The Programmed Death-1 Signaling Axis Modulates Inflammation and LV Structure/Function in a Stress-Induced Cardiomyopathy Model.
The Programmed Death-1 Signaling Axis Modulates Inflammation and LV Structure/Function in a Stress-Induced Cardiomyopathy Model.
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DOI：
10.1016/j.jacbts.2022.05.006
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发表时间：
2022-11
影响因子：
9.7
通讯作者：
Mann, Douglas L.
中科院分区：
文献类型：
--
作者：
Hayashi, Tomohiro;Tiwary, Sajal K.;Lavine, Kory J.;Acharya, Sandeep;Brent, Michael;Adamo, Luigi;Kovacs, Attila;Mann, Douglas L.
单次腹腔注射 ISO 会引起心脏急性炎症反应，并伴有左心室结构和功能的可逆性变化。单细胞 RNA 测序显示，ISO 损伤会引起多个抑制性免疫检查点基因的表达短暂增加，包括 Pdcd1 (PD-1) 和 Cd274 (PD-L1)，主要出现在心脏固有免疫细胞中，包括 LYVE1− 巨噬细胞和树突状细胞。与野生型小鼠相比，抗PD-L1抗体治疗导致ISO注射后心肌炎症增加，而PD-1−/−小鼠中ISO注射导致炎症反应持续时间延长、左心室扩张延长和左心室功能障碍。用坏死心肌细胞体外刺激腹膜来源的炎症细胞，以 TLR2/TLR4/NF-κB 依赖性方式增加巨噬细胞和 T 细胞中表达 PD-1 的细胞百分比。免疫检查点在组织损伤中的作用仍不清楚。使用异丙肾上腺素 (ISO) 诱导的应激性心肌病的实验模型，我们发现 ISO 诱导的心肌损伤会引起心脏固有免疫细胞和 T 细胞中程序性死亡 1 (PD-1)：程序性死亡配体 (PD-L) 轴的组织自主上调。 PD-1 信号传导负责调节急性炎症反应，以及注射 ISO 后受损的左心室结构和功能的正常化。坏死心脏提取物足以在体外增加巨噬细胞和 T 细胞中 PD-1 的表达。综合来看，这些研究表明 PD-1:PD-L 信号轴调节对心脏组织损伤的免疫反应，对于恢复心肌稳态非常重要。
A single intraperitoneal dose of ISO provokes an acute inflammatory response in the heart that is accompanied by reversible changes in LV structure and function. Single-cell RNA sequencing reveals that ISO injury elicits a transient increase in expression of multiple inhibitory immune checkpoints genes, including Pdcd1 (PD-1) and Cd274 (PD-L1), predominantly in the cardiac resident innate immune cells, including LYVE1− macrophages and dendritic cells. Treatment with an anti-PD-L1 antibody results in increased myocardial inflammation after ISO injection, whereas ISO injection in PD-1−/− mice results in increased duration of the inflammatory response, prolonged LV dilation, and LV dysfunction relative to wild-type mice. In vitro stimulation of peritoneal derived inflammatory cells with necrotic cardiac myocytes increases the percentage of cells expressing PD-1 in macrophages and T cells in a TLR2/TLR4/NF-κB–dependent manner. The role of immune checkpoints in the setting of tissue injury remains unknown. Using an experimental model of isoproterenol (ISO)-induced stress cardiomyopathy, we show that ISO-induced myocardial injury provokes tissue-autonomous up-regulation of the programmed death-1 (PD-1):programmed death ligand (PD-L) axis in cardiac resident innate immune cells and T cells. PD-1 signaling was responsible for modulating the acute inflammatory response, as well as normalization of impaired left ventricular structure and function after ISO injection. Necrotic cardiac extracts were sufficient to increase the expression of PD-1 in macrophages and T cells in vitro. Viewed together these studies suggest that the PD-1:PD-L signaling axis regulates immune responses to cardiac tissue injury and is important for restoring myocardial homeostasis.
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影响因子：
20.1
作者：
Frangogiannis NG
通讯作者：
Frangogiannis NG
影响因子：
8
作者：
Adamo, Luigi;Rocha-Resende, Cibele;Mann, Douglas L.
通讯作者：
Mann, Douglas L.
影响因子：
3.7
作者：
Baban B;Liu JY;Qin X;Weintraub NL;Mozaffari MS
通讯作者：
Mozaffari MS
影响因子：
3.7
作者：
Murakami T;Yoshikawa T;Maekawa Y;Ueda T;Isogai T;Sakata K;Nagao K;Yamamoto T;Takayama M
通讯作者：
Takayama M
DOI：
10.4049/jimmunol.1203441
发表时间：
2014-09-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Beswick EJ;Johnson JR;Saada JI;Humen M;House J;Dann S;Qiu S;Brasier AR;Powell DW;Reyes VE;Pinchuk IV
通讯作者：
Pinchuk IV