Bone marrow NLRP3 inflammasome-IL-1β signal regulates post-myocardial infarction megakaryocyte development and platelet production

2021 ◽  
Author(s):  
You Wang ◽  
Hong Jiang ◽  
Xiaorong Hu ◽  
Wenwen Fu
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Nlrp3 Inflammasome ◽  
Post Myocardial Infarction ◽  
Platelet Production

Long-term tracking of bone marrow progenitor cells following intracoronary injection post-myocardial infarction in swine using MRI

2010 ◽  
Vol 299 (1) ◽  
pp. H125-H133 ◽  
Author(s):  
John J. Graham ◽  
Warren D. Foltz ◽  
Andrea K. Vaags ◽  
Michael R. Ward ◽  
Yuesong Yang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Coronary Artery ◽  
Ejection Fraction ◽  
Cell Viability ◽  
Progenitor Cells ◽  
Infarct Volume ◽  
Post Myocardial Infarction ◽  
Bone Marrow Progenitor Cells ◽  
Bone Marrow Progenitor

Magnetic resonance imaging (MRI) can track progenitor cells following direct intramyocardial injection. However, in the vast majority of post-myocardial infarction (MI) clinical trials, cells are delivered by the intracoronary (IC) route, which results in far greater dispersion within the myocardium. Therefore, we assessed whether the more diffuse distribution of cells following IC delivery could be imaged longitudinally with MRI. In 11 pigs (7 active, 4 controls), MI was induced by 90-min balloon occlusion of the left anterior descending coronary artery. Seven (0) days [median (interquartile range)] following MI, bone marrow progenitor cells (BMCs) were colabeled with an iron-fluorophore and a cell viability marker and delivered to the left anterior descending coronary artery distal to an inflated over-the-wire percutaneous transluminal coronary angioplasty balloon. T2*-weighted images were used to assess the location of the magnetically labeled cells over a 6-wk period post-MI. Immediately following cell delivery, hypointensity characteristic of the magnetic label was observed in the infarct border rather than within the infarct itself. At 6 wk, the cell signal hypointensity persisted, albeit with significantly decreased intensity. BMC delivery resulted in significant improvement in infarct volume and ejection fraction (EF): infarct volume in cell-treated animals decreased from 7.1 ± 1.5 to 4.9 ± 1.0 ml ( P < 0.01); infarct volume in controls was virtually unchanged at 4.64 ± 2.1 to 4.39 ± 2.1 ml ( P = 0.7). EF in cell-treated animals went from 30.4 ± 5.2% preinjection to 34.5 ± 2.5% 6 wk postinjection ( P = 0.013); EF in control animals went from 34.3 ± 4.7 to 31.9 ± 6.8% ( P = 0.5). Immunohistochemical analysis revealed intracellular colocalization of the iron fluorophore and cell viability dye with the labeled cells continuing to express the same surface markers as at baseline. MRI can track the persistence and distribution of magnetically labeled BMCs over a 6-wk period following IC delivery. Signal hypointensity declines with time, particularly in the first week following delivery. These cells maintain their original phenotype during this time course. Delivery of these cells appears safe and results in improvement in infarct size and left ventricular ejection fraction.

scholarly journals Impaired therapeutic efficacy of bone marrow cells from post-myocardial infarction patients in the TIME and LateTIME clinical trials

PLoS ONE ◽  
2020 ◽  
Vol 15 (8) ◽  
pp. e0237401
Author(s):  
Xiaoyin Wang ◽  
Lourdes I. Chacon ◽  
Ronak Derakhshandeh ◽  
Hilda J. Rodriguez ◽  
Daniel D. Han ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Therapeutic Efficacy ◽  
Bone Marrow Cells ◽  
Post Myocardial Infarction ◽  
Marrow Cells

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.

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.

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