2j, k), establishing that asthma blocks optic glioma formation. Ccl[5] expression was reduced in the optic nerves of Nf1OPG mice following OVA and HDM treatment at 12 (Fig. 2e) and 24 (Supplementary Fig. 3g) weeks of age.
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