Lymphatic exosomes promote dendritic cell migration along guidance cues.

Markus Brown,Michael Detmar,Dontscho Kerjaschki,Peter Majek,Young-Kwon Hong,Brigitte Langer,Gabriele Asfour,Kari Vaahtomeri,Nora Bukosza,Katja Parapatics,David G Jackson,Michael Sixt,Renate Kain,Keiryn L Bennett,Louise A Johnson,Daniel Senfter,Robert Hauschild,Dario A Leone,Helga Schachner

doi:10.1083/jcb.201612051

Abstract

Lymphatic endothelial cells (LECs) release extracellular chemokines to guide the migration of dendritic cells. In this study, we report that LECs also release basolateral exosome-rich endothelial vesicles (EEVs) that are secreted in greater numbers in the presence of inflammatory cytokines and accumulate in the perivascular stroma of small lymphatic vessels in human chronic inflammatory diseases. Proteomic analyses of EEV fractions identified >1,700 cargo proteins and revealed a dominant motility-promoting protein signature. In vitro and ex vivo EEV fractions augmented cellular protrusion formation in a CX3CL1/fractalkine-dependent fashion and enhanced the directional migratory response of human dendritic cells along guidance cues. We conclude that perilymphatic LEC exosomes enhance exploratory behavior and thus promote directional migration of CX3CR1-expressing cells in complex tissue environments.

Highlights

The interstitial space contains membrane vesicles (Yáñez-Mó et al, 2015; Weigelin et al, 2016), which according to their biogenesis, are commonly classified as apoptotic bodies, ectosomes, and exosomes
We report that Lymphatic endothelial cells (LECs) release basolateral exosome-rich endothelial vesicles (EEVs) that are secreted in greater numbers in the presence of inflammatory cytokines and accumulate in the perivascular stroma of small lymphatic vessels in human chronic inflammatory diseases
LECs release EEVs To determine whether the lymphatic endothelium could be a source of the putative exosome halos, we imaged the ultrastructure of human dermal LECs in vitro and in situ (Fig. 2 a)

Summary

Introduction

The interstitial space contains membrane vesicles (Yáñez-Mó et al, 2015; Weigelin et al, 2016), which according to their biogenesis, are commonly classified as apoptotic bodies, ectosomes, and exosomes. Exosomes transfer numerous factors that promote cell migration in auto- and paracrine modes (Truman et al, 2008; Baj-Krzyworzeka et al, 2011; Sung et al, 2015; Majumdar et al, 2016) and are potentially relevant for immune and cancer cell migration (Hoshino et al, 2015; Wendler et al, 2017). En route to their target organs migratory cells have to overcome various architectural hindrances, including interstitial matrix structures, basement membranes, and intercellular junctions. To navigate through such complex environments, migrating cells have to maintain dynamic cellular protrusions, which constantly sample and explore the chemical and geometrical features of their surroundings for guidance (Leithner et al, 2016)

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Conclusion