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 1

CCR7-mediated interactions of DCs with lymphatic collecting vessels outside of LNs.

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CCR7-mediated interactions of DCs with lymphatic collecting vessels outs...
(A) Whole-mount preparation of brachial adipose tissue containing the brachial LNs with CCL21 staining shown in white. DyLight 594–conjugated lectin (red) was injected s.c. to visualize the draining lymphatic vasculature, and DyLight 488–conjugated lectin was i.v. administered in order to map the blood vasculature. White inset is placed around the major lymphatic collecting vessel afferent to the brachial LNs and shown at greater magnification on the right. (B) Contact area between DCs and lymphatic collecting vessels in Cd11c-YFP Ccr7+/+ and Cd11c-YFP Ccr7–/– mice was quantified from single videos prepared during 2-photon intravital imaging, as described in Methods (see also Supplemental Video 2). Each data point represents analysis of 1 Z-stack, with 5 to 7 Z-stacks examined per mouse. Other measurements assessed from these videos were mean DC velocity (C), meandering index (D), and motility coefficient (E). From 4 to 5 mice per genotype were examined, with multiple areas along the lymphatic collecting vessel analyzed per mouse. For C–E, each data point represents tracking from an individual cell, with 7 to 10 cells tracked from 4 to 5 mice per genotype. In C–E, each mouse is plotted using a distinct symbol shape. Mann-Whitney U tests were performed for assessment of statistical significance. **P < 0.01; ***P < 0.001.