Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Immunity. 2022 Jan 11;55(1):145-158.e7. doi: 10.1016/j.immuni.2021.11.005. Epub 2021 Dec 7.
Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4 T cells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders.
自闭症谱系障碍儿童常表现出免疫反应失调和相关的胃肠道症状。然而，导致这两种表型发展的潜在机制尚未阐明。在这里，我们表明，由于母亲炎症引起的产前暴露而表现出自闭症样表型的小鼠后代，在以后的生活中更容易受到肠道炎症的挑战。与它在神经发育表型中的产前作用相反，白细胞介素-17A（IL-17A）通过改变母体肠道微生物群产生免疫预表型，导致幼稚 CD4 T 细胞染色质景观的出生后改变。将具有增强的 IL-17A 反应的怀孕小鼠的粪便样本转移到无菌母鼠中，可在后代中产生免疫预表型。我们的研究为为什么暴露于子宫内炎症增加的儿童除了神经发育障碍外，还可能增加患炎症性疾病的风险提供了机制上的见解。
