Johnson LA, Clasper S, Holt AP, Lalor PF, Baban D, Jackson DGAn inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J Exp Med 203:2763-2777
The exit of antigen-presenting cells and lymphocytes from inflamed skin to afferent lymph is vital for the initiation and maintenance of dermal immune responses. How such an exit is achieved and how cells transmigrate the distinct endothelium of lymphatic vessels are unknown. We show that inflammatory cytokines trigger activation of dermal lymphatic endothelial cells (LECs), leading to expression of the key leukocyte adhesion receptors intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin, as well as a discrete panel of chemokines and other potential regulators of leukocyte transmigration. Furthermore, we show that both ICAM-1 and VCAM-1 are induced in the dermal lymphatic vessels of mice exposed to skin contact hypersensitivity where they mediate lymph node trafficking of dendritic cells (DCs) via afferent lymphatics. Lastly, we show that tumor necrosis factor alpha stimulates both DC adhesion and transmigration of dermal LEC monolayers in vitro and that the process is efficiently inhibited by ICAM-1 and VCAM-1 adhesion-blocking monoclonal antibodies. These results reveal a CAM-mediated mechanism for recruiting leukocytes to the lymph nodes in inflammation and highlight the process of lymphatic transmigration as a potential new target for antiinflammatory therapy.
[Show abstract] [Hide abstract] ABSTRACT: Classical dendritic cells (cDCs) form a critical interface between innate and adaptive immunity. As myeloid immune cell sentinels, cDCs are specialized in the sensing of pathogen challenges and cancer. They translate the latter for T cells into peptide form. Moreover, cDCs provide additional critical information on the original antigen context to trigger a diverse spectrum of appropriate protective responses. Here we review recent progress in our understanding of cDC subsets in mice. We will discuss cDC subset ontogeny and transcription factor dependencies, as well as emerging functional specializations within the cDC compartment in lymphoid and nonlymphoid tissues.0Comments 75Citations
- "Complementary roles in cDC migration have been suggested for other chemokine receptors and S1P1/S1P3 signaling, but CCR7 seems to be the major player. Integrins, on the other hand, are dispensable for the migration of cDCs to LNs under physiological conditions (Lä mmermann et al., 2008) but are needed for optimal migration during contact sensitization (Johnson et al., 2006). "
[Show abstract] [Hide abstract] ABSTRACT: Tissue drains fluid and macromolecules through lymphatic vessels (LVs), which are lined by a specialized endothelium that expresses peculiar differentiation proteins, not found in blood vessels (i.e., LYVE-1, Podoplanin, PROX-1, and VEGFR-3). Lymphatic capillaries are characteristically devoid of a continuous basal membrane and are anchored to the ECM by elastic fibers that act as pulling ropes which open the vessel to avoid edema if tissue volume increases, as it occurs upon inflammation. LVs are also crucial for the transit of T lymphocytes and antigen presenting cells from tissue to draining lymph nodes (LN). Importantly, cell traffic control across lymphatic endothelium is differently regulated under resting and inflammatory conditions. Under steady-state non-inflammatory conditions, leukocytes enter into the lymphatic capillaries through basal membrane gaps (portals). This entrance is integrin-independent and seems to be mainly guided by CCL21 chemokine gradients acting on leukocytes expressing CCR7. In contrast, inflammatory processes in lymphatic capillaries involve a plethora of cytokines, chemokines, leukocyte integrins, and other adhesion molecules. Importantly, under inflammation a role for integrins and their ligands becomes apparent and, as a consequence, the number of leukocytes entering the lymphatic capillaries multiplies several-fold. Enhancing transmigration of dendritic cells en route to LN is conceivably useful for vaccination and cancer immunotherapy, whereas interference with such key mechanisms may ameliorate autoimmunity or excessive inflammation. Recent findings illustrate how, transient cell-to-cell interactions between lymphatic endothelial cells and leukocytes contribute to shape the subsequent behavior of leukocytes and condition the LV for subsequent trans-migratory events.0Comments 6Citations
- "PECAM (CD31) is a molecule expressed on most endothelial cells and involved in leukocyte extra- and intravasation (112). LVs express less CD31 (113) than their blood counterparts and it is mostly distributed at cell–cell homotypic interactions (17, 29). Studies made with human cells have shown that blocking this molecule as well as CD99 in CXCL12 treated LEC was able to reduce TEM, both in vitro and on ex vivo tissue cultures (62). "
[Show abstract] [Hide abstract] ABSTRACT: The mobilization of antigen-presenting dendritic cells (DCs) from peripheral tissues to draining lymph nodes drives the initiation of adaptive immune responses. Recent advances have been made in understanding how and where DCs enter the lymphatic vasculature and what mechanisms control this process. In this chapter, we highlight these advances. Delineating DC-lymphatic vessel interactions is critical for our fundamental understanding of DC trafficking in states of health and disease and for efforts to manipulate DC mobilization for immunotherapy and vaccination.0Comments 20Citations
- "In the steady state, lymphatic capillaries express little to no ICAM-1 and VCAM-1 (Johnson et al., 2006) and adoptively transferred integrindeficient DCs migrate to the LN normally (Lammermann et al., 2008). However, ICAM-1 and VCAM-1 are upregulated during inflammation (Johnson et al., 2006) and are needed for optimal migration of DCs to LNs during contact sensitization (Johnson et al., 2006; Ma, Wang, Guo, Sy, & Bigby, 1994; Xu et al., 2001), along with other adhesive cues (Fig. 2.2). Delineating the distinct requirements for DC migration under inflammatory and resting conditions and the underlying reasons why the requirements are different under these conditions requires more research. "