Peroxisome proliferator-activated receptor gamma inhibits the migration of dendritic cells: consequences for the immune response.
The migration of dendritic cells (DCs) from the epithelia to the lymphoid organs represents a tightly regulated multistep event involved in the induction of the immune response. In this process fatty acid derivatives positively and negatively regulate DC emigration. In the present study we investigated whether activation of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors activated by naturally occurring derivatives of arachidonic acid, could control DC migration from the peripheral sites of Ag capture to the draining lymph nodes (DLNs). First, we show that murine epidermal Langerhans cells (LCs) express PPAR gamma, but not PPAR alpha, mRNA, and protein. Using an experimental murine model of LC migration induced by TNF-alpha, we show that the highly potent PPAR gamma agonist rosiglitazone specifically impairs the departure of LCs from the epidermis. In a model of contact allergen-induced LC migration, PPAR gamma activation not only impedes LC emigration, and their subsequent accumulation as DCs in the DLNs, but also dramatically prevents the contact hypersensitivity responses after challenge. Finally, after intratracheal sensitization with an FITC-conjugated Ag, PPAR gamma activation inhibits the migration of DCs from the airway mucosa to the thoracic LNs and also profoundly reduces the priming of Ag-specific T lymphocytes in the DLNs. Our results suggest a novel regulatory pathway via PPAR gamma for DC migration from epithelia that could contribute to the initiation of immune responses.
Unité 547, Institut National de la Santé et de la Recherche Médicale, Institut Pasteur de Lille, Lille, France.
Véronique
V
Angeli
Hamida
H
Hammad
Bart
B
Staels
Monique
M
Capron
Bart N
BN
Lambrecht
François
F
Trottein
D000818:Animals; D002464:Cell Migration Inhibition; D002465:Cell Movement / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000502:physiology; D003877:Dermatitis, Contact / Q000517:prevention & control; D004817:Epidermis / Q000276:immunology / Q000378:metabolism; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000008:administration & dosage; D006241:Haptens / Q000008:administration & dosage / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007801:Langerhans Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D013909:Thorax; D014157:Transcription Factors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D016207:Cytokines; D006241:Haptens; D007166:Immunosuppressive Agents; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D010047:Ovalbumin; D016650:Fluorescein-5-isothiocyanate