Pathogenic Stress Induces Human Monocyte to Express an Extracellular Web of Tunneling Nanotubes.

Michal Shahar,Haim Rosen,Auryan Szalat

doi:10.3389/fimmu.2021.620734

Abstract

Actin-based tunneling nanotubes are a means of intercellular communication between remote cells. In the last decade, this type of nanotube was described in a wide variety of cell types and it became widely accepted that communication through these nanotubes is related to response to environmental changes. Few reports, however, are available regarding the expression of similar nanotubes in vivo or in primary cells. Moreover, the functional significance of this intercellular communication for health and disease is largely unknown. In this context, and as a first step in unraveling these questions, we examined the formation of similar nanotubes in primary peripheral human monocytes. To that end, we combined the use of a live cell imaging system along with advanced methods of fluorescent and scanning electron microscopy. This experimental approach reveals for the first time that the bacterial lipopolysaccharide endotoxin induces a transient expression of an unexpected abundance of actin-based tunneling nanotubes associated with vesicles. In addition, it was found that a similar response can be achieved by treating human monocytes with various bacterial and yeast membrane components, as well as with a viral component analog. In all these cases, this response is mediated by distinct complexes of toll-like receptors. Therefore, we suggest that the observed phenomena are related to a broad type of monocyte pathogen response, and raise the possibility that the phenomena described above may be involved in many clinical situations related to inflammation as a new topic of study.

Highlights

Cell-to-cell communication is fundamental to the existence and survival of multicellular organisms and occurs in different ways: indirect communication via intercellular messengers that travel for short or long distances, or direct communication via contact between adjacent cells
A large body of knowledge has been accumulated demonstrating how these cells contribute to inflammation and host defense by pattern recognition receptor-mediated recruitment and cytokine release, phagocytosis, oxidative burst, and antigen presentation [42]; novel studies show that macrophages and neutrophils can release extracellular nucleic acids capable of entrapping exogenous pathogens, a phenomenon currently defined as METosis and NETosis, respectively [48, 49]
Beyond the classic known mechanisms of action of monocytes-macrophages and the latter cited entrapment phenomenon, our study adds another new type of capacity for peripheric human monocytes and a new type of response: intercellular network of tunneling nanotubes (TNTs) formed by stimulated circulating monocytes mediated by pattern recognition receptors

Summary

Introduction

Cell-to-cell communication is fundamental to the existence and survival of multicellular organisms and occurs in different ways: indirect communication via intercellular messengers that travel for short or long distances, or direct communication via contact between adjacent cells. TNTs have several specific characteristics and are highly heterogeneous in both structure and function: they are ultrafine intercellular structures spanning tens to hundreds of microns, a length of up to several cellular diameters and a width ranging from 50 to 1,500 nm [24, 25]. They are membranous extensions from one cell to the other, supported by cytoskeletal fibers including F-actin and/or microtubules allowing unidirectional and/or bidirectional transmission of cellular components, a phenomenon known as “cargo transport,” for review, see [26,27,28]. The involved mechanisms in TNT formation are complex, but distinct from those occurring in the formation of filopodia and cytonemes [24, 25, 30]

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