Inflammation, Lymphatic Function, And Dendritic Cell Migration

Abstract

The lymphatic system is not only essential for maintenance of normal fluid balance, but also for proper immunologic function by providing an extensive network of vessels, important for cell trafficking and antigen delivery, as well as an exclusive environment, the lymph node (LN), where antigen-presenting cells (APCs) and lymphocytes can encounter and interact. Among APCs, dendritic cells (DCs) have a remarkable capacity to traffic from peripheral tissues to the draining LN, which is critical for execution of their functions. To reach the LN, DCs must migrate towards and enter lymphatic vessels. Here, the authors review what is known about the factors that drive this process. They touch particularly on the topic of how DC migration is affected by inflammation and discuss this in the context of lymphatic function. Traditionally, inflammatory mediators are regarded to support DC migration to LNs because they induce molecules on DCs known to guide them to lymphatics. The authors recently showed that inflammatory signals present in a strong vaccine adjuvant induce swelling in LNs accompanied by lymphangiogenesis in the draining LN and radius of peripheral tissue. These increased lymphatics, at least for several days, lead to a more robust migration of DCs. However, the density of lymphatic vessels can become overly extended and/or their function impaired as observed during lymphedema and various chronic inflammatory reactions. Diseases characterized by chronic inflammation often present with impaired DC migration and adaptive immunity. Gaining a better understanding of how lymphatic vessel function may impact adaptive immunity by, for example, altering DC migration will benefit clinical research aiming to manipulate immune responses and manage chronic inflammatory diseases.

Serotonin receptor 5-HT7 regulates morphology and migratory properties of dendritic cells

“…Our finding that 5-HT 7 R can modulate the migratory properties of mature dendritic cells suppose that impaired 5-HT 7 R-mediated signaling in dendritic cells might be involved in the pathogenesis of inflammatory diseases, which are often accompanied by reduced dendritic cell motility (Angeli and Randolph, 2006;Eriksson and Singh, 2008;Hermida et al, 2014). In our recent work, we have demonstrated that 5-HT 7 R-mediated signaling is crucially involved in the progression of chemically induced acute and chronic colitis in mice (Guseva et al, 2014).…”

Role of COX-2 in lymphangiogenesis and restoration of lymphatic flow in secondary lymphedema

“…19,20 Molecular characterization of the tissues with lymphedema revealed the prominence of inflammatory mediators affecting the inflammatory nature of this acquired microvascular disorder. [21][22][23] Lymph stasis is known to induce the tissue destruction associated with lymphedema. Inflammation in lymphedema may be in response to loss of lymphatic vascular integrity, and thus a rational target for intervention in this experimental model.…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…the diameter of lymphatic capillaries increases while their density remains unchanged) [50]. In general, lymphatic hyperplasia and lymphangiogenesis have not been carefully distinguished in the literature, even though these are likely to have different effects on tissue fluid clearance and drainage to the lymph node [1,28,51]. Molecular mediators of lymphangiogenesis are well described in several recent reviews [1,52,53] and will not be discussed in detail here.…”

“…Transport of lymph to the draining LN is achieved in such a way as to optimize the delivery of pathogenic signals, antigens, and immune cells to promote antigen capture by B cells and DCs, and facilitate T cell education and priming [5,51] (Fig. 1).…”

“…Another pro-inflammatory cytokine, interleukin (IL)-1β, promotes lymphangiogenesis by stimulating VEGF-A, VEGF-C, and VEGF-D [104]. In addition to the inflamed tissue, lymphangiogenesis also occurs in the LN draining this tissue [14,16,51].…”