RESUMEN
T cell migration via afferent lymphatics to draining lymph nodes (dLNs) depends on expression of CCR7 in T cells and CCL21 in the lymphatic vasculature. Once T cells have entered lymphatic capillaries, they slowly migrate into contracting collecting vessels. Here, lymph flow picks up, inducing T cell detachment and rapid transport to the dLNs. We find that the atypical chemokine receptor 4 (ACKR4), which binds and internalizes CCL19 and CCL21, is induced by lymph flow in endothelial cells lining lymphatic collectors, enabling them to scavenge these chemokines. In the absence of ACKR4, migration of T cells to dLNs in TPA-induced inflammation is significantly reduced. While entry into capillaries is not impaired, T cells accumulate in the ACKR4-deficient dermal collecting vessel segments. Overall, our findings identify an ACKR4-mediated mechanism by which lymphatic collectors facilitate the detachment of lymph-borne T cells in inflammation and their transition from crawling to free-flow toward the dLNs.
Asunto(s)
Inflamación/metabolismo , Receptores CCR7/metabolismo , Receptores CCR/metabolismo , Linfocitos T/metabolismo , Animales , Movimiento Celular/fisiología , Células Dendríticas/metabolismo , Células Endoteliales/metabolismo , Humanos , Ganglios Linfáticos/metabolismo , Vasos Linfáticos/metabolismo , Ratones , Piel/metabolismoRESUMEN
The lymphatic vasculature plays an essential role in the maintenance of tissue interstitial fluid balance and in the immune response. After capture of fluids, proteins and antigens by lymphatic capillaries, lymphatic collecting vessels ensure lymph transport. An important component to avoid lymph backflow and to allow a unidirectional flow is the presence of intraluminal valves. Defects in the function of collecting vessels lead to lymphedema. Several important factors and signaling pathways involved in lymphatic collecting vessel maturation and valve morphogenesis have now been discovered. The present review summarizes the current knowledge about the key steps of lymphatic collecting vessel development and maturation and focuses on the regulatory mechanisms involved in lymphatic valve formation.
Asunto(s)
Linfangiogénesis/fisiología , Vasos Linfáticos/embriología , Animales , Tipificación del Cuerpo , Vasos Linfáticos/metabolismo , Linfedema , Ratones , Modelos Biológicos , Morfogénesis/fisiología , Transducción de SeñalRESUMEN
Lymphatic vasculature is necessary for maintaining fluid homeostasis in vertebrates. During embryogenesis lymphatic endothelial cells originate from the veins as a homogeneous population. These cells undergo a series of changes at the morphological and molecular levels to become mature lymphatic vasculature that consists of lymphatic capillaries, collecting lymphatic vessels and valves. In this article we summarize our current knowledge about these steps and highlight some black boxes that require further clarification.