Upregulation of Programmed Death-1 and Its Ligand in Cardiac Injury Models: Interaction with GADD153.
Upregulation of Programmed Death-1 and Its Ligand in Cardiac Injury Models: Interaction with GADD153.
复制标题
DOI：
10.1371/journal.pone.0124059
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Mozaffari MS
中科院分区：
文献类型：
--
作者：
Baban B;Liu JY;Qin X;Weintraub NL;Mozaffari MS
程序性死亡-1（PD-1）及其配体PD-L1是免疫/炎症机制的调节剂。我们探讨了PD-1/PD-L1通路在心脏损伤模型中的炎症反应和组织损伤中的潜在参与。对缺血再灌注和冷冻损伤的心脏进行流式细胞术和免疫组织化学研究，以在评估生长停滞和DNA损伤诱导蛋白153（GADD 153）的背景下测定心脏PD-1和PD-L1，GADD 153调节炎症和细胞死亡。此外，我们还探讨了受损心肌细胞影响T淋巴细胞增殖的潜在能力。离体缺血再灌注心脏显示心肌细胞中PD-1和PD-L1表达显著增加;然而，免疫荧光研究表明PD-1和PD-L1主要不在同一心肌细胞上共表达。PD-1/PD-L1的上调与a）GADD 153和白细胞介素（IL）-17显著增加，但IL-10轻度增加和B）线粒体膜电位（Km）破坏以及凋亡和坏死细胞死亡相关。重要的是，虽然同种型匹配治疗不影响上述变化，但PD-L1阻断抗体治疗逆转了与显著心脏保护相关的这些作用。此外，缺血-再灌注心肌细胞减少了T淋巴细胞的增殖，PD-L1抗体部分逆转了这一作用。随后使用心肌梗死冷冻损伤模型的研究显示PD-1、PD-L1、GADD 153和IL-17阳性细胞显著增加，并伴有显著的凋亡/坏死。这些数据表明，心脏损伤模型中PD-1/PD-L1通路的上调可能通过旁分泌机制介导组织损伤。重要的是，缺血再灌注心肌细胞对T细胞增殖的抑制与PD-1/PD-L1通路的负性免疫调节作用一致，可能反映了内源性心脏机制，以减少浸润免疫细胞对受损心肌的有害影响。这些抵消作用的平衡决定了心脏损伤的程度。
Programmed Death-1 (PD-1) and its ligand, PD-L1, are regulators of immune/ inflammatory mechanisms. We explored the potential involvement of PD-1/PD-L1 pathway in the inflammatory response and tissue damage in cardiac injury models. Ischemic-reperfused and cryoinjured hearts were processed for flow cytometry and immunohistochemical studies for determination of cardiac PD-1 and PD-L1 in the context of assessment of the growth arrest- and DNA damage-inducible protein 153 (GADD153) which regulates both inflammation and cell death. Further, we explored the potential ability of injured cardiac cells to influence proliferation of T lymphocytes. The isolated ischemic-reperfused hearts displayed marked increases in expression of PD-1 and PD-L1 in cardiomyocytes; however, immunofluorescent studies indicate that PD-1 and PD-L1 are not primarily co-expressed on the same cardiomyocytes. Upregulation of PD-1/PD-L1 was associated with a) marked increases in GADD153 and interleukin (IL)-17 but a mild increase in IL-10 and b) disruption of mitochondrial membrane potential (ψm) as well as apoptotic and necrotic cell death. Importantly, while isotype matching treatment did not affect the aforementioned changes, treatment with the PD-L1 blocking antibody reversed those effects in association with marked cardioprotection. Further, ischemic-reperfused cardiac cells reduced proliferation of T lymphocytes, an effect partially reversed by PD-L1 antibody. Subsequent studies using the cryoinjury model of myocardial infarction revealed significant increases in PD-1, PD-L1, GADD153 and IL-17 positive cells in association with significant apoptosis/necrosis. The data suggest that upregulation of PD-1/PD-L1 pathway in cardiac injury models mediates tissue damage likely through a paracrine mechanism. Importantly, inhibition of T cell proliferation by ischemic-reperfused cardiac cells is consistent with the negative immunoregulatory role of PD-1/PD-L1 pathway, likely reflecting an endogenous cardiac mechanism to curtail the deleterious impact of infiltrating immune cells to the damaged myocardium. The balance of these countervailing effects determines the extent of cardiac injury.
登录
查看更多内容
影响因子：
9.3
作者：
Bodhankar S;Chen Y;Vandenbark AA;Murphy SJ;Offner H
通讯作者：
Offner H
影响因子：
3.2
作者：
Baban, Babak;Liu, Jun Yao;Mozaffari, Mahmood S.
通讯作者：
Mozaffari, Mahmood S.
DOI：
10.1161/atvbaha.111.224709
发表时间：
2011-05
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Bu DX;Tarrio M;Maganto-Garcia E;Stavrakis G;Tajima G;Lederer J;Jarolim P;Freeman GJ;Sharpe AH;Lichtman AH
通讯作者：
Lichtman AH
DOI：
10.1084/jem.20100643
发表时间：
2010-09-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sakuishi K;Apetoh L;Sullivan JM;Blazar BR;Kuchroo VK;Anderson AC
通讯作者：
Anderson AC
影响因子：
11.5
作者：
Nomi, Takeo;Sho, Masayuki;Nakajima, Yoshiyuki
通讯作者：
Nakajima, Yoshiyuki