Endothelial antigen presentation to T cells as a pathogenic mechanism in influenza-induced acute lung injury
内皮抗原呈递给 T 细胞作为流感诱导的急性肺损伤的致病机制
基本信息
- 批准号:10675250
- 负责人:
- 金额:$ 23.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-03-15 至 2026-02-28
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
Endothelial antigen presentation to T cells as a pathogenic mechanism in influenza-induced acute lung
injury.
ABSTRACT
Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a form of acute respiratory failure with
substantial mortality, characterized by massive loss of lung vascular barrier function due to excessive
inflammation, endothelial cell injury and death. Up to 20% of hospitalized patients with an influenza infection
develop ALI or ARDS and require mechanical ventilation. Unfortunately, there are no targeted therapies available
to prevent death secondary to ALI/ARDS. Therefore, it is imperative to understand the mechanisms by which
the influenza virus induces ALI and identify novel therapeutic targets. Lung epithelial injury has been well studied
in influenza infections, however the mechanisms of endothelial injury induced by influenza virus are still poorly
understood despite the fact that endothelial injury is a central feature of ALI/ARDS. Besides their role in
maintaining vascular barrier function, vascular endothelial cells (ECs) play an important role in regulating
inflammation. Our novel supporting data indicate that lung ECs consist of at least two major subpopulations –
pro-inflammatory ECs and pro-regenerative or developmental ECs during baseline conditions. Developmental
lung EC express the developmental transcription factor Sox17 which regenerates the injured endothelium during
infections. Inflammatory lung ECs, on the other hand, express low levels of Sox17 and instead express higher
levels of the major histocompatibility complex (MHC) class I and II molecules. H1N1 infection significantly
upregulates the expression of MHC class I and II molecules in ECs. The infection also significantly increases the
number of CD8+ cytotoxic T lymphocytes in the lung. Therefore, we hypothesize that inflammatory ECs act as
antigen presenting cells and present antigens to T lymphocytes and thus promote acute lung injury. We will study
whether expression of developmental and regenerative transcription factor Sox17 prevents the activation of
inflammatory signaling and antigen presentation. We will also assess whether the lung ECs present antigens to
CD8+ and CD4+ T lymphocytes by MHC class I and II molecules during H1N1-induced ALI. Finally, we will study
whether the activation of CD8 cytotoxic T cells induces EC death via the release of Granzyme B and cleavage
of its intracellular target Gasdermin E during H1N1-induced ALI. Here, we propose a novel mechanism of
endothelial cells as antigen presenting cells in influenza-induced ALI/ARDS. Unravelling this mechanism will
provide new insights and identify novel therapeutic targets into virus-induced ALI.
内皮细胞抗原提呈T细胞是流感所致急性肺损伤的致病机制
受伤。
摘要
急性肺损伤(ALI)或急性呼吸窘迫综合征(ARDS)是一种急性呼吸衰竭,具有
大量死亡,特征是过量的肺血管屏障功能的大量丧失
炎症、内皮细胞损伤和死亡。高达20%的流感住院患者
发展为ALI或ARDS,需要机械通气。不幸的是,目前还没有针对性的治疗方法。
预防继发于ALI/ARDS的死亡。因此,必须了解通过什么机制
流感病毒可诱发ALI,并识别新的治疗靶点。肺上皮损伤已经得到了很好的研究
然而,在流感感染中,流感病毒诱导血管内皮细胞损伤的机制仍不清楚。
尽管内皮细胞损伤是ALI/ARDS的一个主要特征,但我们仍然理解这一点。除了他们在
血管内皮细胞(ECs)在维持血管屏障功能中起着重要的调节作用
发炎。我们新的支持数据表明,肺内皮细胞至少由两个主要亚群组成-
在基线条件下,促炎症的内皮细胞和促再生或发育性的内皮细胞。发展中
肺内皮细胞表达发育转录因子Sox17,该因子可再生受损的内皮细胞
感染。另一方面,炎症性肺内皮细胞低水平表达Sox17,而高水平表达Sox17
主要组织相容性复合体(MHC)I、II类分子水平。H1N1感染显著
上调内皮细胞MHC I、II类分子的表达。感染还显著增加了
肺组织中CD8+细胞毒性T淋巴细胞的数量。因此,我们假设炎症性内皮细胞扮演着
抗原提呈细胞和提呈抗原给T淋巴细胞,从而促进急性肺损伤。我们会研究
发育和再生转录因子Sox17的表达是否能阻止
炎症信号和抗原呈递。我们还将评估肺内皮细胞是否将抗原呈递给
甲型H1N1流感急性肺损伤过程中MHC I、II类分子对CD8+、CD4+T细胞的影响最后,我们将研究
CD8细胞毒性T细胞的激活是否通过颗粒酶B的释放和裂解诱导内皮细胞死亡
在甲型H1N1流感诱导的ALI过程中,其胞内靶标Gasdermin E的表达。在这里,我们提出了一种新的机制
内皮细胞在流感ALI/ARDS中作为抗原提呈细胞。解开这一机制将
为病毒诱导的急性肺损伤提供新的见解和确定新的治疗靶点。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lianghui Zhang其他文献
Lianghui Zhang的其他文献
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{{ truncateString('Lianghui Zhang', 18)}}的其他基金
Endothelial antigen presentation to T cells as a pathogenic mechanism in influenza-induced acute lung injury.
内皮抗原呈递给 T 细胞作为流感诱导的急性肺损伤的致病机制。
- 批准号:
10182393 - 财政年份:2021
- 资助金额:
$ 23.55万 - 项目类别:
Endothelial antigen presentation to T cells as a pathogenic mechanism in influenza-induced acute lung injury
内皮抗原呈递给 T 细胞作为流感诱导的急性肺损伤的致病机制
- 批准号:
10583575 - 财政年份:2021
- 资助金额:
$ 23.55万 - 项目类别:
Endothelial antigen presentation to T cells as a pathogenic mechanism in influenza-induced acute lung injury.
内皮抗原呈递给 T 细胞作为流感诱导的急性肺损伤的致病机制。
- 批准号:
10363717 - 财政年份:2021
- 资助金额:
$ 23.55万 - 项目类别:
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