期刊
NATURE COMMUNICATIONS
卷 12, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-27455-6
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资金
- National Institute of Neurological Disorders and Stroke [1-R35-NS07211-01]
- National Heart, Lung, and Blood Institute [R35-HL145242]
- NIH T35 NHLBI Training Grant [5-T35-HL007815]
- POST grant from Alex's Lemonade Stand Foundation
- National Eye Institute [P30EY002687]
- NCI Cancer Center Support Grant [P30-CA091842]
- ICTS/CTSA from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) [UL1TR002345]
- NIH Roadmap for Medical Research
- Washington University School of Medicine, The Children's Discovery Institute of Washington University
- St. Louis Children's Hospital [CDI-CORE-2015-505, CDI-CORE-2019-813]
- Foundation for Barnes-Jewish Hospital [3770, 4642]
Through leveraging mouse models and RNAseq data, this study demonstrates a potential mechanistic etiology for the reduced incidence of brain tumors, specifically optic gliomas, in children with asthma. Experimental asthma induction leads to decreased glioma formation and growth in Neurofibromatosis type 1 associated low grade optic glioma models, attributed to T cell-dependent inhibition of microglia-mediated tumor support.
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 (Nf1(OPG)) 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), Nf1(OPG) 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 NF kappa B signaling. Decorin or NF kappa B inhibitor treatment of Nf1(OPG) 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. Clinical studies have suggested a reduced incidence of brain tumors, including optic gliomas, in children with asthma. Here, in a mouse model of Neurofibromatosis type 1 associated low grade optic glioma, the authors show that experimental asthma induction decreases glioma formation and growth, resulting from T cell-dependent inhibition of microglia-mediated tumor support.
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