Retention of the NLRP3 Inflammasome-primed Neutrophils in the Bone Marrow is Essential for Myocardial Infarction-induced Granulopoiesis

Circulation ◽  
2021 ◽  
Author(s):  
Gopalkrishna Sreejit ◽  
Sunil K. Nooti ◽  
Robert M. Jaggers ◽  
Baskaran Athmanathan ◽  
Ki Ho Park ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Cardiac Function ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Elevated Serum ◽  
Serum Levels ◽  
Time Dependent ◽  
New Paradigm ◽  
Sites Of Action

Background: Acute myocardial infarction (MI) results in overzealous production and infiltration of neutrophils to the ischemic heart. This is mediated in-part by granulopoiesis induced by the S100A8/A9-NLRP3-IL-1β signaling axis in injury-exposed neutrophils. Despite the transcriptional upregulation of the NLRP3 inflammasome and associated signaling components in neutrophils, the serum levels of IL-1β, the effector molecule in granulopoiesis was not impacted by MI suggesting that IL-1β is not released systemically. We hypothesize that IL-1β is released locally within the bone marrow (BM) by inflammasome-primed and reverse-migrating neutrophils. Methods: Using a combination of time-dependent parabiosis and flow cytometry techniques, we first characterized the migration patterns of different blood cell types across the parabiotic barrier. We next induced MI in parabiotic mice by permanent ligation of the LAD artery, and examined the ability of injury-exposed neutrophils to permeate the parabiotic barrier and induce granulopoiesis in non-infarcted parabionts. Finally, utilizing multiple neutrophil adoptive and BM transplant studies, we studied the molecular mechanisms that govern reverse migration and retention of the primed neutrophils, IL-1β secretion and granulopoiesis. Cardiac function was assessed by echocardiography. Results: MI promoted greater accumulation of the inflammasome-primed neutrophils in the BM. Introducing a time-dependent parabiotic barrier to the free movement of neutrophils inhibited their ability to stimulate granulopoiesis in the non-infarcted parabionts. Prior priming of the NLRP3 inflammasome is not a prerequisite, but the presence of a functional CXCR4 (C-X-C-motif chemokine receptor 4) on the primed neutrophils and elevated serum S100A8/A9 levels are necessary for homing and retention of the reverse-migrating neutrophils. In the BM, the primed neutrophils secrete IL-1β through formation of gasdermin D pores and, promote granulopoiesis. Pharmacological and/ or genetic strategies aimed at inhibition of neutrophil homing or release of IL-1β in the BM markedly suppressed MI-induced granulopoiesis and, improved cardiac function. Conclusions: Our data reveal a new paradigm of how circulatory cells establish a direct communication between organs by delivering signaling molecules (e.g., IL-1β) directly at the sites of action rather through systemic release. We suggest that this pathway may exist to limit the off-target effects of systemic IL-1β release.

Abstract 228: Inflammasome-Primed Neutrophils Return to the Bone Marrow to Stimulate Leukocytosis Following Myocardial Infarction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Prabhakara R Nagareddy ◽  
Gopalkrishna Sreejit ◽  
Man K Lee ◽  
Baskaran Athmanathan ◽  
Greg A Quaife-Ryan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Nlrp3 Inflammasome ◽  
Major Adverse Cardiovascular Events ◽  
Dependent Manner ◽  
New Paradigm ◽  
Pyrin Domain ◽  
One Year ◽  
The One ◽  
Sites Of Action

Myocardial infarction (MI) triggers myelopoiesis resulting in heightened number of neutrophils in the circulation. However, the mechanism that sustain their number and recruitment to the infarcted heart are unclear. Here, we show that in a mouse model of MI (permanent ligation of LAD), neutrophils are rapidly recruited to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins acting either in an autocrine or paracrine manner, primed the Nod Like Receptor (NLR) family Pyrin Domain Containing 3 (Nlrp3) inflammasome in naïve neutrophils via their interaction with the Toll Like Receptor (TLR) 4. The interaction did not result in the release of IL1β systemically. However, the primed neutrophils, loaded with pro-interleukin-1β (IL-1β) returned to the bone marrow (BM) in a CXCR4 (C-X-C-motif chemokine receptor 4)- dependent manner. While at the BM, the primed-neutrophils released IL-1β through Gasdermin D pores and, stimulated granulopoiesis in a cell-autonomous manner. Strategies aimed at preventing the Nlrp3 inflammasome-priming or re-entry of the primed neutrophils to the BM dampened MI-induced granulopoiesis and markedly improved cardiac function. In subjects with acute ST-elevation myocardial infarction (STEMI), the number of neutrophils in the circulation increased both at the time of admission and following revascularization. Most importantly, patients with higher peak neutrophil counts demonstrated significantly higher incidence of major adverse cardiovascular events (MACE) during the one year follow up period. Similar to mouse data, the plasma levels of IL-1β did not change in STEMI patients at any time. However, the circulating neutrophils carried greater amounts of pro-IL-1β confirming our mouse data that granulopoiesis is likely not induced by systemic but locally delivered IL-1β by reverse migrating neutrophils. These data reveal a new paradigm of how circulatory cells establish direct communication between organs by delivering signaling molecules directly at the sites of action rather through systemically.

Inhibition of mitochondrial fission as a novel therapeutic strategy to reduce mortality upon myocardial infarction

2018 ◽  
Vol 132 (20) ◽  
pp. 2163-2167 ◽  
Author(s):  
Hannah A. Cooper ◽  
Satoru Eguchi
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion ◽  
Mitochondrial Fission ◽  
Future Research ◽  
Mitochondrial Homeostasis ◽  
Acute Mi ◽  
Future Research Directions ◽  
Receive Treatment

Ischemia reperfusion (I/R) injury is a common event following myocardial infarction (MI) resulting in excessive oxidative stress, calcium overload, inflammation, and cardiomyocyte death. Mitochondrial homeostasis including their dynamics are imbalanced in cardiac I/R injury in favor of increased mitochondrial fission. Inhibition of mitochondrial fission prior to I/R injury is protective and improves cardiac function following MI. Clinically, patients with MI often receive treatment following initiation of the ischemic event. Thus, treatments with more realistic timing would have better translational value and are important to research. In a recent study published in Clinical Science, Maneechote et al. [Clin. Sci. (2018) 132, 1669–1683] examined the effect of inhibiting mitochondrial fission using the mitochondrial division inhibitor (Mdivi-1) at different time points, pre-ischemia, during-ischemia, and upon onset of reperfusion, in a rat cardiac I/R model. The findings showed the greatest cardiac function improvement with pre-ischemia treatment along with decreased mitochondrial fragmentation and increased mitochondrial function. Mdivi-1 given during ischemia and at onset of reperfusion also improved cardiac function, but to a lesser extent than pre-ischemia intervention. Maneechote et al. postulated that the LV protection by Mdivi-1 in cardiac I/R could be due to an improvement in mitochondrial dysfunction through attenuating excessive mitochondrial fission which then reduces apoptotic myocytes. Their findings provide new insights into future treatment of patients suffering acute MI which could consider targetting the excessive mitochondrial fission during cardiac ischemia or at onset of reperfusion. Here, we will further discuss the background of the study, potential molecular mechanisms of mitochondrial fission, consequences of the fission, and future research directions.

scholarly journals CLINICAL STUDY OF ACUTE MYOCARDIAL INFARCTION IN YOUNG ADULTS WITH REFERENCE TO SERUM LIPOPROTEIN, SERUM HOMOCYSTEINE AND HS-CRP

2020 ◽  
pp. 1-3
Author(s):  
Felin Ann Francis
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Elevated Serum ◽  
Young Patients ◽  
Serum Levels ◽  
Serum Lipoprotein ◽  
Considerable Proportion ◽  
Serum Homocysteine ◽  
Younger Generation ◽  
Hs Crp

• Introduction - Recently, the prevalence of acute myocardial infarction (AMI) has been increasing in the younger generation. With the advances in the field of medicine, elevated serum levels of various biomarkers like c-reactive protein (CRP), various lipoproteins and homocysteine have been identified to be related to AMI. • Objective - To clinically diagnose acute myocardial infarction in young patients and correlate the levels of serum lipoprotein, serum homocysteine and serum hs-crp and to calculate the level of risk depending on their levels. • Method - A hospital based observational study in which 50 subjects were enrolled in the study as per the inclusion and exclusion criteria. • Results - The results support the current global findings of the younger generation, especially the males, being affected by AMI (Acute Myocardial Infarction). Sedentary lifestyle and BMI >25 can be considered as major risk factors leading to AMI. A considerable proportion of our AMI patients had significantly elevated levels of homocysteine, hs-CRP and lipoprotein A and low levels of HDL-C indicating their correlation with AMI.

Abstract 81: B Lymphocytes Trigger MCP3-Dependent Mobilization of Monocytes and Promote Adverse Ventricular Remodeling After Myocardial Infarction

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Yasmine Zouggari ◽  
Hafid Ait-Oufella ◽  
Philippe Bonnin ◽  
José Vilar ◽  
Coralie Guerin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Inflammatory Response ◽  
Cardiac Function ◽  
B Cell ◽  
B Lymphocytes ◽  
Cardiac Remodeling ◽  
Ventricular Remodeling ◽  
Cell Depletion ◽  
B Cell Depletion

Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and persistent infiltration of innate immune cells, such as neutrophils and Ly6Chi monocytes, has been shown to promote adverse cardiac tissue remodeling. However, little is known regarding the role of mature B lymphocytes, which play a crucial role in the activation of the inflammatory response in several immune-mediated diseases. Here, we hypothesized that B lymphocytes might modulate the inflammatory response and affect the immune-dependent adverse cardiac remodeling. In a mouse model of myocardial infarction, cardiac B lymphocytes levels peaked at day 5 after the onset of infarction. Of interest, treatment with a CD20-specific monoclonal antibody decreased circulating and infiltrating B cell numbers (p=0.0008 and p=0.0002 vs control), reduced infarct size and post-ischemic immunoinflammatory response, and improved cardiac function (p=0.02 vs control) assessed by echocardiography. Intriguingly, B cell depletion was associated with an impairment of Ly6Chi monocytes mobilization from bone marrow (p=0.02 vs control), leading to reduced levels of circulating and infiltrating cardiac monocytes. The acute infarction led to transient increase of both MCP-1 and MCP-3 levels. Interestingly, B cell depletion was associated with a significant and selective reduction of MCP-3 (p=0.03 vs control) but did not alter MCP-1 levels (p=0.11). Cultured activated B cells released MCP-3 and treatment with a neutralizing MCP-3 antibody abrogated B lymphocytes-induced migration of cultured monocytes. Finally, transfer of B cell-depleted splenocytes into Rag1 -/- mice improved cardiac function after myocardial infarction compared to the transfer of non-depleted splenocytes (p=0.005). This effect was abrogated after re-supplementation with B lymphocytes isolated from wild-type mice (p=0.0007) but not from MCP-3-deficient animals (p=0.7008). In conclusion, we show that following acute myocardial infarction, B lymphocytes, trigger an MCP-3-dependent mobilization of Ly6Chi monocytes from the bone marrow to the blood, leading to their recruitment into the injured myocardium and to exacerbation of tissue inflammation, thereby promoting adverse cardiac remodeling.

scholarly journals Association of GDF-15 and Syntax Score in Patient with Acute Myocardial Infarction

2019 ◽  
Vol 2019 ◽  
pp. 1-6
Author(s):  
Shiqiang Liu ◽  
Xu Chen ◽  
Hua Wang ◽  
Bo Ming ◽  
Mingle Wu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Protective Factor ◽  
Smoking Status ◽  
Elevated Serum ◽  
Serum Levels ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Syntax Score ◽  
Online Methods

Aims. GDF-15 is considered to be an important biomarker for cardiovascular events, but the differences in serum GDF-15 levels between acute myocardial infarction (AMI) patients and non-AMI patients warrant further investigation. Methods. A cohort of 409 subjects was enrolled in the current study. The Syntax score was calculated from the baseline coronary angiography results by using online methods. Blood samples were obtained at the start of the study for an assessment of GDF-15 by using ELISA methods. Results. Patients with AMI had significantly higher levels of serum GDF-15 (Wilcox test, P < 0.001), Syntax scores (Wilcox test, P = 0.006), and left ventricular ejection fractions (LEVF, Wilcox test, P< 0.001). However, no significant differences were present among the other clinical characteristics. The logistical regression analysis indicated that serum GDF-15 levels (P=0.01534) were independent predictors of non-AMI and AMI after adjusting for age, sex, smoking status, and LVEF. Conclusions. Elevated serum levels of GDF-15 are independently associated with the risk of MI, and GDF-15 may serve as a protective factor for MI in the cardiovascular system.

Effect of G-CSF and Intramyocardial Injection of Bone Marrow Cells on Cardiac Function in Mouse Model of Myocardial Infarction: A Word for Neo-Vasculogenesis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2693-2693
Author(s):  
Larissa Verda ◽  
Kehuan Luo ◽  
Xiaoqiang Han ◽  
Andrew Wasserstrom ◽  
Jon Lomasney ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Bone Marrow ◽  
Cardiac Function ◽  
Bone Marrow Cells ◽  
Ischemia Reperfusion ◽  
Myocardial Repair ◽  
Intramyocardial Injection ◽  
Border Zones ◽  
Marrow Cells

Abstract Recent studies suggest that primitive stem cells derived from bone marrow (BM) possess greater functional plasticity that was expected previously. It has been shown that bone marrow stem cells (BMSC) promote repairing mechanisms within myocardium following ischemia/reperfusion models of myocardial infarction (MI). Although it remains unclear whether BMSC transdifferentiate into or just fuse with cardiomyocytes, hemodynamic improvement after intramyocardial BMSC injection as well as after G-CSF injection has been demonstrated. Here, we investigated the contribution of BMSC versus G-CSF administration in myocardial repair following MI. Ten weeks old C57BL/6J mice were irradiated and transplanted with green fluorescent protein (GFP) positive bone marrow cells. Three months later, these mice underwent ligation of left anterior descending branch (LAD) of coronary artery and subsequently divided into three groups. One group (n=7) received G-CSF administration at 200ug/kg for 10 consecutive days. Another group (n=9) was injected with GFP+ marrow cells directly into ischemic heart. The third group was held as control (n=7). One month after coronary ligation we found significant improvement in cardiac function determined as a cardiac output, maximum power and dP/dt, in the G-CSF group compared to control. We evaluated the phenotype of GFP+ cells within myocardium in each treatment group by 488 nm laser-scanning confocal miscroscopy (of whole heart and slides) 35 days after LAD ligation. We found no evidence of myocardial transdifferentiation or cardiomyocyte cell fusion. Instead GFP+ capillaries were present and exclusively located in infarct border zones in both the G-CSF and bone marrow implantation groups, confirmed by anti-factor VIII staining. G-CSF administration and to a lesser extent marrow injection resulted in improved post infarct cardiac function indices. This beneficial effect is not due to transdifferentiation but could be explained by marrow injected or G-CSF mobilized endothelial progenitor cells (EPC) and/or cytokine mediated neo-vasculogenesis.

Multiplex Analysis of Serum Cytokine Levels in Waldenström Macroglobulinemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2616-2616
Author(s):  
Sherine F. Elsawa ◽  
Anne J. Novak ◽  
Steven C. Ziesmer ◽  
Thomas E. Witzig ◽  
Vincent Rajkumar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Elevated Serum ◽  
Fold Increase ◽  
Serum Levels ◽  
Healthy Controls ◽  
Β2 Microglobulin ◽  
Healthy Donors ◽  
Cytokine Levels

Abstract Waldenström macroglobulinemia (WM) is a monoclonal B cell disorder characterized by a circulating monoclonal IgM protein that may lead to serum hyperviscosity in association with an infiltration of lymphoplasmacytic cells into the bone marrow. Although proinflammatory and chemotactic cytokines can profoundly affect tumor cells and the tumor microenvironment, and many cytokines have been shown to have potent therapeutic efficacy in preclinical cancer models, the role of cytokine networks in WM is not fully understood. In this study, we used a high-throughput xMAP multiplex immunobead assay technology (Luminex Corp., Austin, TX) to simultaneously test 30 cytokines, chemokines, angiogenic factors as well as growth factors and soluble receptors in the sera of WM patients and compared them with other B cell malignancies including IgM monoclonal gammopathy of undetermined significance (MGUS), follicular lymphoma, chronic lymphocytic leukemia (CLL) as well as healthy controls. Using a Mann-Whitney U test to analyze the differences between the groups, 15 of the 30 cytokines tested had significantly different levels in WM compared to healthy controls. Of those 15 cytokines, 11 were elevated in WM patients and 4 were decreased. Cytokines were grouped into 3 groups; those with &lt; 2-fold difference, 2–8 fold difference and those having &gt; 8-fold difference in their cytokine levels compared to healthy donors. There was a greater than 8-fold increase in the serum levels of Rantes, G-CSF and IL-2R (p&lt;0.0001) in WM patients. Furthermore, 3 cytokines had between 2–8-fold increase in WM patients including IL-4 (p&lt;0.0001), IL-6 (p&lt;0.0019) and IP-10 (p&lt;0.0006). Five cytokines had statistically elevated levels in WM patients compared to healthy controls, however the fold increase was &lt; 2 including HGF (p&lt;0.0185), IL-10 (p&lt;0.0002), MIP-1α (P&lt;0.0484), IL-2 (P&lt;0.0130) and IL-12 (P&lt;0.0155). Of the cytokines that had significantly lower levels in the sera of WM patients, IL-8 (p&lt;0.0001) and EGF (p&lt;0.0001) were &gt; 8-fold decreased, MCP-1 (p&lt;0.0001) was 2–8 fold lower and Eotaxin (p&lt;0.0004) was &lt; 2-fold lower in WM patients. All of the cytokines that had the greatest fold difference (&gt; 8-fold) in WM patients compared to healthy donors also differed significantly from the MGUS patients. Rantes, G-CSF, IL-2R and EGF had significantly different levels compared to other B cell malignancies. We tested for a correlation between the cytokines that had &gt; 2-fold difference between the WM group and control group with clinical features of the disease and found the cytokines IL-6 and IL-2R had a significant correlation with β2-microglobulin levels (p&lt;0.01). We analyzed cytokine levels in the bone marrow plasma of the same patients and found that high levels of IL-2R in the bone marrow microenvironment significantly correlated with anemia and elevated serum β2-microglobulin (p&lt;0.01). In conclusion, we have simultaneously analyzed sera from WM patients for 30 cytokines and found the most significantly elevated cytokines are Rantes, G-CSF and IL-2R and the most significantly downregulated cytokines are IL-8 and EGF. Furthermore, we found that elevated serum levels of IL-6 and IL-2R correlated with β2-microglobulin levels, a measure of disease activity. Further analysis of the biological role of these cytokines in WM may offer insight into disease pathogenesis and provide a basis for novel targeted therapies.

scholarly journals Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction

2016 ◽  
Vol 213 (7) ◽  
pp. 1353-1374 ◽  
Author(s):  
Anta Ngkelo ◽  
Adèle Richart ◽  
Jonathan A. Kirk ◽  
Philippe Bonnin ◽  
Jose Vilar ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Mast Cells ◽  
Cardiac Function ◽  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Troponin I ◽  
Heart Function ◽  
Ischemic Disease ◽  
Cardiomyocyte Contractility ◽  
The Impact

Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles for mast cells (MCs) in postischemic cardiac remodeling. Because c-Kit mutations affect multiple cell types of both immune and nonimmune origin, we addressed the impact of MCs on cardiac function after MI, using the c-Kit–independent MC-deficient (Cpa3Cre/+) mice. In response to MI, MC progenitors originated primarily from white adipose tissue, infiltrated the heart, and differentiated into mature MCs. MC deficiency led to reduced postischemic cardiac function and depressed cardiomyocyte contractility caused by myofilament Ca2+ desensitization. This effect correlated with increased protein kinase A (PKA) activity and hyperphosphorylation of its targets, troponin I and myosin-binding protein C. MC-specific tryptase was identified to regulate PKA activity in cardiomyocytes via protease-activated receptor 2 proteolysis. This work reveals a novel function for cardiac MCs modulating cardiomyocyte contractility via alteration of PKA-regulated force–Ca2+ interactions in response to MI. Identification of this MC-cardiomyocyte cross-talk provides new insights on the cellular and molecular mechanisms regulating the cardiac contractile machinery and a novel platform for therapeutically addressable regulators.

Sign in / Sign up

Export Citation Format

Share Document