scholarly journals Plasmacytoid Dendritic Cells Mediate Myocardial Ischemia/Reperfusion Injury by Secreting Type I Interferons

2021 ◽  
Author(s):  
Lina Lai ◽  
Aimee Zhang ◽  
Boris Yang ◽  
Eric J. Charles ◽  
Irving L. Kron ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Cyclic Gmp ◽  
Type I Interferon ◽  
Ischemia Reperfusion ◽  
Interferon Α ◽  
Type I ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Background We previously demonstrated that ischemically injured cardiomyocytes release cell‐free DNA and HMGB1 (high mobility group box 1 protein) into circulation during reperfusion, activating proinflammatory responses and ultimately exacerbating reperfusion injury. We hypothesize that cell‐free DNA and HMGB1 mediate myocardial ischemia‐reperfusion injury by stimulating plasmacytoid dendritic cells (pDCs) to secrete type I interferon (IFN‐I). Methods and Results C57BL/6 and interferon alpha receptor‐1 knockout mice underwent 40 minutes of left coronary artery occlusion followed by 60 minutes of reperfusion (40′/60′ IR) before infarct size was evaluated by 2,3,5‐Triphenyltetrazolium chloride–Blue staining. Cardiac perfusate was acquired in ischemic hearts without reperfusion by antegrade perfusion of the isolated heart. Flow cytometry in pDC‐depleted mice treated with multiple doses of plasmacytoid dendritic cell antigen‐1 antibody via intraperitoneal injection demonstrated plasmacytoid dendritic cell antigen‐1 antibody treatment had no effect on conventional splenic dendritic cells but significantly reduced splenic pDCs by 60%. pDC‐depleted mice had significantly smaller infarct size and decreased plasma interferon‐α and interferon‐β compared with control. Blockade of the type I interferon signaling pathway with cyclic GMP‐AMP synthase inhibitor, stimulator of interferon genes antibody, or interferon regulatory factor 3 antibody upon reperfusion similarly significantly attenuated infarct size by 45%. Plasma levels of interferon‐α and interferon‐β were significantly reduced in cyclic GMP‐AMP synthase inhibitor‐treated mice. Infarct size was significantly reduced by >30% in type I interferon receptor monoclonal antibody–treated mice and interferon alpha receptor‐1 knockout mice. In splenocyte culture, 40′/0′ cardiac perfusate treatment stimulated interferon‐α and interferon‐β production; however, this effect disappeared in the presence of cyclic GMP‐AMP synthase inhibitor. Conclusions Type I interferon production is stimulated following myocardial ischemia by cardiogenic cell‐free DNA/HMGB1 in a pDC‐dependent manner, and subsequently activates type I interferon receptors to exacerbate reperfusion injury. These results identify new potential therapeutic targets to attenuate myocardial ischemia‐reperfusion injury.

Abstract 13871: Plasmacytoid Dendritic Cell-derived Interferons Mediate Myocardial Ischemia-reperfusion Injury by Activating Type I Interferon Receptor

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Aimee Zhang ◽  
Katherine Marsh ◽  
Irving Kron ◽  
Zequan Yang
Keyword(s):  
Dendritic Cells ◽  
Myocardial Ischemia ◽  
Reperfusion Injury ◽  
Type I Interferon ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Blue Staining ◽  
Type I ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Introduction: We have previously demonstrated type I interferon (IFN-I) is elevated during and mediates myocardial ischemia-reperfusion injury (IRI). Hypothesis: Plasmacytoid dendritic cells (pDCs) secrete IFN-I to exacerbate myocardial IRI by activating IFN-I receptor (IFNAR). Methods: C57BL/6 (WT) and IFNAR1 knockout (KO) mice underwent 40 minutes of left coronary artery occlusion followed by 60 minutes of reperfusion. At the end of reperfusion, plasma was obtained and hearts were harvested for TTC-Phthalo-blue staining to calculate infarct size (IS), denoted as a percentage of the ischemic risk region (RR). In pDC-depleted mice, WT mice were treated with PDCA-1 antibody (250 μg via intraperitoneal injection) on days 1, 3, 5, 7 prior to undergoing IRI on day 11. Control mice were treated with isotype IgG. For IFNAR blockade, IFNAR1 antibody (MAR1-5A3 2.0 μg/g) was administered as an IV bolus to WT mice 5 minutes before reperfusion. Results: Flow cytometry demonstrated that PDCA-1 antibody treatment had no effect on the number of splenic conventional dendritic cells (1.87±0.33% vs. 1.55±0.12% in IgG control, p=NS), but significantly reduced splenic pDCs by 60% (0.47±0.01% vs. 1.41±0.29% in IgG control, p<0.05. Figure). pDC-depleted mice had significantly smaller IS compared to control after IRI (31.4±2.8 vs. 51.1±6.0, p<0.05. Figure). At the end of reperfusion, plasma levels of IFNα and IFNβ were significantly elevated in IgG control but not in pDC-depleted mice. RRs were comparable in WT mice with/without IFNAR1 blockade and congenic IFNAR1 KO mice following IRI. WT control and IgG control mice had similar IS (53±4 vs. 49±4, p=NS). IS was significantly reduced by greater than 30% in IFNAR1 mAb-treated mice and IFNAR1 KO mice (p<0.05 vs. controls). Conclusions: pDCs are activated during myocardial IRI and secrete IFN-I, which subsequently activates IFNARs and exacerbates IS. This pathway presents potential new therapeutic targets to attenuate myocardial IRI.

Abstract 16598: The Role of Paraoxonase 2 in Myocardial Ischemia/Reperfusion Injury

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Jingyuan Li ◽  
Victor R Grijalva ◽  
Srinivasa T Reddy ◽  
Mansoureh Eghbali
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Er Stress ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Ros Production ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

Objectives: Paraoxonases (PON) gene family consists of three proteins PON1, PON2, and PON3. PON2 is an intracellular membrane-associated protein that is widely expressed in vascular cells and many tissues. At the subcellular level, PON2 is localized to both the ER and mitochondria, and protects against oxidative stress. Hypothesis: The aim of this study was to investigate the role of PON2 in myocardial ischemia reperfusion injury. Methods: PON2 deficient (PON2-/-) and WT male mice were subjected to in-vivo ischemia/reperfusion injury. The left anterior descending coronary artery was occluded for 30 min followed by 24 hr of reperfusion. The infarct size, mitochondrial calcium retention capacity (CRC) and reactive oxygen species (ROS) generation were measured. The expression of C/EBP homologous protein (CHOP), GSK3b and phosphate GSK3b protein were examined by Western Blot. The number of animals was 5-7/group and data were expressed as mean±SEM. T test were used for statistical analysis. Probability values <0.05 were considered statistically significant. Results: The infarct size was ~2 fold larger in PON2 deficient mice compared to WT mice (p<0.05). The threshold for opening of mitochondrial permeability transition pore (mPTP) in response to calcium overload was much lower in PON2-/- mice compared with WT mice (173±19 in PON2-/-, 250±41 in WT, nmol/mg-mitochondrial protein, p<0.05). The ROS production was ~2 fold higher in isolated cardiac mitochondria from PON2-/- mice compared with WT mice (p<0.05). ER stress protein CHOP increased significantly in PON2-/- mice compared to WT mice (normalized to WT: 1±0.05 in WT, 1.66±0.08 in PON2-/-, p<0.001). Phospho-GSK3b level was significantly downregulated in in PON2-/- mice compared to WT mice (pGSK3b/GSK3b normalized to WT: 1±0.06 in WT 0.67±0.08 in PON2-/-, p<0.05). Conclusions: PON2 regulates myocardial ischemia/reperfusion injury via inhibiting the opening of mPTP, which is associated with reduced mitochondria ROS production, deactivation of ER stress signaling CHOP and GSK3b.

Abstract 1000: Dichotomous Roles Of TNF-α Receptors p55 And p75 In Acute Ischemia/reperfusion Injury And Late Ischemic Preconditioning

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Michael P Flaherty ◽  
Yiru Guo ◽  
Xian-Liang Tang ◽  
Sumit Tiwari ◽  
Greg Hunt ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Infarct Size ◽  
Reperfusion Injury ◽  
Ischemic Preconditioning ◽  
Coronary Occlusion ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Acute Myocardial Ischemia ◽  
Myocardial Ischemia Reperfusion Injury ◽  
Myocardial Ischemia Reperfusion

We have previously demonstrated that TNF-alpha signaling is critical for the development of protection afforded by the late phase of ischemic preconditioning (PC). In the current study, we investigated the roles of p55 (TNFR-I) and p75 (TNFR-II) in acute myocardial ischemia/reperfusion injury as well as late PC. Wild-type (WT, B6 and B6,129 strains), TNF-a−/−, p55−/−, p75−/−, and p55−/−/p75−/− double-knockout mice underwent a 30-min coronary occlusion followed by 4 h of reperfusion with or without six cycles of coronary occlusion/reperfusion (O/R) 24 h earlier. Six cycles of O/R reduced infarct size 24 h later in B6 as well as B6,129 WT mice, indicating a rob ust late PC effect (Figure ). This infarct-sparing effect of late PC was abolished in the absence of TNF-a, p55, p75, and both p55/p75, indicating that TNF-a signaling is critical for the development of late PC protection; and that signaling via both p55 and p75 is necessary for the development of protection. In nonpreconditioned TNF-a−/− and p75−/− mice, infarct size was similar to that observed in strain-matched WT mice (Figure ). However, infarct size in nonpreconditioned p55−/− mice was reduced compared with nonpreconditioned WT mice (46.8 ± 2.8% vs. 63.4 ± 3.2%, P < 0.05, Figure ). These observations were confirmed via linear regression analysis of myocardial risk region and infarct size. We conclude that nonredundant TNF-a signaling via both p55 and p75 is crucial for the development of late PC protection. However, the reduction in infarct size in naïve p55−/− mice indicates a deleterious role of this receptor during acute myocardial ischemia/reperfusion injury.

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