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.
Cancer Gene Therapy Unit, Cancer Immunotherapy and Gene Therapy Program, Scientific Institute H. San Raffaele, Milan, Italy.
Eduardo J
EJ
Villablanca
Dan
D
Zhou
Barbara
B
Valentinis
Aurora
A
Negro
Laura
L
Raccosta
Laura
L
Mauri
Alessandro
A
Prinetti
Sandro
S
Sonnino
Claudio
C
Bordignon
Catia
C
Traversari
Vincenzo
V
Russo
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