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Splenic leukocytes define the resolution of inflammation in heart failure.

ABSTRACT: Inflammation promotes healing in myocardial infarction but, if unresolved, leads to heart failure. To define the inflammatory and resolving responses, we quantified leukocyte trafficking and specialized proresolving mediators (SPMs) in the infarcted left ventricle and spleen after myocardial infarction, with the goal of distinguishing inflammation from its resolution. Our data suggest that the spleen not only served as a leukocyte reservoir but also was the site where SPMs were actively generated after coronary ligation in mice. Before myocardial infarction, SPMs were more abundant in the spleen than in the left ventricle. At day 1 after coronary ligation, the spleen was depleted of leukocytes, a phenomenon that was associated with greater numbers of leukocytes in the infarcted left ventricle and increased generation of SPMs at the same site, particularly resolvins, maresin, lipoxins, and protectin. In addition, the infarcted left ventricle showed increased expression of genes encoding lipoxygenases and enhanced production of SPMs generated by these enzymes. We found that macrophages were necessary for SPM generation. The abundance of SPMs in the spleen before myocardial infarction and increased SPM concentrations in the infarcted left ventricle within 24 hours after myocardial infarction were temporally correlated with the resolution of inflammation. Thus, the acute inflammatory response coincided with the active resolving phase in post-myocardial infarction and suggests that further investigation into macrophage-derived SPMs in heart failure is warranted.

SUBMITTER: Halade GV

PROVIDER: S-EPMC6145858 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Splenic leukocytes define the resolution of inflammation in heart failure.

Halade Ganesh V GV Norris Paul C PC Kain Vasundhara V Serhan Charles N CN Ingle Kevin A KA

Science signaling 20180306 520

Inflammation promotes healing in myocardial infarction but, if unresolved, leads to heart failure. To define the inflammatory and resolving responses, we quantified leukocyte trafficking and specialized proresolving mediators (SPMs) in the infarcted left ventricle and spleen after myocardial infarction, with the goal of distinguishing inflammation from its resolution. Our data suggest that the spleen not only served as a leukocyte reservoir but also was the site where SPMs were actively generate ...[more]

PMID: 29511119

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Project description:ObjectiveRecently, we observed that the specialized proresolving mediator (SPM) entity resolvin D1 activates lipoxin A4/formyl peptide receptor 2 (ALX/FPR2), which facilitates cardiac healing and persistent inflammation is a hallmark of impaired cardiac repair in aging. Splenic leukocyte-directed SPMs are essential for the safe clearance of inflammation and cardiac repair after injury; however, the target of SPMs remains undefined in cardiac healing and repair.MethodsTo define the mechanistic basis of ALX/FPR2 as a resolvin D1 target, ALX/FPR2-null mice were examined extensively. The systolic-diastolic heart function was assessed using echocardiography, leukocytes were phenotyped using flow cytometry, and SPMs were quantitated using mass spectrometry. The presence of cardiorenal syndrome was validated using histology and renal markers.ResultsLack of ALX/FPR2 led to the development of spontaneous obesity and diastolic dysfunction with reduced survival with aging. After cardiac injury, ALX/FPR2-/- mice showed lower expression of lipoxygenases (-5, -12, -15) and a reduction in SPMs in the infarcted left ventricle and spleen, indicating nonresolving inflammation. Reduced SPM levels in the infarcted heart and spleen are suggestive of impaired cross-talk between the injured heart and splenic leukocytes, which are required for the resolution of inflammation. In contrast, cyclooxygenases (-1 and -2) were over amplified in the infarcted heart. Together, these results suggest interorgan signaling in which the spleen acts as both an SPM biosynthesizer and supplier in acute heart failure. ALX/FPR2 dysfunction magnified obesogenic cardiomyopathy and renal inflammation (↑NGAL, ↑TNF-α, ↑CCL2, ↑IL-1β) with elevated plasma creatinine levels in aging mice. At the cellular level, ALX/FPR2-/- mice showed impairment of macrophage phagocytic function ex-vivo with expansion of neutrophils after myocardial infarction.ConclusionsLack of ALX/FPR2 induced obesity, reduced the life span, amplified leukocyte dysfunction, and facilitated profound interorgan nonresolving inflammation. Our study shows the integrative and indispensable role of ALX/FPR2 in lipid metabolism, cardiac inflammation-resolution processes, obesogenic aging, and renal homeostasis.

Project description:Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.

Project description:BackgroundAlthough human studies have shown that inflammation plays a role in the development of congestive heart failure, scarce information exists on white blood cell count (WBC) and differential cell counts in various stages of heart failure in man and dogs. A few studies demonstrated increased concentrations of C-reactive protein (CRP), a major acute-phase protein, in cardiac diseases in dogs. Our research aimed to investigate whether CRP concentration, WBC and neutrophil count (NEUT), as markers of systemic inflammation, are elevated in canine cardiovascular patients. We also aimed to find out whether there is an association between CRP concentration and WBC and NEUT, as well as associations between these inflammatory markers and selected echocardiographic parameters. Sixty-two client-owned canine cardiac patients and 12 healthy dogs were included in the study. The patients were classified into International Small Animal Cardiac Health Council classes (ISACHC I-III). The serum CRP concentration was determined using a canine CRP test kit. WBC and NEUT were determined using an automated hematology analyzer.ResultsSignificantly higher serum CRP concentration, WBC and NEUT were found in the decompensated stage of heart failure (ISACHC III) compared with healthy dogs and with patients in ISACHC group II and ISACHC group I. Serum CRP concentration significantly positively correlated with WBC (r = 0.65, P < 0.001) and NEUT (r = 0.58, P = 0.002) in the ISACHC III group, while no significant correlations were found in the ISACHC I and II groups. A significant negative correlation between serum CRP concentration and the left ventricular ejection fraction (r = - 0.49, P = 0.046) and a significant positive correlation between CRP and the E wave velocity of the mitral valve inflow (r = 0.52, P = 0.046) were found in the ISACHC III group.ConclusionsThe CRP concentration, WBC and NEUT were significantly increased in advanced-stage heart failure patients in comparison with compensated patients and healthy dogs, which indicate the presence of systemic inflammation. However, normal CRP concentration and normal WBC and NEUT can also be present in heart failure.

Project description:To identify a novel target for the treatment of heart failure, we examined gene expression in the failing heart. Among the genes analyzed, 12/15 lipoxygenase (12/15-LOX) was markedly up-regulated in heart failure. To determine whether increased expression of 12/15-LOX causes heart failure, we established transgenic mice that overexpressed 12/15-LOX in cardiomyocytes. Echocardiography showed that 12/15-LOX transgenic mice developed systolic dysfunction. Cardiac fibrosis increased in 12/15-LOX transgenic mice with advancing age, and was associated with the infiltration of macrophages. Consistent with these observations, cardiac expression of monocyte chemoattractant protein-1 (Mcp-1) was up-regulated in 12/15-LOX transgenic mice compared with wild-type mice. Treatment with 12-hydroxy-eicosatetraenotic acid, a major metabolite of 12/15-LOX, increased MCP-1 expression in cardiac fibroblasts and endothelial cells, but not in cardiomyocytes. Inhibition of Mcp-1 reduced the infiltration of macrophages into the myocardium and prevented both systolic dysfunction and cardiac fibrosis in 12/15-LOX transgenic mice. Likewise, disruption of 12/15-LOX significantly reduced cardiac Mcp-1 expression and macrophage infiltration, thereby improving systolic dysfunction induced by chronic pressure overload. Our results suggest that cardiac 12/15-LOX is involved in the development of heart failure and that inhibition of 12/15-LOX could be a novel treatment for this condition. Heart failure is still one of the leading causes of death worldwide. Therefore, it is important to elucidate the underlying mechanisms of heart failure and develop more effective treatments for this condition. To clarify the molecular mechanisms of heart failure, we performed microarray analysis using cardiac tissue samples obtained from a hypertensive heart failure model (Dahl salt-sensitive rats). ~300 genes showed significant changes of expression in the failing hearts compared with control hearts. Among the genes analyzed, 12/15-lipoxygenase (12/15-LOX) was most markedly up-regulated in failing hearts compared with control hearts .

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Splenic leukocytes define the resolution of inflammation in heart failure.

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Splenic leukocytes define the resolution of inflammation in heart failure.

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