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2017 ; 8
(ä): 1007
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The Activity of the Neutral Sphingomyelinase Is Important in T Cell Recruitment
and Directional Migration
#MMPMID28871263
Collenburg L
; Beyersdorf N
; Wiese T
; Arenz C
; Saied EM
; Becker-Flegler KA
; Schneider-Schaulies S
; Avota E
Front Immunol
2017[]; 8
(ä): 1007
PMID28871263
show ga
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-?/IFN-? 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-?,
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-? 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.