Mast cell modulation of the vascular and lymphatic endothelium

Abstract

Mast cells (MCs) promote a wide range of localized and systemic inflammatory responses. Their involvement in immediate as well as chronic inflammatory reactions at both local and distal sites points to an extraordinarily powerful immunoregulatory capacity with spatial and temporal versatility. MCs are preferentially found in close proximity to both vascular and lymphatic vessels. On activation, they undergo a biphasic secretory response involving the rapid release of prestored vasoactive mediators followed by de novo synthesized products. Many actions of MCs are related to their capacity to regulate vascular flow and permeability and to the recruitment of various inflammatory cells from the vasculature into inflammatory sites. These mediators often work in an additive fashion and achieve their inflammatory effects locally by directly acting on the vascular and lymphatic endothelia, but they also can affect distal sites. Along these lines, the lymphatic and endothelial vasculatures of the host act as a conduit for the dissemination of MC signals during inflammation. The central role of the MC-endothelial cell axis to immune homeostasis is emphasized by the fact that some of the most effective current treatments for inflammatory disorders are directed at interfering with this interaction.

Figures

Figure 1

MCs and vascular endothelium are intimately associated. (A) MCs (blue, stained with the heparin-binding probe, avidin) are visible lining blood vessels (CD31, red) in tissue from the mouse ear, which was stained in whole mount (20× mag. 20×/0.75). (B) Proximity of MCs (blue) to blood (red, CD31) and lymphatic (green, LYVE-1) vessels in the mouse skin (20× mag. 20×/0.75 objective). (C) Extensive association of MCs with both vasculatures is apparent after staining mouse ear tissue in whole mount as in other panels for vascular and lymphatic endothelia (10× magnification, 10×/0.25 NA objective). Images were acquired using a Nikon Eclipse TE200 microscope and EZ-C1 Version 3.6 software. Additional image processing was performed using Autoquant software and Adobe Photoshop (Version 9).

Figure 2

Particulate release of MC Mediators. (A) Rat lymphoblastic leukemia-2H3 cells (a MC-like cell line), which express a TNF–green fluorescent protein fusion protein (green), incorporate TNF and other mediators, including serotonin (red), into their granules. Colocalization of these markers can be viewed in the merged image where the overlapping areas appear yellow. The construction of these cells is described in Kunder et al (60×/1.40 NA, oil objective). (B) A resting MC (left) and a compound 48/80-activated mast cell (right), both obtained from rat peritoneal lavage, and stained with toluidine blue (60×/1.40 NA oil objective). (C) An activated, rat peritoneal MC stained with avidin to show the granules, some of which have diffused away from the cell after release as discrete particles. Confocal images were acquired using a Nikon Eclipse TE200 microscope and EZ-4 Version 3.6 software. Bright field images were captured using a Nikon Eclipse TE200 microscope and a Nikon Coolpix 4500 camera. Additional image processing was performed using Adobe Photoshop Version 9.

Figure 3

Local effect of MCs on the vasculature during acute inflammation. In this diagram, activated MCs release inflammatory mediators, which then induce changes along vascular endothelium. Some of these mediators directly act on ECs and smooth muscle cells to promote vasodilation and vascular leakiness. In addition, vascular ECs up-regulate many adhesion molecules and release WPBs to promote the rolling and extravasation of leukocytes into the inflamed tissue. Concurrently, increased vascular leakiness promotes the loss of fluid and blood proteins into the tissue, or edema. Additional MC-derived mediators can limit clotting and these responses cumulatively act to increase vascular flow through the site of inflammation. Presumably, the compromised barrier function of the vascular ECs would also facilitate the dissemination of MC products systemically.