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.
Bibliographical noteFunding 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).