Prenatal disruption of blood-brain barrier formation via cyclooxygenase activation leads to lifelong brain inflammation.
Prenatal disruption of blood-brain barrier formation via cyclooxygenase activation leads to lifelong brain inflammation.
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DOI：
10.1073/pnas.2113310119
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发表时间：
2022-04-12
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
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作者：
本研究表明，妊娠期母体炎症通过激活胎儿小胶质细胞环氧化酶干扰血脑屏障的形成，导致脑血管功能异常和慢性脑炎症持续整个后代的生命周期。因此，血脑屏障形成的发育中断可能是神经发育障碍病理的重要病因因素。小鼠妊娠期母体免疫激活（MIA）在成年后代中诱导持续的脑小胶质细胞激活和一系列神经病变。尽管长期表型已被充分记录，但子宫内MIA如何导致持续的脑炎症尚不清楚。在这里，我们发现在妊娠第13天用多核糖素-多核糖素酸[poly(I:C)]诱导MIA的母亲的后代在一生中都表现出血脑屏障（BBB）功能障碍。MIA后2 d宫内MRI显示胎儿血脑屏障高通透性。在胎儿和1岁和6岁的后代大脑中发现，脑血管中周细胞-内皮偶联减少，小胶质细胞活化增加。胎儿脑实质和血管周围空间中表达环氧化酶-2 （COX2; Ptgs2）的小胶质细胞增殖增加，导致产前血脑屏障形成异常，从而导致持久的破坏。在免疫激活24小时后，在胎儿髓细胞中靶向删除Ptgs2基因或使用抑制剂塞来昔布（celecoxib）处理可阻止小胶质细胞增殖和血脑屏障形成和功能的破坏，表明产前COX2激活是MIA效应的一个因果途径。因此，妊娠期MIA破坏胎儿血脑屏障的形成，诱导持续的血脑屏障功能障碍，从而促进小胶质细胞过度激活和后代一生的行为改变。综上所述，这些数据表明妊娠期MIA对血脑屏障形成的破坏可能是神经精神疾病的病因。
This study demonstrates that maternal inflammation during pregnancy perturbs blood–brain barrier formation via cyclooxygenase activation in fetal microglia, leading to abnormal cerebrovascular function and chronic brain inflammation persisting across the offspring life span. Therefore, developmental disruption of blood–brain barrier formation could be an important etiological factor contributing to the pathology of neurodevelopmental disorders. Gestational maternal immune activation (MIA) in mice induces persistent brain microglial activation and a range of neuropathologies in the adult offspring. Although long-term phenotypes are well documented, how MIA in utero leads to persistent brain inflammation is not well understood. Here, we found that offspring of mothers treated with polyriboinosinic–polyribocytidylic acid [poly(I:C)] to induce MIA at gestational day 13 exhibit blood–brain barrier (BBB) dysfunction throughout life. Live MRI in utero revealed fetal BBB hyperpermeability 2 d after MIA. Decreased pericyte–endothelium coupling in cerebral blood vessels and increased microglial activation were found in fetal and 1- and 6-mo-old offspring brains. The long-lasting disruptions result from abnormal prenatal BBB formation, driven by increased proliferation of cyclooxygenase-2 (COX2; Ptgs2)-expressing microglia in fetal brain parenchyma and perivascular spaces. Targeted deletion of the Ptgs2 gene in fetal myeloid cells or treatment with the inhibitor celecoxib 24 h after immune activation prevented microglial proliferation and disruption of BBB formation and function, showing that prenatal COX2 activation is a causal pathway of MIA effects. Thus, gestational MIA disrupts fetal BBB formation, inducing persistent BBB dysfunction, which promotes microglial overactivation and behavioral alterations across the offspring life span. Taken together, the data suggest that gestational MIA disruption of BBB formation could be an etiological contributor to neuropsychiatric disorders.
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影响因子：
6.2
作者：
Fiorentino M;Sapone A;Senger S;Camhi SS;Kadzielski SM;Buie TM;Kelly DL;Cascella N;Fasano A
通讯作者：
Fasano A
影响因子：
2.7
作者：
Barnes SR;Ng TS;Santa-Maria N;Montagne A;Zlokovic BV;Jacobs RE
通讯作者：
Jacobs RE
影响因子：
9.3
作者：
Calvello, Rosa;Panaro, Maria Antonietta;Scilimati, Antonio
通讯作者：
Scilimati, Antonio
影响因子：
64.8
作者：
Ben-Zvi, Ayal;Lacoste, Baptiste;Kur, Esther;Andreone, Benjamin J.;Mayshar, Yoav;Yan, Han;Gu, Chenghua
通讯作者：
Gu, Chenghua
影响因子：
2.6
作者：
Blanchette, Marie;Daneman, Richard
通讯作者：
Daneman, Richard