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中文摘要:
中風(fēng)的醫(yī)療負(fù)擔(dān)超出了腦損傷本身,很大程度上是由繼發(fā)性慢性合并癥決定的。我們假設(shè)這些合并癥可能有一個(gè)共同的免疫學(xué)原因,但中風(fēng)后對(duì)全身免疫的慢性影響尚未得到充分探索。在這里,我們將髓系先天免疫記憶確定為中風(fēng)后遠(yuǎn)端器官功能障礙的原因。單細(xì)胞測(cè)序顯示,在腦損傷后長(zhǎng)達(dá) 3 個(gè)月的多個(gè)器官(尤其是心臟)中,單核細(xì)胞/巨噬細(xì)胞持續(xù)存在促炎變化,導(dǎo)致小鼠和中風(fēng)患者的心臟纖維化和功能障礙。IL-1β被確定為先天免疫記憶表觀遺傳變化的關(guān)鍵驅(qū)動(dòng)因素。這些變化可以移植到幼稚小鼠身上,誘發(fā)心功能障礙。通過(guò)中和中風(fēng)后的IL-1β或用CCR2/5抑制劑阻斷促炎性單核細(xì)胞運(yùn)輸,我們預(yù)防了中風(fēng)后心功能不全。這種免疫靶向療法有可能預(yù)防各種IL-1β介導(dǎo)的合并癥,為二級(jí)預(yù)防免疫療法提供框架。
英文摘要:
The medical burden of stroke extends beyond the brain injury itself and is largely determined by chronic comorbidities that develop secondarily. We hypothesized that these comorbidities might share a common immunological cause, yet chronic effects post-stroke on systemic immunity are underexplored. Here, we identify myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Single-cell sequencing revealed persistent pro-inflammatory changes in monocytes/macrophages in multiple organs up to 3 months after brain injury, notably in the heart, leading to cardiac fibrosis and dysfunction in both mice and stroke patients. IL-1β was identified as a key driver of epigenetic changes in innate immune memory. These changes could be transplanted to naive mice, inducing cardiac dysfunction. By neutralizing post-stroke IL-1β or blocking pro-inflammatory monocyte trafficking with a CCR2/5 inhibitor, we prevented post-stroke cardiac dysfunction. Such immune-targeted therapies could potentially prevent various IL-1β-mediated comorbidities, offering a framework for secondary prevention immunotherapy.
論文信息:
論文題目:Innate immune memory after brain injury drives inflammatory cardiac dysfunction
期刊名稱(chēng):Cell
時(shí)間期卷:在線(xiàn)2024-7-22pages685–700 (2024)
在線(xiàn)時(shí)間:2024年7月22日
研究亮點(diǎn):
- 急性的腦缺血導(dǎo)致持續(xù)的先天免疫記憶
- 先天免疫記憶導(dǎo)致慢性中風(fēng)后心功能不全
- IL-1β通過(guò)表觀遺傳修飾誘導(dǎo)中風(fēng)后免疫
- 阻斷 IL-1β 或單核細(xì)胞募集可預(yù)防心功能不全
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