Suppression of IL-1β Promotes Beneficial Accumulation of Fibroblast-Like Cells in Atherosclerotic Plaques in Clonal Hematopoiesis

Authors

Trevor P Fidler
Andrew Dunbar
Eunyoung Kim
Brian Hardaway
Jessica Pauli
Chenyi Xue
Sandra Abramowicz
Tong Xiao
Kavi O'Connor
Nadja Sachs
Nan Wang
Lars Maegdefessel
Ross Levine
Muredach Reilly
Alan R Tall

Publication Date

1-1-2024

Journal

Nature Cardiovascular Research

Abstract

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 during plaque regression promoted fibroblast accumulation and fibrous cap thickening. Our studies suggest that suppression of inflammasomes promotes plaque stabilization by recruiting fibroblast-like cells to the fibrous cap.

Comments

Supplementary Materials

PMID: 38362011