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Thesis

English

ID: <

10670/1.84hbd5

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Where these data come from
The transcriptional response of dendritic cells to mechanical stress dictates their steady-state migration to the lymph node

Abstract

In response to mechanical stress, cells assemble a pool of actin around their nucleus, which results in nucleus compression and facilitates cell migration in confined environments. How this phenomenon is regulated and whether it impacts on the fate and function(s) of cells is unclear. Here, we show that actin nucleation at the nucleus of dendritic cells (DCs), sentinels of the immune system, is negatively regulated by Arpin, a recently described inhibitor of the Arp2/3 complex. Limitation of actin polymerization by Arpin protects immature DCs from initiating an Arp2/3-dependent “maturation-like” gene expression program in response to mechanical stress. Activation of this program requires cytosolic phospholipase 2 (cPLA2)-dependent NFKB activation and leads to the expression of ~350 genes, including CCR7, i.e., the chemokine receptor that drives DC migration to lymph nodes. Consistent with these results, we observed that Arpin KO DCs exhibit enhanced migration to lymph nodes even in the absence of inflammation. Remarkably, we found that this transcriptional program also includes anti-inflammatory genes and, accordingly, that mechanically stressed-DCs harbor tolerogenic properties. These results show that by controlling cPLA2 and NFKB activation, Arpin prevents DC spontaneous maturation and migration to lymph nodes in response to physical confinement. They further suggest that the mechanical stress experienced by DCs in peripheral tissues might constitute one of them so far unknown signal(s) that trigger CCR7 expression and DC migration to lymph nodes in homeostasis for maintenance of peripheral tolerance.

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