Peroxisome proliferator-activated receptor γ 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 PPARgamma, but not PPARalpha, mRNA, and protein. Using an experimental murine model of LC migration induced by TNF-alpha, we show that the highly potent PPARgamma agonist rosiglitazone specifically impairs the departure of LCs from the epidermis. In a model of contact allergen-induced LC migration, PPARgamma 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, PPARgamma 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 PPARgamma for DC migration from epithelia that could contribute to the initiation of immune responses.