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

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

doi:10.1172/JCI84518

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

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

Pediatrics - Genetics and Metabolism

Research output: Contribution to journal › Article › peer-review

72 Scopus citations

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 Irf4^fl/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.

Original language	English (US)
Pages (from-to)	1581-1591
Number of pages	11
Journal	Journal of Clinical Investigation
Volume	126
Issue number	4
DOIs	https://doi.org/10.1172/JCI84518
State	Published - Apr 1 2016

Bibliographical note

Funding Information:
This work was supported by NIH R21 AG046734, R01 AI 049653, Pioneer Award DP1DK109668, and an Innovator Award from the Rainin Foundation (to G.J. Randolph); NIH HL120867 to (M.J. Davis); ERC Advanced Grant GA-322645-Lymphatics-Homing (to R. Förster); NIH R01 HL088554 (to B.E. Isakson); NIH K99 HL124142 and 5T32DK7296 (to J.P. Scallan); and award no. 00056835 from the Fondation de France to (E.L. Gautier).

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Ivanov, S., Scallan, J. P., Kim, K. W., Werth, K., Johnson, M. W., Saunders, B. T., Wang, P. L., Kuan, E. L., Straub, A. C., Ouhachi, M., Weinstein, E. G., Williams, J. W., Briseño, C., Colonna, M., Isakson, B. E., Gautier, E. L., Förster, R., Davis, M. J., Zinselmeyer, B. H., & Randolph, G. J. (2016). CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability. Journal of Clinical Investigation, 126(4), 1581-1591. https://doi.org/10.1172/JCI84518

Ivanov, S, Scallan, JP, Kim, KW, Werth, K, Johnson, MW, Saunders, BT, Wang, PL, Kuan, EL, Straub, AC, Ouhachi, M, Weinstein, EG, Williams, JW, Briseño, C, Colonna, M, Isakson, BE, Gautier, EL, Förster, R, Davis, MJ, Zinselmeyer, BH & Randolph, GJ 2016, 'CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability', Journal of Clinical Investigation, vol. 126, no. 4, pp. 1581-1591. https://doi.org/10.1172/JCI84518

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title = "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.",

author = "Stoyan Ivanov and Scallan, {Joshua P.} and Kim, {Ki Wook} and Kathrin Werth and Johnson, {Michael W.} and Saunders, {Brian T.} and Wang, {Peter L.} and Kuan, {Emma L.} and Straub, {Adam C.} and Melissa Ouhachi and Weinstein, {Erica G.} and Williams, {Jesse W.} and Carlos Brise{\~n}o and Marco Colonna and Isakson, {Brant E.} and Gautier, {Emmanuel L.} and Reinhold F{\"o}rster and Davis, {Michael J.} and Zinselmeyer, {Bernd H.} and Randolph, {Gwendalyn J.}",

note = "Funding Information: This work was supported by NIH R21 AG046734, R01 AI 049653, Pioneer Award DP1DK109668, and an Innovator Award from the Rainin Foundation (to G.J. Randolph); NIH HL120867 to (M.J. Davis); ERC Advanced Grant GA-322645-Lymphatics-Homing (to R. F{\"o}rster); NIH R01 HL088554 (to B.E. Isakson); NIH K99 HL124142 and 5T32DK7296 (to J.P. Scallan); and award no. 00056835 from the Fondation de France to (E.L. Gautier).",

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AU - Ivanov, Stoyan

AU - Scallan, Joshua P.

AU - Kim, Ki Wook

AU - Werth, Kathrin

AU - Johnson, Michael W.

AU - Saunders, Brian T.

AU - Wang, Peter L.

AU - Kuan, Emma L.

AU - Straub, Adam C.

AU - Ouhachi, Melissa

AU - Weinstein, Erica G.

AU - Williams, Jesse W.

AU - Briseño, Carlos

AU - Colonna, Marco

AU - Isakson, Brant E.

AU - Gautier, Emmanuel L.

AU - Förster, Reinhold

AU - Davis, Michael J.

AU - Zinselmeyer, Bernd H.

AU - Randolph, Gwendalyn J.

N1 - Funding Information: This work was supported by NIH R21 AG046734, R01 AI 049653, Pioneer Award DP1DK109668, and an Innovator Award from the Rainin Foundation (to G.J. Randolph); NIH HL120867 to (M.J. Davis); ERC Advanced Grant GA-322645-Lymphatics-Homing (to R. Förster); NIH R01 HL088554 (to B.E. Isakson); NIH K99 HL124142 and 5T32DK7296 (to J.P. Scallan); and award no. 00056835 from the Fondation de France to (E.L. Gautier).

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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.

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

Abstract

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