Lymphatic endothelial-cell expressed ACKR3 is dispensable for postnatal lymphangiogenesis and lymphatic drainage function in mice.

Elena C Sigmund,Marcus Thelen,Cornelia Halin,Rolf A K Stahl,Victor Collado-Diaz,Martina Vranova,Philipp Schineis,Lilian Baur,Jorge Arasa,Jean-Léon Thomas

doi:10.1371/journal.pone.0249068

Elena C Sigmund, Marcus Thelen + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0249068

Copy DOI

Abstract

Atypical chemokine receptor ACKR3 (formerly CXCR7) is a scavenging receptor that has recently been implicated in murine lymphatic development. Specifically, ACKR3-deficiency was shown to result in lymphatic hyperplasia and lymphedema, in addition to cardiac hyperplasia and cardiac valve defects leading to embryonic lethality. The lymphatic phenotype was attributed to a lymphatic endothelial cell (LEC)-intrinsic scavenging function of ACKR3 for the vascular peptide hormone adrenomedullin (AM), which is also important during postnatal lymphangiogenesis. In this study, we investigated the expression of ACKR3 in the lymphatic vasculature of adult mice and its function in postnatal lymphatic development and function. We show that ACKR3 is widely expressed in mature lymphatics and that it exerts chemokine-scavenging activity in cultured murine skin-derived LECs. To investigate the role of LEC-expressed ACKR3 in postnatal lymphangiogenesis and function during adulthood, we generated and validated a lymphatic-specific, inducible ACKR3 knockout mouse. Surprisingly, in contrast to the reported involvement of ACKR3 in lymphatic development, our analyses revealed no contribution of LEC-expressed ACKR3 to postnatal lymphangiogenesis, lymphatic morphology and drainage function.

Highlights

Atypical chemokine receptors (ACKRs) are chemokine receptors that do not signal via G proteins but instead act as scavenging receptors
In support of our working hypothesis, i.e. that ACKR3 might be important for regulating lymphatic endothelial cell (LEC) responses to AM during adulthood, we detected the expression of the conventional AM 1 receptor subunits [44], namely the calcitonin receptor- like receptor (Fig 1F) and the receptor activity-modifying protein 2 in LECs (Fig 1G)
Far, ACKR3 expression and function in postnatal lymphatic vessels have not been investigated, but could be important considering that ACKR3 is currently under investigation as a drug target in cancer therapy [12,13,14,15,53]

Summary

Introduction

Atypical chemokine receptors (ACKRs) are chemokine receptors that do not signal via G proteins but instead act as scavenging receptors. ACKR3 binds and scavenges the chemokine ligands CXCL12 and CXCL11 [1,2]. In the case of CXCL12, ACKR3 is well known to shape local and systemic CXCL12 levels, thereby impacting its activity on CXCR4 [3,4,5,6]. By this means, ACKR3 exerts important functions during embryonic development, in leukocyte migration and in the regulation of the humoral immune response [7,8,9,10,11]. ACKR3 is upregulated in various types of cancer [12] and was found to be involved in tumor

Methods

Results

Conclusion