The CXCL10/CXCR3 Axis and Cardiac Inflammation: Implications for Immunotherapy to Treat Infectious and Noninfectious Diseases of the Heart.

Accumulating evidence reveals involvement of T lymphocytes and adaptive immunity in the chronic inflammation associated with infectious and noninfectious diseases of the heart, including coronary artery disease, Kawasaki disease, myocarditis, dilated cardiomyopathies, Chagas, hypertensive left ventricular (LV) hypertrophy, and nonischemic heart failure. Chemokine CXCL10 is elevated in cardiovascular diseases, along with increased cardiac infiltration of proinflammatory Th1 and cytotoxic T cells. CXCL10 is a chemoattractant for these T cells and polarizing factor for the proinflammatory phenotype. Thus, targeting the CXCL10 receptor CXCR3 is a promising therapeutic approach to treating cardiac inflammation. Due to biased signaling CXCR3 also couples to anti-inflammatory signaling and immunosuppressive regulatory T cell formation when activated by CXCL11. Numbers and functionality of regulatory T cells are reduced in patients with cardiac inflammation, supporting the utility of biased agonists or biologicals to simultaneously block the pro-inflammatory and activate the anti-inflammatory actions of CXCR3. Other immunotherapy strategies to boost regulatory T cell actions include intravenous immunoglobulin (IVIG) therapy, adoptive transfer, immunoadsorption, and low-dose interleukin-2/interleukin-2 antibody complexes. Pharmacological approaches include sphingosine 1-phosphate receptor 1 agonists and vitamin D supplementation. A combined strategy of switching CXCR3 signaling from pro- to anti-inflammatory and improving Treg functionality is predicted to synergistically lessen adverse cardiac remodeling

Recent Developments on the Crosstalk Between STAT3 and Inflammation in Heart Function and Disease

The transcription factor STAT3 has a protective function in the heart. Until recently, the role of STAT3 in hypertension-induced cardiac hypertrophy was unsettled. Earlier studies revealed that global reduction of STAT3 activity reduced cardiac hypertrophy with hypertension, but caused a disruption of myofilaments and increased contractile dysfunction. However, newer studies with cardiomyocyte-specific deletion of STAT3 indicate that STAT3 does not cause cardiac hypertrophy with increased blood pressure. Rather, cardiac STAT3 is important for maintaining metabolic homeostasis, and loss of STAT3 in cardiomyocytes makes the heart more susceptible to chronic pathological insult, for example by disrupting glucose metabolism and protective signaling networks via the upregulation of certain microRNAs. This scenario has implications for understanding peripartum cardiomyopathy as well. In viral myocarditis, STAT3 opposes the initiation of the dilated phenotype by maintaining membrane integrity via the expression of dystrophin. STAT3 signaling was also found to attenuate myocarditis by polarizing macrophages to a less inflammatory phenotype. On the other hand, STAT3 contributes to immune-mediated myocarditis due to IL-6-induced complement component C3 production in the liver, as well as the differentiation of Th17 cells, which play a role in initiation and development of myocarditis. Besides canonical signaling pathways, unphosphorylated STAT3 (U-STAT3) and redox-activated STAT3 have been shown to couple to transcription in the heart. In addition, tissue signaling cytokines such as IL-22 and IL-17 have been proposed to have actions on the heart that involve STAT3, but are not fully defined. Understanding the novel and often protective aspects of STAT3 in the myocardium could lead to new therapeutic approaches to treat heart disease

Conflicting vascular and metabolic impact of the IL-33/sST2 axis.

Interleukin 33 (IL-33), which is expressed by several immune cell types, endothelial and epithelial cells, and fibroblasts, is a cytokine of the IL-1 family that acts both intra- and extracellularly to either enhance or resolve the inflammatory response. Intracellular IL-33 acts in the nucleus as a regulator of transcription. Once released from cells by mechanical stress, inflammatory cytokines, or necrosis, extracellular IL-33 is proteolytically processed to act in an autocrine/paracrine manner as an 'alarmin' on neighbouring or various immune cells expressing the ST2 receptor. Thus, IL-33 may serve an important role in tissue preservation and repair in response to injury; however, the actions of IL-33 are dampened by a soluble form of ST2 (sST2) that acts as a decoy receptor and is produced by endothelial and certain immune cells. Accumulating evidence supports the conclusion that sST2 is a biomarker of vascular health with diagnostic and/or prognostic value in various cardiovascular diseases, including coronary artery disease, myocardial infarction, atherosclerosis, giant-cell arteritis, acute aortic dissection, and ischaemic stroke, as well as obesity and diabetes. Although sST2 levels are positively associated with cardiovascular disease severity, the assumption that IL-33 is always beneficial is naïve. It is increasingly appreciated that the pathophysiological importance of IL-33 is highly dependent on cellular and temporal expression. Although IL-33 is atheroprotective and may prevent obesity and type 2 diabetes by regulating lipid metabolism, IL-33 appears to drive endothelial inflammation. Here, we review the current knowledge of the IL-33/ST2/sST2 signalling network and discuss its pathophysiological and translational implications in cardiovascular diseases

Cardiac STAT3 Deficiency Impairs Contractility and Metabolic Homeostasis in Hypertension

Signal transducer and activator of transcription 3 (STAT3) protects the heart from acute ischemic stress. However, the importance of STAT3 to the heart in chronic stress, such as hypertension, is not known. To study this, we used cardiomyocyte-targeted STAT3 knockout (KO) mice and ANG II infusion by osmotic minipumps. After 4 weeks, ANG II induced similar cardiac hypertrophy in wild type (WT) and cardiac Cre-expressing control (CTRL) mice with no impairment of cardiac function. In contrast, STAT3 KO mice exhibited reduced contractile function but similar hypertrophy to CTRL mice. Ejection fraction and fractional shortening decreased by 22.5% and 27.3%, respectively. Since STAT3 has direct protective effects on mitochondrial function, we examined rates of glucose and oleate oxidation by isolated perfused hearts using a Langendorff system. Hearts of ANG II-treated STAT3 KO and CTRL mice had similar rates of oleate oxidation as saline-infused WT mice. Rates of glucose oxidation were similar between hearts of WT plus saline and CTRL plus ANG II mice; however, glucose oxidation was increased by 66% in hearts of ANG II-treated STAT3 KO mice. The ratio of maximal ATP yield from glucose to fatty acid oxidation was 21.1 ± 3.1 in hearts of ANG II-treated STAT3 KO mice vs. 12.6 ± 2.2 in hearts of ANG II-treated CTRL mice. Lactate production was also elevated in hearts of ANG II-treated STAT3 KO mice by 162% compared to ANG II-treated CTRL mice. Our findings indicate that (1) STAT3 is important for maintaining contractile function and metabolic homeostasis in the hypertensive heart, and (2) STAT3 deficiency promotes a switch toward glucose utilization

STAT3 and Endothelial Cell—Cardiomyocyte Dialog in Cardiac Remodeling

This article presents an overview of the central role of STAT3 in the crosstalk between endothelial cells and cardiac myocytes in the heart. Endothelial cell STAT3 has a key role in inflammation that underlies cardiovascular disease and impacts on cardiac structure and function. STAT3 in endothelial cells contributes to adverse cardiomyocyte genetic reprograming, for instance, during peripartum cardiomyopathy. Conversely, cardiomyocyte STAT3 is important for maintaining endothelial cell function and capillary integrity with aging and hypertension. In addition, STAT3 serves as a sentinel for stress in the heart. Recent evidence has revealed that the redox nature of STAT3 is regulated, and STAT3 is responsive to oxidative stress (ischemia-reperfusion) so as to induce protective genes. At the level of the mitochondrion, STAT3 is important in regulating reactive oxygen species (ROS) formation, metabolism, and mitochondrial integrity. STAT3 may also control calcium release from the ER so as to limit its subsequent uptake by mitochondria and the induction of cell death. Under normal conditions, some STAT3 localizes to intercalated discs of cardiomyocytes and serves to transmit pro-fibrotic gene induction signals in the nucleus with increased blood pressure. Further research is needed to understand how the sentinel role of STAT3 in both endothelial cells and cardiomyocytes is integrated in order to coordinate the response of the heart to both physiological and pathological demands

Evidence That IL-6-Type Cytokine Signaling in Cardiomyocytes Is Inhibited by Oxidative Stress: Parthenolide Targets JAK1 Activation by Generating ROS

Parthenolide, an anti-inflammatory compound, was reported to inhibit signal transducer and activator of transcription 3 (STAT3) activation by the interleukin (IL)-6-type cytokines by an undefined process, which was the focus of our study. Here we report that parthenolide reduced both basal and leukemia inhibitory factor (LIF)-induced STAT3 tyrosine 705 (Y705) phosphorylation in cardiomyocytes in a dose-dependent manner, but stimulated the MAP kinase signaling pathways. Activation of Janus kinase I (JAK1) tyrosine kinase was markedly reduced by parthenolide. Pretreatment with parthenolide inhibited JAK1-mediated phosphorylation of the LIF receptor subunits LIF receptor (LIFR) α and glycoprotein 130 (gp130), and reduced the LIF-induced increase in JAK1 association with both components. In addition, we documented that parthenolide, over the same concentration range, does not have a direct inhibitory effect on JAK1 autophosphorylation. However, we observed that parthenolide increased intracellular reactive oxygen species (ROS). Pretreatment with the antioxidant, N-acetyl-L-cysteine, completely suppressed the effect of parthenolide on JAK1 and STAT3. From these results, we conclude ROS generation in cardiomyocytes blocks STAT3 signaling of the IL-6-type cytokines by targeting JAK1. The finding that signaling by the IL-6-type cytokine may be redox-sensitive defines a novel mechanism of regulation that has implications for exploiting their therapeutic potential

STAT3 and Endothelial Cell-Cardiomyocyte Dialog in Cardiac Remodeling

This article presents an overview of the central role of STAT3 in the crosstalk between endothelial cells and cardiac myocytes in the heart. Endothelial cell STAT3 has a key role in inflammation that underlies cardiovascular disease and impacts on cardiac structure and function. STAT3 in endothelial cells contributes to adverse cardiomyocyte genetic reprograming, for instance, during peripartum cardiomyopathy. Conversely, cardiomyocyte STAT3 is important for maintaining endothelial cell function and capillary integrity with aging and hypertension. In addition, STAT3 serves as a sentinel for stress in the heart. Recent evidence has revealed that the redox nature of STAT3 is regulated, and STAT3 is responsive to oxidative stress (ischemia-reperfusion) so as to induce protective genes. At the level of the mitochondrion, STAT3 is important in regulating reactive oxygen species (ROS) formation, metabolism, and mitochondrial integrity. STAT3 may also control calcium release from the ER so as to limit its subsequent uptake by mitochondria and the induction of cell death. Under normal conditions, some STAT3 localizes to intercalated discs of cardiomyocytes and serves to transmit pro-fibrotic gene induction signals in the nucleus with increased blood pressure. Further research is needed to understand how the sentinel role of STAT3 in both endothelial cells and cardiomyocytes is integrated in order to coordinate the response of the heart to both physiological and pathological demands