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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 Article has an altmetric score of 6

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

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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 6

Analysis of DC subsets in perinodal adipose tissue and LNs of Cd11c-Cre Irf4fl/fl (Irf4ΔDC) mice and Irf4fl/fl controls.

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Analysis of DC subsets in perinodal adipose tissue and LNs of Cd11c-Cre ...
(A) Gating strategy used for identification of adipose tissue DC subsets, with mesenteric adipose tissue shown after pregating on CD45+CD64+ macrophages. DCs were identified as CD45+CD64–MHC II+CD11c+ (upper panel). Further, DCs were subdivided according to their cell-surface expression of the markers CD11b and CD24 (lower panel). (B) Enumeration of the DCs in the perinodal adipose tissue around brachial LNs (n = 3 for each genotype, mean ± SEM). (C) Cellularity of the brachial LNs of control and Irf4ΔDC mice (n = 5 for each genotype, mean ± SEM). (D) Gating strategy used for identification of migratory (MHC IIhi) and resident DCs in the brachial LNs. Quantification of the populations of migratory (E) and resident (F) DCs in the brachial LNs (n = 5 for each genotype, mean ± SEM). (G) Gating strategy used for identification of DC subsets in the mesenteric LNs. DCs were pregated as MHC II+CD11c+ cells and then gated into 3 populations as shown, including CD11b+CD103+ cells, which are migratory DCs that fall between 2 resident DC subsets. (H) Quantification of the populations of DCs in the mesenteric LNs (n = 4–5 for each genotype, mean ± SEM). (I) Cellularity of the mesenteric LNs of control and Irf4ΔDC mice (n = 4–5 for each genotype, mean ± SEM). For statistical evaluation, data were assessed using the Mann-Whitney U test. *P < 0.05; **P < 0.01; ***P < 0.001. Ctrl, control.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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