Abstract
Migration is crucial for the function of dendritic cells (DCs), which act as outposts of the immune system. Upon detection of pathogens, skin- and mucosa-resident DCs migrate to secondary lymphoid organs where they activate T cells. DC motility relies critically on the actin cytoskeleton, which is regulated by the actin-related protein 2/3 (ARP2/3) complex, a nucleator of branched actin networks. Consequently, loss of ARP2/3 stimulators and upstream Rho family GTPases dramatically impairs DC migration. However, nothing is known yet about the relevance of ARP2/3 inhibitors for DC migration. We previously demonstrated that the AP-1-associated adaptor protein Gadkin inhibits ARP2/3 by sequestering it on intracellular vesicles. Consistent with a role of Gadkin in DC physiology, we here report Gadkin expression in bone marrow-derived DCs and show that its protein level and posttranslational modification are regulated upon LPS-induced DC maturation. DCs derived from Gadkin-deficient mice were normal with regards to differentiation and maturation, but displayed increased actin polymerization. While the actin-dependent processes of macropinocytosis and cell spreading were not affected, loss of Gadkin significantly impaired DC migration in vitro, however, in vivo DC migration was unperturbed suggesting the presence of compensatory mechanisms.
Highlights
Cell migration is essential for the functioning of the immune system
These results demonstrate the expression of the actin-related protein 2/3 (ARP2/3) inhibitor Gadkin in highly motile immune cells, including bone marrow-derived DCs (BMDCs), and lay the basis for investigating the role of Gadkin in Dendritic cells (DCs) migration
Immune cell migration throughout the organism is essential for successful immune surveillance and the induction of innate and adaptive immunity. This holds true for DCs, which have to navigate throughout the body in order to sample foreign antigens in peripheral tissues and display them to T cells in secondary lymphoid organs to mount immune responses
Summary
Cell migration is essential for the functioning of the immune system. Dendritic cells (DCs) are a pivotal example for this fact due to their far apart lying places of action [1]. DC migration from the periphery to draining lymph nodes is crucial for the induction of an adaptive immune response against invading pathogens [2]. Immature DCs reside as sentinels for the detection of pathogens in exposed tissues such as skin and mucosal surfaces, where they continuously sample foreign antigens [1]. Pathogen encounter triggers DC maturation e.g. via Toll-like receptors, which includes an increase in the surface levels of the chemokine receptor CCR7 [3] as well as the upregulation of co-stimulatory molecules to efficiently prime T cells. Guided by PLOS ONE | DOI:10.1371/journal.pone.0143883 December 1, 2015
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