Biology subjects

Tall, A. R.

Publications and source records attributed to Tall, A. R..

3 recordsLinked to original sources

bioRxiv2025

Aggressive Cholesterol Lowering Normalizes Atherosclerosis Regression in Jak2V617F Clonal Hematopoiesis

BackgroundThe Jak2V617F (Jak2VF) mutation is an important cause of both clonal hematopoiesis of indeterminate potential (CHIP) and myeloproliferative neoplasms (MPN). Mouse models of Jak2VF CHIP and MPN show accelerated atherosclerosis progression, driven by macrophage inflammasome activation. We undertook the present study to assess the hypothesis that ongoing inflammation would impede atherosclerosis resolution in Jak2VF mice. Methods and ResultsChimeric Jak2VF/WT or control WT/WT bone marrow was transplanted into Ldlr-/-mice and, following 13-16 weeks of Western diet-induced atherosclerosis progression, cholesterol was lowered either moderately (to 200-300 mg/dl) or markedly (to 100 mg/dl). With moderate cholesterol lowering, there was impaired resolution of lesions in Jak2VFMPN mice compared to controls. However, with marked cholesterol lowering, progression of lesions was halted in both Jak2VF MPN and control mice while macrophage burden was decreased and lesional collagen was increased similarly in Jak2VFMPN and control mice. Two mechanisms of low-density lipoprotein (LDL) lowering-induced suppression of inflammation in plaques were implicated: 1) reversal of increased proliferation, DNA damage and Absent in Melanoma 2 (AIM2) inflammasome activation specifically in Jak2VF macrophages and 2) markedly increased macrophage triggering receptor expressed on myeloid cells 2 (TREM2), c-myc expressing macrophages in both Jak2VF and control mice. ConclusionsAggressive LDL lowering reverses inflammasome activation and induces pro-resolving changes in macrophages in Jak2VF MPN, halting atherosclerosis progression and promoting features of plaque stabilization. These findings suggest that aggressive LDL cholesterol lowering could reverse atherosclerotic cardiovascular disease (ACVD) risk in individuals with JAK2VFCHIP or MPN.

molecular biology↗

bioRxiv2025

IL-18 inhibition enlarges lesions, necrotic cores and thickens fibrous caps in Jak2V617F clonal hematopoiesis-driven atherosclerosis.

BackgroundInflammasome activation promotes atherosclerosis in clonal hematopoiesis (CH). Active inflammasomes secrete both IL-1{beta} and IL-18. Plasma IL-18 levels are elevated in Jak2VFCH. Genetic deficiency of IL-18 has been shown to reduce atherosclerosis in non-CH murine models. However, whether IL-18 inhibition promotes atherosclerosis in control or Jak2VF CH is unknown. Methods and resultsLdlr-/- mice were transplanted with bone marrow (BM) from Mx1-cre Jak2VF (20%) and wild-type (80%) mice or with control BM, fed a Western-type diet (WTD) for 8, 10 or 16 weeks and administered control or IL-18 IgG from 4 weeks onwards. IL-18 antibody treatment increased plaque collagen content and cap thickness. Unexpectedly, IL-18 antibody treatment increased the size of early lesions and promoted formation of advanced lesions with large necrotic cores in Jak2VF CH mice. IL-18 antibody treatment was associated with diminished interferon (IFN)-{gamma} and AIM2 levels and reduced macrophage pyroptosis especially in Jak2VF CH mice. However, IL-18 antibodies increased cleaved Caspase-3 and TUNEL+ macrophages (indicating increased apoptosis) and reduced efferocytosis. Sc-RNA-seq analysis showed that IL-18 antibody treatment reduced expression of MHC class II genes, a marker of IFN-{gamma} signaling, and of genes mediating efferocytosis (Mertk and Axl), in resident-like macrophage subpopulations in Jak2VF CH mice. Consistently, IFN-{gamma} injection increased Axl and Mertk expression in resident peritoneal macrophages. ConclusionsDespite improvements in collagen and fibrous cap thickness in Jak2VF CH mice, IL-18 antibody treatment increased advanced necrotic lesions, reflecting a shift from pyroptotic to apoptotic cell death coupled with defective efferocytosis, events which were coordinated by reduced IFN-{gamma} signaling. These findings indicate a mixed atherosclerosis phenotype resulting from IL-18 inhibition, advocating for alternative therapeutic strategies. Inhibition of IL-18 has been considered as a novel therapeutic approach to reduce atherosclerosis and stabilize atherosclerotic plaques. We show that IL-18 antibodies have adverse effects on atherosclerotic lesional necrosis, calling this approach into question. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/657754v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@a93b2forg.highwire.dtl.DTLVardef@6cc057org.highwire.dtl.DTLVardef@1c7afc5org.highwire.dtl.DTLVardef@e4da82_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIInflammasome activation produces active IL-1 and IL-18 and worsens atherosclerosis in clonal hematopoiesis (CH) however the contribution of IL-18 is unknown. C_LIO_LIAntibody inhibition of IL-18 increased plaque collagen but also increased early lesion area and late lesions with large necrotic cores in Jak2VF CH mice. C_LIO_LIThere was a reversal of AIM2 inflammasome activation but a switch to apoptosis which along with reduced efferocytosis increased necrosis C_LIO_LIThese events appeared to be coordinated by reduced IFN-{gamma} which increased collagen but also decreased expression of efferocytotic genes. Our studies call into question whether inhibition of IL-18 would stabilize plaques in CH. C_LI

molecular biology↗

bioRxiv2025

Comprehensive Multimodal Profiling of Atherosclerosis Reveals Bhlhe40 as a Potential Regulator of Vascular Smooth Muscle Cell Phenotypic Modulation

BackgroundVascular smooth muscle cells (VSMCs) play a central role in atherosclerosis by undergoing phenotypic modulation from a quiescent, contractile state to a range of synthetic phenotypes, including fibroblast-like, macrophage-like, and lipid-laden foam cell-like states. However, a comprehensive multimodal characterization and understanding of the transcriptional programs driving these transitions remain incomplete. MethodsTo comprehensively define the phenotypic diversity of VSMCs during atherosclerosis progression, we performed in-depth profiling using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and bulk RNA sequencing in a VSMC lineage-tracing atherosclerotic mouse model. Insights from these datasets guided the design of targeted in vitro experiments to investigate candidate regulatory mechanisms. ResultsSingle-cell multi-omics revealed extensive cellular heterogeneity within atherosclerotic plaques, including a rare population of VSMC-derived macrophage-like cells, whose presence was confirmed by histological analysis. These studies also identified a substantial population of VSMC-derived foam cells, comprising approximately 70% of all foam cells in the lesions. These cells exhibited activation of gene programs associated with lipid metabolism, proliferation, and tumor-like features. The transcription factor Bhlhe40 emerged as a key regulator of this phenotypic transition, with elevated expression in VSMC-derived foam cells during disease progression. Functional knockdown of Bhlhe40 suppressed VSMC phenotypic switching and foam cell characteristics, underscoring its potential role as a driver of VSMC modulation. ConclusionsThese findings advance our understanding of VSMC phenotypic modulation in atherosclerosis and highlight Bhlhe40 as a key regulator of this process. Elucidating the mechanisms governing VSMC plasticity may offer new therapeutic opportunities to reduce cardiovascular risk by targeting disease-driving cellular transitions.

molecular biology↗