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

Abstract

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.