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 4

Lymphatic transport and permeability in CCR7-deficient mouse strains.

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Lymphatic transport and permeability in CCR7-deficient mouse strains. (A...
(A) 1 μl of Cy5-conjugated dextran (70 kDa) was injected in the ear pinnae of anesthetized mice (5 to 10 weeks old), and the decrease of fluorescence intensity associated with its transport from the initial site of deposition was assessed using a fluorescence stereoscope (n = 12 WT, 7 Ccr7–/– mice, mean ± SEM). (B) Measurement of lymphatic collecting vessel permeability from mesenteric and popliteal adipose tissue in WT and Ccr7–/– mice (n = 5 WT and 8 Ccr7–/– mice combined from 2 independent experiments with mice at 10 to 12 weeks of age, mean ± SEM). (C) Measurement of the lymphatic collecting vessel permeability in 5-week-old WT and Ccr7–/– mice (n = 5 WT and 7 Ccr7–/– mice, mean ± SEM). (D) 2-Photon intravital analysis of adventitial wall thickness, assessed through measurement of second harmonic signal, around lymphatic collecting vessels in mice in which the human CCR7 gene has been used to disrupt the mouse Ccr7 locus (CCR7stop/stop) or mice in which human CCR7 is expressed selectively on CD4+ T cells (T-Ccr7+/+) or CD11c+ DCs (DC-Ccr7+/+). In control mice, the Ccr7 gene is not disrupted (Total-Ccr7–/–). Six mice per genotype were examined at multiple areas along the lymphatic collecting vessels. Each data point represents the mean wall thickness of 1 mouse after blind scoring of 9 Z-stacks per mouse. For statistical evaluation, data in A–C were assessed using the Mann-Whitney U test and data in D employed 1-way ANOVA test, with Tukey’s post hoc test. *P < 0.05; **P < 0.01.