Clonal haematopoiesis, which is highly prevalent in older individuals, arises from somatic mutations that endow a proliferative advantage to haematopoietic cells. Clonal haematopoiesis increases the risk of myocardial infarction and stroke independently of traditional risk factors¹. Among the common genetic variants that give rise to clonal haematopoiesis, the JAK2^V617F (JAK2^VF) mutation, which increases JAK–STAT signalling, occurs at a younger age and imparts the strongest risk of premature coronary heart disease^1,2. Here we show increased proliferation of macrophages and prominent formation of necrotic cores in atherosclerotic lesions in mice that express Jak2^VF selectively in macrophages, and in chimeric mice that model clonal haematopoiesis. Deletion of the essential inflammasome components caspase 1 and 11, or of the pyroptosis executioner gasdermin D, reversed these adverse changes. Jak2^VF lesions showed increased expression of AIM2, oxidative DNA damage and DNA replication stress, and Aim2 deficiency reduced atherosclerosis. Single-cell RNA sequencing analysis of Jak2^VF lesions revealed a landscape that was enriched for inflammatory myeloid cells, which were suppressed by deletion of Gsdmd. Inhibition of the inflammasome product interleukin-1β reduced macrophage proliferation and necrotic formation while increasing the thickness of fibrous caps, indicating that it stabilized plaques. Our findings suggest that increased proliferation and glycolytic metabolism in Jak2^VF macrophages lead to DNA replication stress and activation of the AIM2 inflammasome, thereby aggravating atherosclerosis. Precise application of therapies that target interleukin-1β or specific inflammasomes according to clonal haematopoiesis status could substantially reduce cardiovascular risk.

在老年人中非常普遍的克隆性造血是由赋予造血细胞增殖优势的体细胞突变引起的。^{克隆性造血独立于传统危险因素1}增加心肌梗塞和中风的危险。在导致克隆性造血功能的常见遗传变异中，JAK2 ^V617F ( JAK2 ^VF ) 突变会增加 JAK–STAT 信号，发生在较年轻的年龄，并赋予早发性冠心病的最大风险^1,2。在这里，我们显示表达Jak2 ^{VF的小鼠动脉粥样硬化病变中巨噬细胞增殖增加和坏死核心明显形成}选择性地在巨噬细胞和模拟克隆造血的嵌合小鼠中。删除必需的炎性体成分半胱天冬酶 1 和 11，或细胞焦亡刽子手 gasdermin D，可以逆转这些不利变化。Jak2 ^VF病变显示 AIM2 表达增加、DNA 氧化损伤和 DNA 复制应激，Aim2缺陷减少动脉粥样硬化。Jak2 ^VF病变的单细胞 RNA 测序分析揭示了富含炎性骨髓细胞的景观，这些细胞被Gsdmd的删除所抑制. 抑制炎性体产物白细胞介素 1β 可减少巨噬细胞增殖和坏死形成，同时增加纤维帽的厚度，表明它可以稳定斑块。我们的研究结果表明，Jak2 ^VF巨噬细胞增殖和糖酵解代谢的增加导致 DNA 复制应激和 AIM2 炎性体的激活，从而加剧动脉粥样硬化。根据克隆造血状态精确应用靶向白细胞介素 1β 或特定炎性体的疗法可以显着降低心血管风险。