CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability
Stoyan Ivanov, … , Bernd H. Zinselmeyer, Gwendalyn J. Randolph
Stoyan Ivanov, … , Bernd H. Zinselmeyer, Gwendalyn J. Randolph
Published March 21, 2016
Citation Information: J Clin Invest. 2016;126(4):1581-1591. https://doi.org/10.1172/JCI84518.
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Research Article Vascular biology

CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability

Abstract

Lymphatic collecting vessels direct lymph into and from lymph nodes (LNs) and can become hyperpermeable as the result of a previous infection. Enhanced permeability has been implicated in compromised immunity due to reduced flow of lymph and immune cells to LNs, which are the primary site of antigen presentation to T cells. Presently, very little is known about the molecular signals that affect lymphatic collecting vessel permeability. Here, we have shown that lymphatic collecting vessel permeability is controlled by CCR7 and that the chronic hyperpermeability of collecting vessels observed in Ccr7–/– mice is followed by vessel fibrosis. Reexpression of CCR7 in DCs, however, was sufficient to reverse the development of such fibrosis. IFN regulatory factor 4–positive (IRF4+) DCs constitutively interacted with collecting lymphatics, and selective ablation of this DC subset in Cd11c-Cre Irf4fl/fl mice also rendered lymphatic collecting vessels hyperpermeable and fibrotic. Together, our data reveal that CCR7 plays multifaceted roles in regulating collecting vessel permeability and fibrosis, with one of the key players being IRF4-dependent DCs.

Authors

Stoyan Ivanov, Joshua P. Scallan, Ki-Wook Kim, Kathrin Werth, Michael W. Johnson, Brian T. Saunders, Peter L. Wang, Emma L. Kuan, Adam C. Straub, Melissa Ouhachi, Erica G. Weinstein, Jesse W. Williams, Carlos Briseño, Marco Colonna, Brant E. Isakson, Emmanuel L. Gautier, Reinhold Förster, Michael J. Davis, Bernd H. Zinselmeyer, Gwendalyn J. Randolph

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Figure 3

Electron micrographs of lymphatic collecting vessels within afferent s.c. adipose tissue near the brachial LNs from Ccr7+/+ or Ccr7–/– mice.

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Electron micrographs of lymphatic collecting vessels within afferent s.c...
Lymphatic collecting vessels afferent to the brachial LNs of 12-week-old Ccr7+/+ (A, B, and E) or Ccr7–/– (C, D, and F) mice were examined by transmission electron microscopy. Lumens of the collecting vessels are marked with asterisks, and representative fibroblasts (portions of their long and thin cytoplasmic projections), adipocytes, and mast cells (MC) are also labeled. Lymphatic endothelial cells are not labeled, but correspond with the cell type nearest the lumen marked with an asterisk. Matrix accumulation along the ablumenal or adventitial surface of the endothelium is relatively scarce in Ccr7+/+ samples (A and B), but far more evident in Ccr7–/– tissues (C and D). In C, this matrix is observed between the lymphatic lumen and the adipocyte in the lower surface of the panel. In D, the field of extracellular matrix occupies the vast majority of the image. In E and F, representative fibrils of collagen are labeled with arrowheads. Scale bars: 10 microns (A and C); 5 microns (B and D); 1 micron (E and F). Six mice per genotype were examined over the course of 2 independent experiments.