Selected natural and synthetic retinoids impair CCR7- and CXCR4-dependent cell migration in vitro and in vivo.
Dendritic cell (DC) migration to secondary lymphoid organs is a crucial step to initiate adaptive immune responses. This step requires the expression of a functional CCR7 chemokine receptor on DC undergoing maturation. Here, we show that the natural retinoid 9-cis retinoic acid (9cRA) and the synthetic retinoid fenretinide (4-HPR) specifically inhibit the functional up-regulation of CCR7 on maturing human DCs, without affecting early steps of DC maturation. As a consequence, mature DCs do not migrate in vitro toward the chemokine CCL19. Importantly, 4-HPR and 9cRA by inhibiting the expression of CCR7 on bone marrow-derived murine DCs dampen their in vivo migration to draining lymph nodes. 4-HPR also inhibits the expression of the chemokine receptors CXCR4, therefore, impairing in vitro migration of human DCs to CXCL12 and inhibiting in vivo the CXCR4-dependent migration of the posterior lateral line primordium (PLLp) in zebrafish embryos. Taken together, these data highlight a novel function of retinoids and suggest the possibility of using retinoids to treat inflammatory or autoimmune diseases.
Villablanca
Eduardo J
EJ
Cancer Gene Therapy Unit, Cancer Immunotherapy and Gene Therapy Program, Scientific Institute H. San Raffaele, Milan, Italy.
Zhou
Dan
D
Valentinis
Barbara
B
Negro
Aurora
A
Raccosta
Laura
L
Mauri
Laura
L
Prinetti
Alessandro
A
Sonnino
Sandro
S
Bordignon
Claudio
C
Traversari
Catia
C
Russo
Vincenzo
V
D000077556:Alitretinoin; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D017313:Fenretinide / Q000494:pharmacology*; D005434:Flow Cytometry; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054400:Receptors, CCR7 / Q000502:physiology*; D019718:Receptors, CXCR4 / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology*; D015027:Zebrafish / Q000502:physiology; D029961:Zebrafish Proteins / Q000502:physiology*
C578779:Ccr7 protein, zebrafish; D054377:Chemokine CXCL12; D015850:Interleukin-6; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D029961:Zebrafish Proteins; D017313:Fenretinide; D000077556:Alitretinoin; D014212:Tretinoin