Department of Immunology and.
Molecular Cardiology Research Institute Tufts University, Boston, Massachusetts, USA.
JCI Insight. 2019 Apr 4;4(7). doi: 10.1172/jci.insight.125527.
Heart failure (HF) is associated in humans and mice with increased circulating levels of CXCL9 and CXCL10, chemokine ligands of the CXCR3 receptor, predominantly expressed on CD4+ Th1 cells. Chemokine engagement of receptors is required for T cell integrin activation and recruitment to sites of inflammation. Th1 cells drive adverse cardiac remodeling in pressure overload-induced cardiac dysfunction, and mice lacking the integrin ligand ICAM-1 show defective T cell recruitment to the heart. Here, we show that CXCR3+ T cells infiltrate the heart in humans and mice with pressure overload-induced cardiac dysfunction. Genetic deletion of CXCR3 disrupts CD4+ T cell heart infiltration and prevents adverse cardiac remodeling. We demonstrate that cardiac fibroblasts and cardiac myeloid cells that include resident and infiltrated macrophages are the source of CXCL9 and CXCL10, which mechanistically promote Th1 cell adhesion to ICAM-1 under shear conditions in a CXCR3-dependent manner. To our knowledge, our findings identify a previously unrecognized role for CXCR3 in Th1 cell recruitment into the heart in pressure overload-induced cardiac dysfunction.
心力衰竭（HF）与人类和小鼠循环中 CXCL9 和 CXCL10 水平升高有关，CXCL9 和 CXCL10 是 CXCR3 受体的趋化因子配体，主要表达在 CD4+Th1 细胞上。趋化因子与受体的结合对于 T 细胞整合素的激活和募集到炎症部位是必需的。Th1 细胞在压力超负荷诱导的心脏功能障碍中驱动心脏不良重塑，缺乏整合素配体 ICAM-1 的小鼠显示 T 细胞向心脏募集缺陷。在这里，我们显示 CXCR3+T 细胞浸润在人类和压力超负荷诱导的心脏功能障碍的小鼠心脏中。CXCR3 的基因缺失破坏了 CD4+T 细胞心脏浸润，并防止了不良的心脏重塑。我们证明，心脏成纤维细胞和心脏髓样细胞，包括驻留和浸润的巨噬细胞，是 CXCL9 和 CXCL10 的来源，它们在机械上以 CXCR3 依赖的方式促进 Th1 细胞在剪切条件下与 ICAM-1 的粘附。据我们所知，我们的发现确定了 CXCR3 在压力超负荷诱导的心脏功能障碍中 Th1 细胞向心脏募集中的一个以前未被认识到的作用。
