Genotoxicity induces epithelial hyperplasia and lineage infidelity via fibroblast IL-1β
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA578953 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10331331_1.fastq.gz | Fastqsanger.gz | |||
| SRR10331331_2.fastq.gz | Fastqsanger.gz | |||
| SRR10331332_1.fastq.gz | Fastqsanger.gz | |||
| SRR10331332_2.fastq.gz | Fastqsanger.gz | |||
| SRR10331333_1.fastq.gz | Fastqsanger.gz |
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Project description: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 scRNAseq 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 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 during plaque regression promoted fibroblasts accumulation and fibrous cap thickening. Our studies suggest that suppression of inflammasomes promotes plaque stabilization by recruiting fibroblast-like cells to the fibrous cap.
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Project description: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 scRNAseq 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 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 during plaque regression promoted fibroblasts accumulation and fibrous cap thickening. Our studies suggest that suppression of inflammasomes promotes plaque stabilization by recruiting fibroblast-like cells to the fibrous cap.
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