TY - JOUR
T1 - Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia
AU - Chatterjee, Jit
AU - Sanapala, Shilpa
AU - Cobb, Olivia
AU - Bewley, Alice
AU - Goldstein, Andrea K.
AU - Cordell, Elizabeth
AU - Ge, Xia
AU - Garbow, Joel R.
AU - Holtzman, Michael J.
AU - Gutmann, David H.
N1 - Funding Information:
This work is funded by a grant from the National Institute of Neurological Disorders and Stroke (1-R35-NS07211-01 to D.H.G.) and National Heart, Lung, and Blood Institute (R35-HL145242 to M.J.H.). E.C. was supported by NIH T35 NHLBI Training Grant (5-T35-HL007815) and a POST grant from Alex’s Lemonade Stand Foundation. We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The authors thank the Ophthalmology and Pulmonary Morphology Cores at the Washington University School of Medicine for tissue processing. The Washington University Ophthalmology Core facility support is supported by funding from the National Eye Institute (P30EY002687), while the Washington University Genome Engineering and iPSC Core Center is subsidized by funding from an NCI Cancer Center Support Grant (P30-CA091842) and by ICTS/CTSA Grant# UL1TR002345 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of NCRR or NIH. We thank Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813), and the Foundation for Barnes-Jewish Hospital (3770 and 4642). Figure illustrations were created with BioRender.com.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85120915047&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-27455-6
DO - 10.1038/s41467-021-27455-6
M3 - Article
C2 - 34880260
AN - SCOPUS:85120915047
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 7122
ER -