Lymphatic Clearance of Immune Cells in Cardiovascular Disease

Ravaud, Christophe; Ved, Nikita; Jackson, David G.; Vieira, Joaquim Miguel; Riley, Paul R.

doi:10.3390/cells10102594

Cited by 8 publications

(5 citation statements)

References 167 publications

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“…It is known that the passage of immune cells from tissue interstitium toward afferent lymphatic vessels depends on chemotaxis ( 18 ). Previous investigations showed that lymphatic endothelium expressed and secreted various chemokines, including CCL2, CCL12, CCL5, CCL20, CXCL2, and CX3CL1 (fractalkine), which direct selective egress from tissues of leukocytes ( 26 ). We next asked whether LEC-S1pr1 regulated the expression of chemokines, which directs leukocytes toward LECs and enhanced their egress from injured hearts.…”

Section: Discussionmentioning

confidence: 99%

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

Zhou

Zhao

et al. 2022

Front. Cardiovasc. Med.

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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.

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Section: Discussionmentioning

confidence: 99%

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

Zhou

Zhao

et al. 2022

Front. Cardiovasc. Med.

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“…That said, tumors might also influence the composition of residing progenitors as suggested by dominance of the CD11b + /Lyve-1 + population as compared with minor CD3e + and Ter-119 + subsets. The preference for expansion of lymphatics can be explained by their unique and essential role in removing stimulatory immune cells [86] and debris [87] that otherwise sustain chronic inflammation [88] and block tissue repair [89]. Therefore, increased lymphatics address the most pressing tumor need for regeneration that is less likely to be supported by local production of T-cells or erythrocytes plentifully supplied by blood vessels.…”

Section: Plos Onementioning

confidence: 99%

Tumor microenvironment restricts IL-10 induced multipotent progenitors to myeloid-lymphatic phenotype

Volk-Draper,

Athaiya,

Espinosa Gonzalez

et al. 2024

PLoS ONE

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Lymphangiogenesis is induced by local pro-lymphatic growth factors and bone marrow (BM)-derived myeloid-lymphatic endothelial cell progenitors (M-LECP). We previously showed that M-LECP play a significant role in lymphangiogenesis and lymph node metastasis in clinical breast cancer (BC) and experimental BC models. We also showed that differentiation of mouse and human M-LECP can be induced through sequential activation of colony stimulating factor-1 (CSF-1) and Toll-like receptor-4 (TLR4) pathways. This treatment activates the autocrine interleukin-10 (IL-10) pathway that, in turn, induces myeloid immunosuppressive M2 phenotype along with lymphatic-specific proteins. Because IL-10 is implicated in differentiation of numerous lineages, we sought to determine whether this pathway specifically promotes the lymphatic phenotype or multipotent progenitors that can give rise to M-LECP among other lineages. Analyses of BM cells activated either by CSF-1/TLR4 ligands in vitro or orthotopic breast tumors in vivo showed expansion of stem/progenitor population and coincident upregulation of markers for at least four lineages including M2-macrophage, lymphatic endothelial, erythroid, and T-cells. Induction of cell plasticity and multipotency was IL-10 dependent as indicated by significant reduction of stem cell markers and those for multiple lineages in differentiated cells treated with anti-IL-10 receptor (IL-10R) antibody or derived from IL-10R knockout mice. However, multipotent CD11b+/Lyve-1+/Ter-119+/CD3e+ progenitors detected in BM appeared to split into a predominant myeloid-lymphatic fraction and minor subsets expressing erythroid and T-cell markers upon establishing tumor residence. Each sub-population was detected at a distinct intratumoral site. This study provides direct evidence for differences in maturation status between the BM progenitors and those reaching tumor destination. The study results suggest preferential tumor bias towards expansion of myeloid-lymphatic cells while underscoring the role of IL-10 in early BM production of multipotent progenitors that give rise to both hematopoietic and endothelial lineages.

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“…Lymphatic vasculature also plays an important role during cardiac regeneration by enhancing immune cell trafficking and in doing so, reducing inflammation ( 87 ). During the process of remodeling which occurs in the failing heart, angiotensin II (AngII) is expressed and associated with dysfunctions such as the misexpression of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) and VEGFC.…”

Section: Mechanisms Underlying Heart Regenerationmentioning

confidence: 99%

The multifaceted nature of endogenous cardiac regeneration

Rolland

Jopling

2023

Front. Cardiovasc. Med.

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Since the first evidence of cardiac regeneration was observed, almost 50 years ago, more studies have highlighted the endogenous regenerative abilities of several models following cardiac injury. In particular, analysis of cardiac regeneration in zebrafish and neonatal mice has uncovered numerous mechanisms involved in the regenerative process. It is now apparent that cardiac regeneration is not simply achieved by inducing cardiomyocytes to proliferate but requires a multifaceted response involving numerous different cell types, signaling pathways and mechanisms which must all work in harmony in order for regeneration to occur. In this review we will endeavor to highlight a variety of processes that have been identifed as being essential for cardiac regeneration.

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Lymphatic Clearance of Immune Cells in Cardiovascular Disease

Cited by 8 publications

References 167 publications

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

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

Tumor microenvironment restricts IL-10 induced multipotent progenitors to myeloid-lymphatic phenotype

The multifaceted nature of endogenous cardiac regeneration

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