哮喘通过T细胞核心蛋白聚糖介导的小胶质细胞抑制来减少胶质瘤的形成
2021/12/24
摘要
为了阐明1型神经纤维瘤病（NF1）和哮喘儿童脑肿瘤发病率降低的机制，我们利用NF1光学通路胶质瘤（Nf1OPG）小鼠、人类和小鼠RNA序列数据以及两种不同的实验性哮喘模型。在4-6周龄时卵清蛋白或屋尘螨哮喘（WOA）诱导后，Nf1OPG小鼠视神经体积和增殖在12和24周龄时减少，表明没有肿瘤发生。这种抑制伴随着小胶质细胞产生的视神经胶质瘤有丝分裂原Ccl5的表达降低。人类和小鼠T细胞转录组分析显示，抑制小胶质细胞Ccl5的产生是由于核心蛋白聚糖的T细胞表达增加，而核心蛋白聚糖通过减少小胶质细胞NFκB信号传导阻断Ccl4介导的小胶质细胞Ccl5的表达。核心蛋白聚糖或NFκB抑制剂在4-6 WOA时对Nf1OPG小鼠进行治疗，可抑制12 WOA时的肿瘤形成，从而为哮喘儿童中观察到的胶质瘤发病率降低建立了潜在的机制病因学。
Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia.
Jit Chatterjee, Shilpa Sanapala, Olivia Cobb, Alice Bewley, Andrea K Goldstein, Elizabeth Cordell, Xia Ge, Joel R Garbow, Michael J Holtzman, David H Gutmann
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.
为了阐明1型神经纤维瘤病（NF1）和哮喘儿童脑肿瘤发病率降低的机制，我们利用NF1光学通路胶质瘤（Nf1OPG）小鼠、人类和小鼠RNA序列数据以及两种不同的实验性哮喘模型。在4-6周龄时卵清蛋白或屋尘螨哮喘（WOA）诱导后，Nf1OPG小鼠视神经体积和增殖在12和24周龄时减少，表明没有肿瘤发生。这种抑制伴随着小胶质细胞产生的视神经胶质瘤有丝分裂原Ccl5的表达降低。人类和小鼠T细胞转录组分析显示，抑制小胶质细胞Ccl5的产生是由于核心蛋白聚糖的T细胞表达增加，而核心蛋白聚糖通过减少小胶质细胞NFκB信号传导阻断Ccl4介导的小胶质细胞Ccl5的表达。核心蛋白聚糖或NFκB抑制剂在4-6 WOA时对Nf1OPG小鼠进行治疗，可抑制12 WOA时的肿瘤形成，从而为哮喘儿童中观察到的胶质瘤发病率降低建立了潜在的机制病因学。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Nat Commun. 2021 Dec 8;12(1):7122. doi: 10.1038/s41467-021-27455-6.)
(Nat Commun. 2021 Dec 8;12(1):7122. doi: 10.1038/s41467-021-27455-6.)
Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia.
Jit Chatterjee, Shilpa Sanapala, Olivia Cobb, Alice Bewley, Andrea K Goldstein, Elizabeth Cordell, Xia Ge, Joel R Garbow, Michael J Holtzman, David H Gutmann
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.
