Department of Anesthesiology and Intensive Care Medicine, University Hospital Bonn, Bonn, Germany.
Heart Center Bonn, Clinic for Internal Medicine II, University Hospital Bonn, Bonn, Germany.
PLoS One. 2021 Jan 7;16(1):e0243788. doi: 10.1371/journal.pone.0243788. eCollection 2021.
The CX3CL1/CX3CR1 axis mediates recruitment and extravasation of CX3CR1-expressing subsets of leukocytes and plays a pivotal role in the inflammation-driven pathology of cardiovascular disease. The cardiac immune response differs depending on the underlying causes. This suggests that for the development of successful immunomodulatory therapy in heart failure due to chronic pressure overload induced left ventricular (LV) hypertrophy, the underlying immune patterns must be examined. Here, the authors demonstrate that Fraktalkine-receptor CX3CR1 is a prerequisite for the development of cardiac hypertrophy and left ventricular dysfunction in a mouse model of transverse aortic constriction (TAC). The comparison of C57BL/6 mice with CX3CR1 deficient mice displayed reduced LV hypertrophy and preserved cardiac function in response to pressure overload in mice lacking CX3CR1. Moreover, the normal immune response following TAC induced pressure overload which is dominated by Ly6Clow macrophages changed to an early pro-inflammatory immune response driven by neutrophils, Ly6Chigh macrophages and altered cytokine expression pattern in CX3CR1 deficient mice. In this early inflammatory phase of LV hypertrophy Ly6Chigh monocytes infiltrated the heart in response to a C-C chemokine ligand 2 burst. CX3CR1 expression impacts the immune response in the development of LV hypertrophy and its absence has clear cardioprotective effects. Hence, suppression of CX3CR1 may be an important immunomodulatory therapeutic target to ameliorate pressure-overload induced heart failure.
CX3CL1/CX3CR1 轴介导 CX3CR1 表达的白细胞亚群的募集和渗出，并在心血管疾病炎症驱动的病理学中发挥关键作用。心脏的免疫反应因潜在原因而异。这表明，为了在慢性压力超负荷诱导的左心室（LV）肥厚引起的心力衰竭中成功进行免疫调节治疗，必须检查潜在的免疫模式。在这里，作者证明了 fractalkine 受体 CX3CR1 是一种先决条件，在一种小鼠模型中，横主动脉缩窄（TAC）可导致心脏肥大和左心室功能障碍。C57BL/6 小鼠与 CX3CR1 缺陷小鼠的比较显示，在缺乏 CX3CR1 的小鼠中，LV 肥大减轻，对压力超负荷的心脏功能保持不变。此外，TAC 诱导的压力超负荷后正常的免疫反应，主要由 Ly6Clow 巨噬细胞主导，在 CX3CR1 缺陷小鼠中转变为早期由中性粒细胞、Ly6Chigh 巨噬细胞驱动的促炎免疫反应，并改变细胞因子表达模式。在 LV 肥大的早期炎症阶段，Ly6Chigh 单核细胞在 C-C 趋化因子配体 2 爆发的情况下浸润心脏。CX3CR1 的表达影响 LV 肥大发展过程中的免疫反应，其缺失具有明确的心脏保护作用。因此，抑制 CX3CR1 可能是改善压力超负荷诱导性心力衰竭的重要免疫调节治疗靶点。
