Clonal Hematopoiesis–Driver DNMT3A Mutations Alter Immune Cells in Heart Failure

Abstract

Rationale: Clonal hematopoiesis (CH) driven by mutations of DNA methyltransferase 3a (DNMT3A) is associated with increased incidence of cardiovascular disease and poor prognosis of patients with chronic heart failure (HF) and aortic stenosis. Although experimental studies suggest that DNMT3A CH-driver mutations may enhance inflammation, specific signatures of inflammatory cells in humans are missing. Objective: To define subsets of immune cells mediating inflammation in humans using single-cell RNA-sequencing. Methods and Results: Transcriptomic profiles of peripheral blood mononuclear cells were analysed in N=6 HF patients harboring DNMT3A CH-driver mutations and N=4 patients with HF and no DNMT3A mutations by single-cell RNA-sequencing. Monocytes of HF patients carrying DNMT3A mutations demonstrated a significantly increased expression of inflammatory genes compared to monocytes derived from HF patients without DNMT3A mutations. Among the specific up-regulated genes were the prototypic inflammatory interleukin (IL) IL1B, IL6, IL8, the inflammasome NLRP3, and the macrophage inflammatory proteins CCL3 and CCL4 as well as resistin, which augments monocyte-endothelial adhesion. Silencing of DNMT3A in monocytes induced a paracrine pro-inflammatory activation and increased adhesion to endothelial cells. Furthermore, the classical monocyte subset of DNMT3A mutation carriers showed increased expression of T-cell stimulating immunoglobulin superfamily members CD300LB, CD83, SIGLEC12, as well as the CD2 ligand and cell adhesion molecule CD58, all of which may be involved in monocyte-T cell interactions. DNMT3A mutation carriers were further characterized by increased expression of the T-cell alpha receptor constant chain and Th1, Th2, Th17, CD8+ effector, CD4+ memory and Treg specific signatures. Conclusions: This study demonstrates that circulating monocytes and T-cells of HF patients harboring CH-driver mutations in DNMT3A exhibit a highly inflamed transcriptome, which may contribute to the aggravation of chronic heart failure.

Metabolism and Chronic Inflammation: The Links Between Chronic Heart Failure and Comorbidities

“…Innate immune cells, such as neutrophils, natural killer cells, and mast cells ( 52 ), have been revealed to participate in the progress of HF through immune inflammation. For instance, monocytes derived from HF patients have higher secreted cytokines (IL-1β, IL-6) and chemokines (CCL3, CCL4), and can stimulate T cell activation ( 53 ). Monocyte-derived macrophages have a pro-inflammation role in cardiovascular diseases ( 49 ).…”

“…(4) Inflammatory pathways, majorly include the Cytokine-cytokine receptor interaction, TNF signaling, IL-17 signaling, and Toll-like receptor pathways ( Figure 3C ). Additionally, the clonal hematopoiesis pathway is a risk factor of HF enriched in the analysis and may be related to immune inflammation ( 53 , 159 ). (5) Other structural remodeling in addition to hypertrophy, such as fibrosis and amyloidosis.…”

Clonal hematopoiesis and its emerging effects on cellular therapies

“…Diverse mediators of innate and adaptive immunity have been described to be modulated by the occurrence of specific CH-associated somatic mutations [65,66]. Not only cellular components of the myeloid lineage like monocytes/macrophages [56,[67][68][69][70], mast cells [71], neutrophils [72], but also lymphatic cells [73][74][75][76][77] can exert altered function.…”

A feedback loop: Interactions between Inflammatory Signals and Clonal Hematopoiesis in Cardiovascular Disease

“…Additionally, the transcriptome profiles of peripheral blood mononuclear cells in N = 6 HF patients with DNMT3A CH-driver mutation and N = 4 HF patients without DNMT3A mutation were analyzed by single-cell RNA sequencing.This study found that circulating monocytes and T cells of patients with HF harboring clonal hematopoiesis-driver mutations in DNMT3A exhibit a highly inflamed transcriptome, which may result in the aggravation of chronic HF. [27].…”

“…These results suggest that TET2 deficiency may impair inflammatory regression and innate immune response [65]. In 2020, Wesley T Abplanalp and his colleagues using singlecell RNA-sequencing revealed that circulating monocytes and T-cells of HF patients harboring CH-driver mutations in DNMT3A exhibited a highly inflamed transcriptome in humans [66]. It has been demonstrated for the first time that DNMT3A mutation induces activation of inflammatory signals of different immune cells in humans.…”