The Activity of the Neutral Sphingomyelinase Is Important in T Cell Recruitment and Directional Migration.

Christoph Arenz,Katrin Anne Becker-Flegler,Lena Collenburg,Sibylle Schneider-Schaulies,Teresa Wiese,Elita Avota,Niklas Beyersdorf,Essa M. Saied

doi:10.3389/fimmu.2017.01007

Abstract

Breakdown of sphingomyelin as catalyzed by the activity of sphingomyelinases profoundly affects biophysical properties of cellular membranes which is particularly important with regard to compartmentalization of surface receptors and their signaling relay. As it is activated both upon TCR ligation and co-stimulation in a spatiotemporally controlled manner, the neutral sphingomyelinase (NSM) has proven to be important in T cell activation, where it appears to play a particularly important role in cytoskeletal reorganization and cell polarization. Because these are important parameters in directional T cell migration and motility in tissues, we analyzed the role of the NSM in these processes. Pharmacological inhibition of NSM interfered with early lymph node homing of T cells in vivo indicating that the enzyme impacts on endothelial adhesion, transendothelial migration, sensing of chemokine gradients or, at a cellular level, acquisition of a polarized phenotype. NSM inhibition reduced adhesion of T cells to TNF-α/IFN-γ activated, but not resting endothelial cells, most likely via inhibiting high-affinity LFA-1 clustering. NSM activity proved to be highly important in directional T cell motility in response to SDF1-α, indicating that their ability to sense and translate chemokine gradients might be NSM dependent. In fact, pharmacological or genetic NSM ablation interfered with T cell polarization both at an overall morphological level and redistribution of CXCR4 and pERM proteins on endothelial cells or fibronectin, as well as with F-actin polymerization in response to SDF1-α stimulation, indicating that efficient directional perception and signaling relay depend on NSM activity. Altogether, these data support a central role of the NSM in T cell recruitment and migration both under homeostatic and inflamed conditions by regulating polarized redistribution of receptors and their coupling to the cytoskeleton.

Highlights

Polarization of both membrane receptors and intracellular signaling machineries is a prerequisite for directional migration of T lymphocytes, and this is induced by relaying of signals provided by chemoattractants or membrane bound receptors
These processes are highly dependent on regulated sorting of receptors to cellular subdomains, such as the leading edge (LE), the midbody or the uropod, and dynamic reorganization of the actin cytoskeleton which may be coupled to surface receptors such as CXCR4 or LFA-1 by linker proteins, including ezrin/radixin/ moesin (ERM) family proteins or talin [6,7,8]
The recovery of ES048-treated cells from peripheral blood was reduced as that in the spleen (Figure 1, left panel). These data indicate the importance of neutral sphingomyelinase (NSM) activity in rapid T cell homing to lymph nodes in an uninflamed environment, in case of an immediate immune reaction where quick recruitment of effector cells is essential, this could be highly relevant for the initiation of the immune response

Summary

Introduction

Polarization of both membrane receptors and intracellular signaling machineries is a prerequisite for directional migration of T lymphocytes, and this is induced by relaying of signals provided by chemoattractants or membrane bound receptors. These are important upon interaction with inflamed endothelia that provide docking, adherence, and polarizing signals to enable integrin activation and subsequent transmigration [1,2,3,4,5]. Dynamic alterations of local membrane domains are important for the organization and maintenance of membrane domains essentially sorting receptors needed for adhesion, signal perception, and cytoskeletal coupling [12, 13]

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Results

Conclusion