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.
View: Text | PDF
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

×

Figure 7

Analysis of the role of IRF4-dependent DCs in lymphatic transport and permeability.

Options: View larger image (or click on image) Download as PowerPoint
Analysis of the role of IRF4-dependent DCs in lymphatic transport and pe...
(A) Measurement of lymphatic collecting vessel permeability taken from mesenteric and popliteal adipose tissue of control (Ctrl; Irf4fl/fl) and Irf4ΔDC (CD11c-Cre Irf4fl/fl) mice (n = 4–5 mice per genotype, mean ± SEM). (B) 1 μl of Cy5-conjugated dextran (70 kDa) was injected in the ear pinnae of anesthetized mice, and the decrease of fluorescence intensity associated with its transport from the initial site of deposition was assessed using a fluorescence stereoscope (n = 7 mice per genotype, mean ± SEM). (C) 2-Photon intravital analysis of adventitial wall thickness, assessed through measurement of second harmonic signal, around lymphatic collecting vessels in control and Irf4-deficient mice (Irf4–/– or Cd11c-Cre Irf4fl/fl). Eight mice per genotype were examined at multiple areas along the lymphatic collecting vessels, with multiple videos made in different areas per mouse. Each data point represents the mean of 1 mouse after blind scoring of 6 to 12 Z-stacks per mouse. For statistical evaluation, data in A and B were assessed using the Mann-Whitney U test. **P < 0.01; ***P < 0.001. Data in C were assessed using 1-way ANOVA, Tukey’s post hoc test.