Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice

Homma, Tsuneaki; Kinugawa, Shintaro; Takahashi, Masashige; Sobirin, Mochamad Ali; Saito, Akimichi; Fukushima, Arata; Suga, Tadashi; Takada, Shingo; Kadoguchi, Tomoyasu; Masaki, Yoshihiro; Furihata, Takaaki; Taniguchi, Masaru; Nakayama, Toshinori; Ishimori, Naoki; Iwabuchi, Kazuya; Tsutsui, Hiroyuki

doi:10.1016/j.yjmcc.2013.06.004

Cited by 41 publications

(35 citation statements)

References 49 publications

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“…An increasing body of evidence supports the contention that innate immune responses contribute importantly to myocardial I/R injury[11, 17, 24, 52, 53]. I/R injury results in the release of endogenous ‘danger’ signals referred to as danger associated molecular patterns (DAMPs) by necrotic or activated cells that trigger innate immune responses[29].…”

Section: Discussionmentioning

confidence: 99%

The spleen contributes importantly to myocardial infarct exacerbation during post-ischemic reperfusion in mice via signaling between cardiac HMGB1 and splenic RAGE

et al. 2016

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The spleen plays a critical role in post-infarct myocardial remodeling. However, the role of the spleen in exacerbating myocardial infarction (MI) during acute ischemia/reperfusion (I/R) injury is unknown. The present study tests the hypothesis that splenic leukocytes are activated by substances released from ischemic myocardium to subsequently exacerbate myocardial injury during reperfusion. The left coronary artery in C57BL/6 mice underwent various durations of occlusion followed by 60 minutes of reperfusion (denoted as min/min of I/R) with or without splenectomy prior to I/R injury. Splenectomy significantly decreased myocardial infarct size (IS) in 40′/60′ and 50′/60′ groups (p<0.05); however, it had no effect on IS in 10′/60′, 20′/60′ and 30′/60′ groups (p=NS). In the 20′/60′ group, infusion of 40-minute ischemic heart homogenate (40-IHH) upon reperfusion increased IS by >3-fold versus infusion of 10-IHH (p<0.05). Splenectomy abolished the infarct exacerbating effect of 40-IHH, which was restored by splenic leukocyte adoptive transfer (SPAT). Furthermore, depletion of HMGB1 in the 40-IHH group abolished its infarct exacerbating effect (p<0.05), and 40-IHH failed to increase IS in both RAGE−/− mice and splenectomized wild-type mice with SPAT from RAGE−/− mice. The injection of 40-IHH significantly increased formyl peptide receptor 1 (FPR1) expression in sham spleens when compared to 10-IHH-treated sham & control mice. cFLFLF, a specific FPR1 antagonist, reduced myocardial neutrophil infiltration and abrogated the infarct exacerbating effect of 40-IHH during reperfusion. Conclusions A cardio (HMGB1) – splenic (RAGE receptor) signaling axis exists and contributes to myocardial infarct exacerbation during reperfusion after prolonged ischemic insults by activating splenic leukocytes. The FPR1 is a potential therapeutic target for inhibiting the cardio-splenic axis that augments infarct size during post-ischemic reperfusion.

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Section: Discussionmentioning

confidence: 99%

The spleen contributes importantly to myocardial infarct exacerbation during post-ischemic reperfusion in mice via signaling between cardiac HMGB1 and splenic RAGE

et al. 2016

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“…183 A recent study using both genetic and antibody-based approaches to modulate Tregs early post-MI showed that CD4 + Foxp3 + Tregs are also essential for favorable wound healing, scar formation, and inflammation resolution after MI, in part by modulating macrophage differentiation toward an M2-like phenotype. 181 Moreover, the activation of iNKT cells after reperfused 179 or non-reperfused MI 180 has been shown to reduce leukocyte infiltration, myocardial injury, and adverse remodeling, in part by enhancing the expression of anti-inflammatory cytokines such as IL-10. Hence, multiple T-lymphocyte subsets contribute to suppression of the inflammatory response.…”

Section: The Reparative and Proliferative Phasementioning

confidence: 99%

The Biological Basis for Cardiac Repair After Myocardial Infarction

Prabhu

Frangogiannis

2016

Circulation Research

1,645

1,396

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In adult mammals, massive sudden loss of cardiomyocytes following infarction overwhelms the limited regenerative capacity of the myocardium, resulting in formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of pro-inflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/CCL2). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response following myocardial infarction. Dysregulation of immune pathways, impaired suppression of post-infarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for prevention of post-infarction heart failure.

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“…The protective actions of Tregs may involve both secreted mediators and contact-dependent cell-cell interactions[21]. Selective activation of invariant Natural killer T cells (iNKT cells) through administration of α -galactosylceramide also suppressed inflammation and attenuated injury in experimental models of myocardial infarction[22], [23]. These studies suggest that, despite their small numbers[20], [24], infiltrating T cell subpopulations are capable of exerting profound effects on many other cell types involved in cardiac inflammation, repair and remodeling.…”

Section: Lymphocyte Subpopulations: Key Effector Cells Implicated In mentioning

confidence: 99%

Inflammation in cardiac injury, repair and regeneration

Frangogiannis

2015

Current Opinion in Cardiology

165

133

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Purpose of the review Cardiomyocyte necrosis activates an inflammatory response that serves to clear the injured myocardium from dead cells, and stimulates repair, but may also extend injury. Recent findings Recently published studies have identified Interleukin (IL)-1α and RNA released by necrotic cardiomyocytes as key danger signals that trigger the inflammatory response following infarction. IL-1 promotes activation of a pro-inflammatory phenotype in leukocytes and fibroblasts, and delays myofibroblast transdifferentiation. Inhibitory lymphocytes play a crucial role in negative regulation of the post-infarction inflammatory response by modulating macrophage and fibroblast phenotype. Cardiac macrophages exhibit significant heterogeneity and phenotypic plasticity and may orchestrate the reparative response following infarction. In neonatal mice, resident embryonic macrophage subpopulations may promote a regenerative response. In contrast, in adult animals replacement of resident macrophage populations with monocyte-derived macrophages may induce inflammation while inhibiting cardiac regeneration. These exciting observations highlight the crucial role of macrophages in cardiac injury and repair, but should be interpreted with caution considering the limitations of murine models of neonatal myocardial injury. Summary Design of novel strategies to reduce cardiac injury, improve repair and promote regeneration is dependent on understanding of the cell biology of the inflammatory response.

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Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice

Cited by 41 publications

References 49 publications

The spleen contributes importantly to myocardial infarct exacerbation during post-ischemic reperfusion in mice via signaling between cardiac HMGB1 and splenic RAGE

The spleen contributes importantly to myocardial infarct exacerbation during post-ischemic reperfusion in mice via signaling between cardiac HMGB1 and splenic RAGE

The Biological Basis for Cardiac Repair After Myocardial Infarction

Inflammation in cardiac injury, repair and regeneration

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