Suppression of IL-1β promotes beneficial accumulation of fibroblast-like cells in atherosclerotic plaques in clonal hematopoiesis
Nature cardiovascular research
Published On 2024/1/11
Clonal hematopoiesis (CH) is an independent risk factor for atherosclerotic cardiovascular disease. Murine models of CH suggest a central role of inflammasomes and IL-1β in accelerated atherosclerosis and plaque destabilization. Here we show using single-cell RNA sequencing in human carotid plaques that inflammasome components are enriched in macrophages, while the receptor for IL-1β is enriched in fibroblasts and smooth muscle cells (SMCs). To address the role of inflammatory crosstalk in features of plaque destabilization, we conducted SMC fate mapping in Ldlr−/− mice modeling Jak2VF or Tet2 CH treated with IL-1β antibodies. Unexpectedly, this treatment minimally affected SMC differentiation, leading instead to a prominent expansion of fibroblast-like cells. Depletion of fibroblasts from mice treated with IL-1β antibody resulted in thinner fibrous caps. Conversely, genetic inactivation of Jak2VF …
Journal
Nature cardiovascular research
Page
1-16
Authors
Alan R Tall
Columbia University in the City of New York
H-Index
143
Research Interests
medicine
atherosclerosis
lipoproteins
University Profile Page
Nan Wang
Columbia University in the City of New York
H-Index
64
Research Interests
atherosclerosis and athero-thrombosis
University Profile Page
Trevor Fidler
Columbia University in the City of New York
H-Index
15
Research Interests
Thrombosis
Atherosclerosis
Hematopoiesis
Metabolism
University Profile Page
Other Articles from authors
Nan Wang
Columbia University in the City of New York
Blood
Jak2 V617F clonal hematopoiesis promotes arterial thrombosis via platelet activation and cross talk
Abstract JAK2 V617F (JAK2VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD). We assessed the impact of Jak2VF CH on arterial thrombosis and explored the underlying mechanisms. A meta-analysis of 3 large cohort studies confirmed the association of JAK2VF with CVD and with platelet counts and adjusted mean platelet volume (MPV). In mice, 20% or 1.5% Jak2VF CH accelerated arterial thrombosis and increased platelet activation. Megakaryocytes in Jak2VF CH showed elevated proplatelet formation and release, increasing prothrombogenic reticulated platelet counts. Gp1ba-Cre–mediated expression of Jak2VF in platelets (VFGp1ba) increased platelet counts to a similar level as in 20% Jak2VF CH mice while having no effect on leukocyte counts. Like Jak2VF CH mice, VFGp1ba mice showed enhanced platelet …
2024/4/11
Article DetailsTrevor Fidler
Columbia University in the City of New York
Nature Cardiovascular Research
An epigenetic switch in macrophages promotes fibrosis in the failing heart
Older men with loss of the Y chromosome are more susceptible to heart failure but the responsible genes have not been identified. A study now shows that loss of a single Y chromosome gene in bone marrow cells induces heart failure by switching cardiac macrophages from an inflammatory to a fibrogenic pattern of gene activity.
2024/3/8
Article DetailsAlan R Tall
Columbia University in the City of New York
Blood
Jak2 V617F clonal hematopoiesis promotes arterial thrombosis via platelet activation and cross talk
Abstract JAK2 V617F (JAK2VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD). We assessed the impact of Jak2VF CH on arterial thrombosis and explored the underlying mechanisms. A meta-analysis of 3 large cohort studies confirmed the association of JAK2VF with CVD and with platelet counts and adjusted mean platelet volume (MPV). In mice, 20% or 1.5% Jak2VF CH accelerated arterial thrombosis and increased platelet activation. Megakaryocytes in Jak2VF CH showed elevated proplatelet formation and release, increasing prothrombogenic reticulated platelet counts. Gp1ba-Cre–mediated expression of Jak2VF in platelets (VFGp1ba) increased platelet counts to a similar level as in 20% Jak2VF CH mice while having no effect on leukocyte counts. Like Jak2VF CH mice, VFGp1ba mice showed enhanced platelet …
2024/4/11
Article DetailsNan Wang
Columbia University in the City of New York
Journal of Lipid Research
Cholesterol trafficking to the ER leads to the activation of CaMKII/JNK/NLRP3 and promotes atherosclerosis
The deposition of cholesterol-rich lipoproteins in the arterial wall triggers macrophage inflammatory responses, which promote atherosclerosis. The NLRP3 inflammasome aggravates atherosclerosis; however, cellular mechanisms connecting macrophage cholesterol accumulation to inflammasome activation are poorly understood. We investigated the mechanisms of NLRP3 inflammasome activation in cholesterol-loaded macrophages and in atherosclerosis-prone Ldlr−/− mice with defects in macrophage cholesterol efflux. We found that accumulation of cholesterol in macrophages treated with modified LDL or cholesterol crystals, or in macrophages defective in the cholesterol efflux promoting transporters ABCA1 and ABCG1, leads to activation of NLRP3 inflammasomes as a result of increased cholesterol trafficking from the plasma membrane to the ER, via Aster-B. In turn, the accumulation of cholesterol in the …
2024/4/1
Article DetailsAlan R Tall
Columbia University in the City of New York
Journal of Lipid Research
Cholesterol trafficking to the ER leads to the activation of CaMKII/JNK/NLRP3 and promotes atherosclerosis
The deposition of cholesterol-rich lipoproteins in the arterial wall triggers macrophage inflammatory responses, which promote atherosclerosis. The NLRP3 inflammasome aggravates atherosclerosis; however, cellular mechanisms connecting macrophage cholesterol accumulation to inflammasome activation are poorly understood. We investigated the mechanisms of NLRP3 inflammasome activation in cholesterol-loaded macrophages and in atherosclerosis-prone Ldlr−/− mice with defects in macrophage cholesterol efflux. We found that accumulation of cholesterol in macrophages treated with modified LDL or cholesterol crystals, or in macrophages defective in the cholesterol efflux promoting transporters ABCA1 and ABCG1, leads to activation of NLRP3 inflammasomes as a result of increased cholesterol trafficking from the plasma membrane to the ER, via Aster-B. In turn, the accumulation of cholesterol in the …
2024/4/1
Article DetailsAlan R Tall
Columbia University in the City of New York
Nature Cardiovascular Research
An epigenetic switch in macrophages promotes fibrosis in the failing heart
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2024/3/8
Article DetailsTrevor Fidler
Columbia University in the City of New York
Diabetes
Hematopoietic NLRP3 and AIM2 inflammasomes promote diabetes-accelerated atherosclerosis, but increased necrosis is independent of pyroptosis
Serum apolipoprotein C3 (APOC3) predicts incident cardiovascular events in people with type 1 diabetes, and silencing of APOC3 prevents both lesion initiation and advanced lesion necrotic core expansion in a mouse model of type 1 diabetes. APOC3 acts by slowing the clearance of triglyceride-rich lipoproteins, but lipid-free APOC3 has recently been reported to activate an inflammasome pathway in monocytes. We therefore investigated the contribution of hematopoietic inflammasome pathways to atherosclerosis in mouse models of type 1 diabetes. LDL receptor–deficient diabetes mouse models were transplanted with bone marrow from donors deficient in NOD, LRR and pyrin domain–containing protein 3 (NLRP3), absent in melanoma 2 (AIM2) or gasdermin D (GSDMD), an inflammasome-induced executor of pyroptotic cell death. Mice with diabetes exhibited inflammasome activation and …
2023/7/1
Article DetailsAlan R Tall
Columbia University in the City of New York
Blood, The Journal of the American Society of Hematology
Clonal hematopoiesis and ischemic stroke
In this issue of Blood, Arends et al find an association between mutations causing clonal hematopoiesis (CH) and large artery atherosclerosis and white matter lesions in patients with ischemic stroke. 1 In a prospective study, patients with CH showed an increase in recurrent vascular events, stroke, and death compared with those without CH. The event rate is related to clone size, specific CH mutations, and the presence of multiple mutations. The study supports a causal role of CH in large artery atherosclerotic cardiovascular disease (CVD).CH has recently emerged as a major genetic risk factor for CVD. 2 CH arises when somatic mutations in leukemogenic genes endow a fitness advantage to hematopoietic stem and progenitor cells, leading to the clonal expansion of blood cells. CH is common among older people, occurring in> 10% of people aged> 70 years old. 2, 3 CH commonly involves mutations in genes …
2023/2/16
Article DetailsAlan R Tall
Columbia University in the City of New York
Nature cardiovascular research
Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis
Clonal hematopoiesis (CH) increases the risk of atherosclerotic cardiovascular disease possibly due to increased plaque inflammation. Human studies suggest that limitation of interleukin-6 (IL-6) signaling could be beneficial in people with large CH clones, particularly in TET2 CH. Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression. IL-6 induces expression of Csf1r in Tet2-deficient macrophages through enhanced STAT3 binding to its promoter. In mouse and human Tet2-deficient macrophages, IL-6 increases CSF1R expression and enhances macrophage survival. Treatment with the CSF1R inhibitor PLX3397 reversed accelerated atherosclerosis in Tet2 CH mice. Our study demonstrates the causality of IL-6 signaling in Tet2 CH …
2023/6
Article DetailsNan Wang
Columbia University in the City of New York
Blood, The Journal of the American Society of Hematology
Clonal hematopoiesis and ischemic stroke
In this issue of Blood, Arends et al find an association between mutations causing clonal hematopoiesis (CH) and large artery atherosclerosis and white matter lesions in patients with ischemic stroke. 1 In a prospective study, patients with CH showed an increase in recurrent vascular events, stroke, and death compared with those without CH. The event rate is related to clone size, specific CH mutations, and the presence of multiple mutations. The study supports a causal role of CH in large artery atherosclerotic cardiovascular disease (CVD).CH has recently emerged as a major genetic risk factor for CVD. 2 CH arises when somatic mutations in leukemogenic genes endow a fitness advantage to hematopoietic stem and progenitor cells, leading to the clonal expansion of blood cells. CH is common among older people, occurring in> 10% of people aged> 70 years old. 2, 3 CH commonly involves mutations in genes …
2023/2/16
Article DetailsNan Wang
Columbia University in the City of New York
Circulation
BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis
BACKGROUND Clonal hematopoiesis (CH) has emerged as an independent risk factor for atherosclerotic cardiovascular disease, with activation of macrophage inflammasomes as a potential underlying mechanism. The NLRP3 (NLR family pyrin domain containing 3) inflammasome has a key role in promoting atherosclerosis in mouse models of Tet2 CH, whereas inhibition of the inflammasome product interleukin-1β appeared to particularly benefit patients with TET2 CH in CANTOS (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events]). TET2 is an epigenetic modifier that decreases promoter methylation. However, the mechanisms underlying macrophage NLRP3 inflammasome activation in TET2 (Tet methylcytosine dioxygenase 2) deficiency and potential links with epigenetic modifications are poorly understood. METHODS We used cholesterol-loaded TET2-deficient …
2023/11/28
Article DetailsTrevor Fidler
Columbia University in the City of New York
Arteriosclerosis, Thrombosis, and Vascular Biology
Il-1β Inhibition Promotes Fibrous Cap Thickening and Accumulation of Fibroblast Like Cells in Atheromas in Clonal Hematopoiesis
Clonal hematopoiesis (CH), a highly prevalent condition in the elderly, arises from somatic mutations that endow a survival advantage to hematopoietic stem cells. In CANTOS IL-1β inhibition was particularly beneficial in subjects with TET2 CH. Amongst the common genetic variants giving rise to CH, JAK2V617F (JAK2VF) gain of function and TET2 loss of function mutations have been shown to increase macrophage inflammasome activation and atherosclerosis in mice. We have shown that macrophages harboring Jak2 mutations have increased AIM2 inflammasome activation and pyroptosis which promoted features of unstable atherosclerotic lesions marked by prominent necrotic cores and an accumulation of inflammatory macrophages. Inflammasome inhibition led to a thickening of fibrous caps, indicating plaque stabilization. scRNA-Seq analysis of human carotid plaques indicates that myeloid cells were …
2023/5
Article DetailsAlan R Tall
Columbia University in the City of New York
Experimental Hematology
3168–TARGETING JAK1 SIGNALING FOR MOLECULAR PREVENTION IN CLONAL HEMATOPOIESIS
Myeloid malignancies are characterized by the stepwise acquisition of somatic mutations in hematopoietic stem and progenitor cells (HSPCs) that promote subsequent leukemic transformation. This condition, termed clonal hematopoiesis (CH), has been recognized as a risk factor for the development of secondary heme malignancies and cardiovascular disease. Accumulating evidence indicates that inflammatory stressors can enhance myeloproliferation of mutant HSPCs. However, whether hijacking this inflammatory signaling will prevent clonal expansion and leukemogenesis is currently unknown. Our central hypothesis is that TET2-mutant CH progression to acute myeloid leukemia (AML) occurs in the setting of inflammatory stress mediated by JAK1, which acts as a signaling-hub for inflammation.To assess whether Tet2-mediated clonal expansion requires Jak1 signaling, we established a conditional Scl …
2023/1/1
Article DetailsAlan R Tall
Columbia University in the City of New York
Inflammasomes and atherosclerosis: a mixed picture
The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study) and colchicine trials suggest an important role of inflammasomes and their major product IL-1β (interleukin 1β) in human atherosclerotic cardiovascular disease. Moreover, studies in mouse models indicate a causal role of inflammasomes and IL-1β in atherosclerosis. However, recent studies have led to a more granular view of the role of inflammasomes in atherosclerosis. Studies in hyperlipidemic mouse models suggest that prominent activation of the NLRP3 inflammasome requires a second hit such as defective cholesterol efflux, defective DNA repair, clonal hematopoiesis or diabetes. Similarly in humans some mutations promoting clonal hematopoiesis increase coronary artery disease risk in part by promoting inflammasome activation. Recent studies in mice and humans point to a wider role of the AIM2 (absent in melanoma 2 …
2023/5/26
Article DetailsAlan R Tall
Columbia University in the City of New York
Blood Journal
Hematopoietic and eosinophil-specific LNK (SH2B3) deficiency promote eosinophilia and arterial thrombosis
Increased eosinophil counts are associated with cardiovascular disease and may be an independent predictor of major cardiovascular events. However, the causality and underlying mechanisms are poorly understood. GWAS have shown an association of a common LNK variant (R262W, T allele) with eosinophilia and atherothrombotic disorders. LNK(TT) reduces LNK function and Lnk-deficient mice display accelerated atherosclerosis and thrombosis. This study was undertaken to assess the role of eosinophils in arterial thrombosis in mice with hematopoietic Lnk deficiency. Hematopoietic Lnk deficiency increased circulating and activated eosinophils, JAK/STAT signaling in eosinophils and carotid arterial thrombosis with increased eosinophil abundance and extracellular trap formation (EETosis) in thrombi. Depletion of eosinophils by anti-Siglec-F antibody or by the ∆dbIGata1 mutation eliminated eosinophils in …
2023/12/14
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Columbia University in the City of New York
Nature cardiovascular research
Blockade of IL-6 signaling alleviates atherosclerosis in Tet2-deficient clonal hematopoiesis
Clonal hematopoiesis (CH) increases the risk of atherosclerotic cardiovascular disease possibly due to increased plaque inflammation. Human studies suggest that limitation of interleukin-6 (IL-6) signaling could be beneficial in people with large CH clones, particularly in TET2 CH. Here we show that IL-6 receptor antibody treatment reverses the atherosclerosis promoted by Tet2 CH, with reduction of monocytosis, lesional macrophage burden and macrophage colony-stimulating factor 1 receptor (CSF1R) expression. IL-6 induces expression of Csf1r in Tet2-deficient macrophages through enhanced STAT3 binding to its promoter. In mouse and human Tet2-deficient macrophages, IL-6 increases CSF1R expression and enhances macrophage survival. Treatment with the CSF1R inhibitor PLX3397 reversed accelerated atherosclerosis in Tet2 CH mice. Our study demonstrates the causality of IL-6 signaling in Tet2 CH …
2023/6
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Columbia University in the City of New York
Arteriosclerosis, thrombosis, and vascular biology
Endogenous SOD2 (superoxide dismutase) regulates platelet-dependent thrombin generation and thrombosis during aging
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Harvard University
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Nature Cardiovascular Research
Identification of FDA-approved drugs that induce heart regeneration in mammals
Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro–Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation …
2024/3/11
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