Clonal hematopoiesis JAKs up plaque formation
Koral Campbell, Qing Li
Koral Campbell, Qing Li
Published January 2, 2025
Citation Information: J Clin Invest. 2025;135(1):e187529. https://doi.org/10.1172/JCI187529.
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Commentary

Clonal hematopoiesis JAKs up plaque formation

Abstract

Clonal hematopoiesis (CH) is a condition in which hematopoietic stem cells (HSCs) acquire mutations seen in leukemia. While individuals with CH generally do not show signs of hematologic disease, the condition becomes more common with age and correlates with age-related diseases, especially cardiovascular disease (CVD). JAK2 mutations in HSCs can lead to CH and correlate with atherosclerosis, but the condition has been difficult to study because of challenges modeling the mutant cells at very low frequency. In this issue of the JCI, Liu et al. developed a low-allele-burden (LAB) mouse model in which a small number of bone marrow cells carrying the Jak2VF mutation were transplanted into mice predisposed to hyperlipidemia. Along with recapitulating features of plaque development, the authors identified the phagocytic receptors MERTK and TREM2 in WT cells as downstream of the inflammatory cytokine IL-1. These findings provide potential targets for preventing or treating patients at risk for CH-associated CVD.

Authors

Koral Campbell, Qing Li

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Figure 1

Crosstalk between sparse Jak2-mutant CH clones and WT myeloid cells promotes plaque formation.

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Crosstalk between sparse Jak2-mutant CH clones and WT myeloid cells prom...
Sparse Jak2VF-mutant HSCs generate myeloid cells that release high levels of IL-1, which is received by the WT macrophages and neutrophils. In this context, IL-1 induces inflammasome signaling and, eventually, pyroptosis and NETosis, increasing the recruitment of immune cells to the plaques and the size of the necrotic core, which promotes plaque instability.