Lymphatic endothelial sphingosine 1-phosphate receptor 1 enhances macrophage clearance via lymphatic system following myocardial infarction

Abstract

Lymphatic endothelial cell homeostasis plays important roles in normal physiological cardiac functions, and its dysfunction significantly influences pathological cardiac remodeling after myocardial infarction (MI). Our results revealed that sphingosine 1-phosphate receptor 1 (S1pr1) expression in cardiac lymphatic endothelial cells (LECs) was sharply changed after MI. It has been shown that S1pr1 tightly controlled LEC functions and homeostasis. We thus hypothesized that lymphatic endothelial S1pr1 might be involved in post-MI cardiac remodeling. We generated LEC-conditional S1pr1 transgenic mice, in which S1pr1 expression was reduced in cardiac LECs. We performed the left anterior descending coronary artery (LAD) ligation operation to induce MI in these mice. Cardiac functions and remodeling were examined by echocardiography analysis and serial histological analysis. Meanwhile, we performed adoptive cell transfer experiments to monitor macrophage trafficking in post-MI myocardium and their draining lymphatic system. Furthermore, in vitro cell culture experiments and mechanism studies were undertaken to uncover the molecular mechanism by which LEC-S1pr1 regulated cardiac inflammation and remodeling after MI. Our results showed that S1pr1 expression significantly decreased in cardiac LECs after MI. Our in vivo experiments showed that the reduced expression of LEC-S1pr1 deteriorated cardiac function and worsened pathological cardiac remodeling after MI. Our further results demonstrated that the reduced expression of LEC-S1pr1 did not influence macrophage infiltration in an early inflammatory phase of MI, but significantly affected macrophages clearance in the later phase of MI via afferent cardiac lymphatics, and thus influenced inflammatory responses and cardiac outcome after MI. Further study showed that S1P/S1pr1 activated ERK signaling pathway and enhanced CCL2 expression, which promoted macrophage trafficking in a paracrine manner. This study reveals that cardiac lymphatic endothelial cells tightly control macrophage trafficking via lymphatic vessels in injured hearts via S1P/S1pr1/ERK/CCL2 pathway and thus regulate post-MI immune modulation and heart repair. This study highlights the importance of cardiac lymphatic vessel system in orchestrating post-MI immune responses and cardiac remodeling by regulating macrophage transit in injured hearts. Our finding implies that a feasible modulation of S1pr1 signaling in LECs might provide a promising target to resolve excessive inflammation and to ameliorate adverse cardiac remodeling after MI.

Cardiac Lymphangiogenesis in CVDs

“…Indeed, immune cell recruitment by cardiac lymphatics, mediated by chemokines such as CCL21 (CC chemokine ligand) and CCL2, was recently shown to be modulated in LECs post-MI by the main S1P receptor S1PR1 (S1P receptor 1). 19 Overall, the immunomodulatory role of cardiac lymphatics appears somewhat similar as described previously in other tissues and in tumors. This immune-lymphatic interaction may depend, in part, on intercellular adhesion molecules such as Icam, Vcam, and LYVE1.…”

Abnormal Lymphatic Sphingosine-1-Phosphate Signaling Aggravates Lymphatic Dysfunction and Tissue Inflammation

“…Future investigations can determine local S1P levels in lymphedema tissue to better evaluate the status of ligand production in this disease. A previous study demonstrated that LEC S1PR1 deficiency delays macrophage clearance after myocardial infarction, 88 and future assessments may prove a similar mechanism also operates in lymphedema pathogenesis.…”

Lymphangiogenesis: A new strategy for heart disease treatment (Review)

“…S1PR1 is a G-protein-coupled receptor, expressed in lymphatic endothelial cells, and modulates immune cell transportation ( 34 ). In injured hearts, S1PR1/S1P activates downstream signals, including extracellular regulated protein kinases/chemokine ligand 2 (ERK), promoting lymphangiogenesis in the injured heart, driving macrophage trafficking, immune modulation, and cardiac repair after MI ( 35 , 36 ). Estrogen receptor α (ERα)/estrogen ligand plays a protective role in MI, associated with regulating lymphangiogenesis ( 37 ).…”