The lymphatic system has long been known to serve as a highway for migrating leukocytes from peripheral tissue to draining lymph nodes (dLNs) and back to circulation, thereby contributing to the ...induction of adaptive immunity and immunesurveillance. Lymphatic vessels (LVs) present in peripheral tissues upstream of a first dLN are generally referred to as afferent LVs. In contrast to migration through blood vessels (BVs), the detailed molecular and cellular requirements of cellular traffic through afferent LVs have only recently started to be unraveled. Progress in our ability to track the migration of lymph-borne cell populations, in combination with cutting-edge imaging technologies, nowadays allows the investigation and visualization of lymphatic migration of endogenous leukocytes, both at the population and at the single-cell level. These studies have revealed that leukocyte trafficking through afferent LVs generally follows a step-wise migration pattern, relying on the active interplay of numerous molecules. In this review, we will summarize and discuss current knowledge of cellular traffic through afferent LVs. We will first outline how the structure of the afferent LV network supports leukocyte migration and highlight important molecules involved in the migration of dendritic cells (DCs), T cells and neutrophils, i.e. the most prominent cell types trafficking through afferent LVs. Additionally, we will describe how tumor cells hijack the lymphatic system for their dissemination to draining LNs. Finally, we will summarize and discuss our current understanding of the functional significance as well as the therapeutic implications of cell traffic through afferent LVs.
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Mucosal infections with Candida albicans belong to the most frequent forms of fungal diseases. Host protection is conferred by cellular immunity; however, the induction of antifungal immunity is not ...well understood. Using a mouse model of oropharyngeal candidiasis (OPC) we show that interleukin-1 receptor (IL-1R) signaling is critical for fungal control at the onset of infection through its impact on neutrophils at two levels. We demonstrate that both the recruitment of circulating neutrophils to the site of infection and the mobilization of newly generated neutrophils from the bone marrow depended on IL-1R. Consistently, IL-1R-deficient mice displayed impaired chemokine production at the site of infection and defective secretion of granulocyte colony-stimulating factor (G-CSF) in the circulation in response to C. albicans. Strikingly, endothelial cells were identified as the primary cellular source of G-CSF during OPC, which responded to IL-1α that was released from keratinocytes in the infected tissue. The IL-1-dependent crosstalk between two different cellular subsets of the nonhematopoietic compartment was confirmed in vitro using a novel murine tongue-derived keratinocyte cell line and an established endothelial cell line. These data establish a new link between IL-1 and granulopoiesis in the context of fungal infection. Together, we identified two complementary mechanisms coordinating the neutrophil response in the oral mucosa, which is critical for preventing fungal growth and dissemination, and thus protects the host from disease.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The mammalian lymphatic system consists of strategically located lymph nodes (LNs) embedded into a lymphatic vascular network. Mechanisms underlying development of this highly organized system are ...not fully understood. Using high-resolution imaging, we show that lymphoid tissue inducer (LTi) cells initially transmigrate from veins at LN development sites using gaps in venous mural coverage. This process is independent of lymphatic vasculature, but lymphatic vessels are indispensable for the transport of LTi cells that egress from blood capillaries elsewhere and serve as an essential LN expansion reservoir. At later stages, lymphatic collecting vessels ensure efficient LTi cell transport and formation of the LN capsule and subcapsular sinus. Perinodal lymphatics also promote local interstitial flow, which cooperates with lymphotoxin-β signaling to amplify stromal CXCL13 production and thereby promote LTi cell retention. Our data unify previous models of LN development by showing that lymphatics intervene at multiple points to assist LN expansion and identify a new role for mechanical forces in LN development.
Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses
. Circadian rhythms have emerged as important regulators of ...leukocyte trafficking to LNs via the blood
. Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans. Chronopharmacological targeting of the involved factors abrogates circadian migration of DCs. We identify cell-intrinsic circadian oscillations in skin lymphatic endothelial cells (LECs) and DCs that cogovern these rhythms, as their genetic disruption in either cell type ablates circadian trafficking. These observations indicate that circadian clocks control the infiltration of DCs into skin lymphatics, a process that is essential for many adaptive immune responses and relevant for vaccination and immunotherapies.
Lymphatic vessels have traditionally been regarded as a rather inert drainage system, which just passively transports fluids, leukocytes and antigen. However, it is becoming increasingly clear that ...the lymphatic vasculature is highly dynamic and plays a much more active role in inflammatory and immune processes. Tissue inflammation induces a rapid, stimulus-specific upregulation of chemokines and adhesion molecules in lymphatic endothelial cells and a proliferative expansion of the lymphatic network in the inflamed tissue and in draining lymph nodes. Moreover, increasing evidence suggests that inflammation-induced changes in the lymphatic vasculature have a profound impact on the course of inflammatory and immune responses, by modulating fluid drainage, leukocyte migration or the removal of inflammatory mediators from tissues. In this review we will summarize and discuss current knowledge of the inflammatory response of lymphatic endothelium and of inflammation-induced lymphangiogenesis and the current perspective on the overall functional significance of these processes.
To induce adaptive immunity, dendritic cells (DCs) migrate through afferent lymphatic vessels (LVs) to draining lymph nodes (dLNs). This process occurs in several consecutive steps. Upon entry into ...lymphatic capillaries, DCs first actively crawl into downstream collecting vessels. From there, they are next passively and rapidly transported to the dLN by lymph flow. Here, we describe a role for the chemokine CCL21 in intralymphatic DC crawling. Performing time-lapse imaging in murine skin, we found that blockade of CCL21—but not the absence of lymph flow—completely abolished DC migration from capillaries toward collecting vessels and reduced the ability of intralymphatic DCs to emigrate from skin. Moreover, we found that in vitro low laminar flow established a CCL21 gradient along lymphatic endothelial monolayers, thereby inducing downstream-directed DC migration. These findings reveal a role for intralymphatic CCL21 in promoting DC trafficking to dLNs, through the formation of a flow-induced gradient.
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•Downstream-directed DC migration in lymphatic capillaries is lymph flow independent•Downstream-directed DC migration in lymphatic capillaries is CCL21/CCR7 dependent•Low flow creates a downstream-oriented CCL21 gradient along lymphatic endothelium•The flow-induced CCL21 gradient promotes DC trafficking through afferent lymphatics
Intravital microscopy studies have recently revealed that dendritic cells (DCs) migrating to draining lymph nodes actively crawl within afferent lymphatic capillaries. Here, Russo et al. provide evidence that an intraluminal CCL21 gradient, which is deposited by lymph flow, guides DCs migrating within capillaries in the downstream direction of the collecting lymphatic vessels.
Chemokines and adhesion molecules up-regulated in lymphatic endothelial cells (LECs) during tissue inflammation are thought to enhance dendritic cell (DC) migration to draining lymph nodes, but the ...in vivo control of this process is not well understood. We performed a transcriptional profiling analysis of LECs isolated from murine skin and found that inflammation induced by a contact hypersensitivity (CHS) response up-regulated the adhesion molecules ICAM-1 and VCAM-1 and inflammatory chemokines. Importantly, the lymphatic markers Prox-1, VEGFR3, and LYVE-1 were significantly down-regulated during CHS. By contrast, skin inflammation induced by complete Freund adjuvant induced a different pattern of chemokine and lymphatic marker gene expression and almost no ICAM-1 up-regulation in LECs. Fluorescein isothiocyanate painting experiments revealed that DC migration to draining lymph nodes was more strongly increased in complete Freund adjuvant-induced than in CHS-induced inflammation. Surprisingly, DC migration did not correlate with the induction of CCL21 and ICAM-1 protein in LECs. Although the requirement for CCR7 signaling became further pronounced during inflammation, CCR7-independent signals had an additional, albeit moderate, impact on enhancing DC migration. Collectively, these findings indicate that DC migration in response to inflammation is stimulus-specific, mainly CCR7-dependent, and overall only moderately enhanced by LEC-induced genes other than CCL21.
Dendritic cell (DC) migration to draining lymph nodes (dLNs) is a slow process that is believed to begin with DCs approaching and entering into afferent lymphatic capillaries. From capillaries, DCs ...slowly crawl into lymphatic collectors, where lymph flow induced by collector contraction supports DC detachment and thereafter rapid, passive transport to dLNs. Performing a transcriptomics analysis of dermal endothelial cells, we found that inflammation induces the degradation of the basement membrane (BM) surrounding lymphatic collectors and preferential up-regulation of the DC trafficking molecule VCAM-1 in collectors. In crawl-in experiments performed in ear skin explants, DCs entered collectors in a CCR7- and β1 integrin-dependent manner. In vivo, loss of β1-integrins in DCs or of VCAM-1 in lymphatic collectors had the greatest impact on DC migration to dLNs at early time points when migration kinetics favor the accumulation of rapidly migrating collector DCs rather than slower capillary DCs. Taken together, our findings identify collector entry as a critical mechanism enabling rapid DC migration to dLNs in inflammation.
In contrast to leukocyte migration through blood vessels, trafficking via lymphatic vessels (LVs) is much less well characterized. An important cell type migrating via this route is ...antigen-presenting dendritic cells (DCs), which are key for the induction of protective immunity as well as for the maintenance of immunological tolerance. In this review, we will summarize and discuss current knowledge of the cellular and molecular events that control DC migration from the skin towards, into, and within LVs, followed by DC arrival and migration in draining lymph nodes. Finally, we will discuss potential strategies to therapeutically target this migratory step to modulate immune responses.
T cells are the most abundant cell type found in afferent lymph, but their migration through lymphatic vessels (LVs) remains poorly understood. Performing intravital microscopy in the murine skin, we ...imaged T cell migration through afferent LVs in vivo. T cells entered into and actively migrated within lymphatic capillaries but were passively transported in contractile collecting vessels. Intralymphatic T cell number and motility were increased during contact-hypersensitivity-induced inflammation and dependent on ICAM-1/LFA-1 interactions. In vitro, blockade of endothelial cell-expressed ICAM-1 reduced T cell adhesion, crawling, and transmigration across lymphatic endothelium and decreased T cell advancement from capillaries into lymphatic collectors in skin explants. In vivo, T cell migration to draining lymph nodes was significantly reduced upon ICAM-1 or LFA-1 blockade. Our findings indicate that T cell migration through LVs occurs in distinct steps and reveal a key role for ICAM-1/LFA-1 interactions in this process.
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•T cells crawl within initial lymphatic capillaries and flow in collecting vessels•Tissue inflammation increases T cell speed within lymphatic capillaries•Increased speed of T cells within lymphatic capillaries is ICAM-1/LFA-1 dependent•ICAM-1/LFA-1 blockade reduces inflammatory T cell migration to draining lymph nodes
T cell migration through afferent lymphatic vessels contributes to immune surveillance, but the cellular mechanisms of this process are largely unknown. Using intravital microscopy, Teijeira et al. show that T cells crawl in an ICAM-1/LFA-1-dependent manner within inflamed dermal lymphatic capillaries but only flow with lymph once in contracting collectors.
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