Alan R Tall

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 …

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 …

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 …

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.

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 …

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 …

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 …

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 …