Mast cells initiate lymphocyte egress from distant lymph nodes upon skin inflammation via a RANKL-sphingosine-1-phosphate axis
Katsoulis-Dimitriou, K.; Umer, W.; El-Bizri, A.; Knop, L.; Schickschneit, T.; Hoffman, A.; Schmitter, L. M.; Baumgart, K.; Jantz-Naeem, N.; Dovhan, V.; Heidelbach, C.; Philipsen, L.; Mueller, A. J.; Kahlfuss, S.; Schueler, T.; Fricke, S.; Dudeck, J.; Dudeck, A.
Show abstract
Receptor activator of NF{kappa}B ligand (RANKL) is important for bone metabolism, but also modulates immune processes. We showed that mast cells (MCs) are involved in RANKL regulation, but the importance of MC-derived RANKL in skin inflammation has not yet been investigated. In contact hypersensitivity (CHS), the absence of MC-derived RANKL led to reduced skin inflammation due to impaired leukocyte infiltration and blood lymphopenia. Surprisingly, we observed a massive hyperplasia of the distant inguinal lymph nodes in the absence of MC-RANKL. Using adoptive transfers, flow cytometry and whole-mount 3D imaging, we demonstrated that this was not caused by structural maladaptation, but rather by the inability of lymphocytes to exit in a timely manner. Importantly, RANKL deletion in skin MCs only replicated the effect of LN hyperplasia and blood lymphopenia. Moreover, MCs were involved in serum sphingosine-1-phosphate (S1P) regulation during sensitization and challenge. Intravascular administration of S1P restored timely lymphocyte egress, demonstrating a MC-induced organ-spanning RANKL-S1P axis. Consequently, peripheral skin MC-derived RANKL is essential for the timely lymphocyte egress from distant LNs, which may have important implications for the targeted treatment of inflammatory skin diseases.
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