The human cytokine TSLP triggers a cell-autonomous dendritic cell migration in confined environments

Abstract Dendritic cells (DCs) need to migrate in the interstitial environment of peripheral tissues to reach secondary lymphoid organs and initiate a suitable immune response. Whether and how inflamed tissues instruct DCs to emigrate is not fully understood. In this study, we report the unexpected finding that the epithelial-derived cytokine TSLP triggers chemokinesis of resting primary human DCs in a cell-autonomous manner. TSLP induced the polarization of both microtubule and actin cytoskeletons and promoted DC 3-dimensional migration in transwell as well as in microfabricated channels that mimic the confined environment of peripheral tissues. TSLP-induced migration relied on the actin-based motor myosin II and was inhibited by blebbistatin. Accordingly, TSLP triggered the redistribution of phosphorylated myosin II regulatory light chain to the actin cortex, indicating that TSLP induces DC migration by promoting actomyosin contractility. Thus, TSLP produced by epithelial cells in inflamed tissue has a critical function in licensing DCs for cell-autonomous migration. This indicates that cytokines can directly trigger cell migration, which has important implications in immune physiopathology and vaccine design.

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Rab7b regulates dendritic cell migration by linking lysosomes to the actomyosin cytoskeleton

Journal of Cell Science ◽

10.1242/jcs.259221 ◽

2021 ◽

Cited By ~ 1

Author(s):

Katharina Vestre ◽

Irene Persiconi ◽

Marita Borg Distefano ◽

Nadia Mensali ◽

Noemi Antonella Guadagno ◽

...

Keyword(s):

Cell Migration ◽

Immune Cell ◽

Myosin Ii ◽

Small Gtpase ◽

Peripheral Tissues ◽

3 Dimensional ◽

Late Endosomes ◽

Dendritic Cell Migration ◽

Transcription Factor Eb ◽

Actomyosin Cytoskeleton

Lysosomal signaling facilitates the migration of immune cells by releasing calcium to activate the actin-based motor myosin II at the cell rear. However, how the actomyosin cytoskeleton physically associates to lysosomes is unknown. We have previously identified myosin II as a direct interactor of Rab7b, a small GTPase that mediates the transport from late endosomes/lysosomes to the TGN. Here, we show that Rab7b regulates the migration of dendritic cells (DCs) in 1- and 3-dimensional environments. DCs are immune sentinels that transport antigens from peripheral tissues to lymph nodes to activate T lymphocytes and initiate adaptive immune responses. We found that lack of Rab7b reduces myosin II light chain phosphorylation and the activation of the transcription factor EB (TFEB), which controls lysosomal signaling and is required for fast DC migration. Furthermore, we demonstrate that Rab7b interacts with the lysosomal calcium channel TRPML1, enabling the local activation of myosin II at the cell rear. Altogether, our findings identify Rab7b as the missing physical link between lysosomes and the actomyosin cytoskeleton, allowing control of immune cell migration through lysosomal signaling.

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Contribution of Filopodia to Cell Migration: A Mechanical Link between Protrusion and Contraction

International Journal of Cell Biology ◽

10.1155/2010/507821 ◽

2010 ◽

Vol 2010 ◽

pp. 1-13 ◽

Cited By ~ 31

Author(s):

Fei Xue ◽

Deanna M. Janzen ◽

David A. Knecht

Keyword(s):

Cell Migration ◽

Actin Polymerization ◽

Myosin Ii ◽

Temporal Distribution ◽

Leading Edge ◽

Distal Portion ◽

Actin Binding ◽

Actin Networks ◽

Motile Cells ◽

A Cell

Numerous F-actin containing structures are involved in regulating protrusion of membrane at the leading edge of motile cells. We have investigated the structure and dynamics of filopodia as they relate to events at the leading edge and the function of the trailing actin networks. We have found that although filopodia contain parallel bundles of actin, they contain a surprisingly nonuniform spatial and temporal distribution of actin binding proteins. Along the length of the actin filaments in a single filopodium, the most distal portion contains primarily T-plastin, while the proximal portion is primarily bound byα-actinin and coronin. Some filopodia are stationary, but lateral filopodia move with respect to the leading edge. They appear to form a mechanical link between the actin polymerization network at the front of the cell and the myosin motor activity in the cell body. The direction of lateral filopodial movement is associated with the direction of cell migration. When lateral filopodia initiate from and move toward only one side of a cell, the cell will turn opposite to the direction of filopodial flow. Therefore, this filopodia-myosin II system allows actin polymerization driven protrusion forces and myosin II mediated contractile force to be mechanically coordinated.

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Calculation of the force field required for nucleus deformation during cell migration through constrictions

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008592 ◽

2021 ◽

Vol 17 (5) ◽

pp. e1008592

Author(s):

Ian D. Estabrook ◽

Hawa Racine Thiam ◽

Matthieu Piel ◽

Rhoda J. Hawkins

Keyword(s):

Cell Migration ◽

Force Field ◽

Elastic Shell ◽

Elastic Solid ◽

Experimental Measure ◽

Before And After ◽

A Cell ◽

Deformation Force ◽

Pass Through ◽

Confined Environment

During cell migration in confinement, the nucleus has to deform for a cell to pass through small constrictions. Such nuclear deformations require significant forces. A direct experimental measure of the deformation force field is extremely challenging. However, experimental images of nuclear shape are relatively easy to obtain. Therefore, here we present a method to calculate predictions of the deformation force field based purely on analysis of experimental images of nuclei before and after deformation. Such an inverse calculation is technically non-trivial and relies on a mechanical model for the nucleus. Here we compare two simple continuum elastic models of a cell nucleus undergoing deformation. In the first, we treat the nucleus as a homogeneous elastic solid and, in the second, as an elastic shell. For each of these models we calculate the force field required to produce the deformation given by experimental images of nuclei in dendritic cells migrating in microchannels with constrictions of controlled dimensions. These microfabricated channels provide a simplified confined environment mimicking that experienced by cells in tissues. Our calculations predict the forces felt by a deforming nucleus as a migrating cell encounters a constriction. Since a direct experimental measure of the deformation force field is very challenging and has not yet been achieved, our numerical approaches can make important predictions motivating further experiments, even though all the parameters are not yet available. We demonstrate the power of our method by showing how it predicts lateral forces corresponding to actin polymerisation around the nucleus, providing evidence for actin generated forces squeezing the sides of the nucleus as it enters a constriction. In addition, the algorithm we have developed could be adapted to analyse experimental images of deformation in other situations.

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