Epidermal Langerhans cells (LCs) play a key role in immune defense mechanisms and in numerous immunological disorders. In this report, we show that percutaneous infection of C57BL/6 mice with the helminth parasite Schistosoma mansoni leads to the activation of LCs but, surprisingly, to their retention in the epidermis. Moreover, using an experimental model of LC migration induced by tumor necrosis factor (TNF)-α, we show that parasites transiently impair the departure of LCs from the epidermis and their subsequent accumulation as dendritic cells in the draining lymph nodes. The inhibitory effect is mediated by soluble lipophilic factors released by the parasites and not by host-derived antiinflammatory cytokines, such as interleukin-10. We find that prostaglandin (PG)D2, but not the other major eicosanoids produced by the parasites, specifically impedes the TNF-α–triggered migration of LCs through the adenylate cyclase–coupled PGD2 receptor (DP receptor). Moreover, the potent DP receptor antagonist BW A868C restores LC migration in infected mice. Finally, in a model of contact allergen-induced LC migration, we show that activation of the DP receptor not only inhibits LC emigration but also dramatically reduces the contact hypersensitivity responses after challenge. Taken together, we propose that the inhibition of LC migration could represent an additional stratagem for the schistosomes to escape the host immune system and that PGD2 may play a key role in the control of cutaneous immune responses.

Allergic pathologies are often associated with IgE production, mast cell activation, and eosinophilia. PGD2 is the major eicosanoid, among several inflammatory mediators, released by mast cells. PGD2 binds to two membrane receptors, D prostanoid receptor (DP)1 and DP2, endowed with antagonistic properties. In humans, DP2 is preferentially expressed on type 2 lymphocytes, eosinophils, and basophils and mediates chemotaxis in vitro. Although not yet supported by in vivo studies, DP2 is thought to be important in the promotion of Th2-related inflammation. Herein, we demonstrate that mouse eosinophils express both DP1 and DP2 and that PGD2 exerts in vitro chemotactic effects on eosinophils through DP2 activation. Furthermore, 13,14-dihydro-15-keto-PGD2, a specific DP2 agonist not only increases eosinophil recruitment at inflammatory sites but also the pathology in two in vivo models of allergic inflammation: atopic dermatitis and allergic asthma. By contrast, DP1 activation tends to ameliorate the pathology in asthma. Taken together, these results support the hypothesis that DP2 might play a critical role in allergic diseases and underline the interest of DP2 antagonists in human therapy.

Among the factors produced at inflammatory sites and those capable of modulating dendritic cell (DC) functions, PGD2 may be important in the outcome of immune responses. The biological roles for PGD2 are in part effected through two plasma membrane G protein-coupled receptors: the D prostanoid (DP) receptor and the chemoattractant receptor-homologous molecule expressed on Th2 lymphocytes (CRTH2). In this report, we studied the effects of PGD2 and of its major physiological metabolite, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2), on the functions of human monocyte-derived DC. First, we show that PGD2 exerts in vitro chemotactic effects on monocytes via CRTH2 activation while it inhibits the chemokine-driven migration of monocyte-derived DC through DP. We also report that PGD2 and 15d-PGJ2 alter the LPS- and allergen-induced DC maturation and enhance the CD80/CD86 ratio on mature DC in a DP- and CRTH2-independent manner. Moreover, PGD2 and 15d-PGJ2 strongly reduce the secretion of the Th1 promoting cytokine IL-12 and affect the synthesis of chemokines involved in Th1 cell chemotaxis, particularly CXCL10. Inhibition of cytokine/chemokine secretion implicates at least in part DP, but not CRTH2. The effects exerted by PGD2 are associated with the phosphorylation of CREB, but do not parallel with the deactivation of the NF-κB and mitogen-activated protein kinase pathways. In contrast, 15d-PGJ2 seems to target other cellular proteins. Finally, in a model of Th CD45RA+ differentiation induced by allergen- and superantigen-pulsed DC, PGD2 impacts on the orientation of the immune response by favoring a Th2 response.

Dendritic cells (DCs) are professional APCs able to initiate innate and adaptive immune responses against invading pathogens. Different properties such as the efficient Ag processing machinery, the high levels of expression of costimulatory molecules and peptide-MHC complexes, and the production of cytokines contribute in making DCs potent stimulators of naive T cell responses. Recently we have observed that DCs are able to produce IL-2 following bacterial stimulation, and we have demonstrated that this particular cytokine is a key molecule conferring to early bacterial activated DCs unique T cell priming capacity. In the present study we show that many different microbial stimuli, but not inflammatory cytokines, are able to stimulate DCs to produce IL-2, indicating that DCs can distinguish a cytokine-mediated inflammatory process from the actual presence of an infection. The capacity to produce IL-2 following a microbial stimuli encounter is a feature shared by diverse DC subtypes in vivo, such as CD8α+ and CD8α− splenic DCs and epidermal Langerhans cells. When early activated DCs interact with T cells, IL-2 produced by DCs is enriched at the site of cell-cell contact, confirming the importance of DCs-derived IL-2 in T cell activation.

Peroxisome proliferator-activated receptors (PPARs) are activated by an array of polyunsaturated fatty acid derivatives, oxidized fatty acids, and phospholipids and are proposed to be important modulators of immune and inflammatory responses. Recently, we showed that activation of PPAR-gamma alters the maturation process of dendritic cells (DCs), the most potent antigen-presenting cells. In the present report, we investigated the possibility that, by targeting DCs, PPAR-gamma activation may be involved in the regulation of the pulmonary immune response to allergens. Using a model of sensitization, based on the intratracheal transfer of ovalbumin (OVA)-pulsed DCs, we show that rosiglitazone, a selective PPAR-gamma agonist, reduces the proliferation of Ag-specific T cells in the draining mediastinal lymph nodes but, surprisingly enough, dramatically increases the production of the immunoregulatory cytokine interleukin (IL)-10 by T cells, as compared to control mice sensitized with OVA-pulsed DCs. After aerosol challenge, the recruitment of eosinophils in the bronchoalveolar lavage fluids was strongly reduced compared to control mice. Finally, T cells from the mediastinal lymph nodes produced higher amounts of IL-10 and interferon-gamma. Inhibition of IL-10 activity with anti-IL-10R antibodies partly restored the inflammation. The specificity of the phenomenon was confirmed by treating OVA-pulsed DCs with ciglitazone, another PPAR-gamma agonist, and by using GW9662, a PPAR-gamma antagonist. Our data suggest that PPAR-gamma activation prevents induction of Th2-dependent eosinophilic airway inflammation and might contribute to immune homeostasis in the lung.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily. They are divided into three subtypes (K K, L L or N N, and Q Q) and are involved in lipid and glucose homeostasis and in the control of inflammation. In this study, we analyzed the expression of PPARs in murine dendritic cells (DCs), the most potent antigen presenting cells. We find that immature as well as mature spleen-derived DCs express PPARQ Q, but not PPARK K, mRNA and protein. We also show that the PPARQ Q activator rosiglitazone does not interfere with the maturation of DCs in vitro nor modifies their ability to activate naive T lymphocytes in vivo. Finally, we present evidence that PPARQ Q activators down-modulate the CD40-induced secretion of interleukin-12, a potent Th1-driving factor. These data suggest a possible role for PPARQ Q in the regulation of immune responses. ß

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The mobilization of Langerhans cells (LCs) from epithelia to the draining lymph nodes is an essential process to initiate primary immune responses. We have recently shown that in mice, PGD2 is a potent inhibitor of epidermal LC emigration. In this study, we demonstrate that activation of the D prostanoid receptor 1 (DP1) impedes the TNF-alpha-induced migration of human LCs from skin explants and strongly inhibits the chemotactic responses of human LC precursors and of maturing LCs to CC chemokine ligands 20 and 19, respectively. Using a murine model of atopic dermatitis, a chronic Th2-type allergic inflammatory disease, we demonstrate that the potent DP1 agonist BW245C dramatically decreases the Ag-specific T cell activation in the skin draining lymph nodes and markedly prevents the skin lesions following repeated epicutaneous sensitization with OVA. Interestingly, analysis of the local response indicates that BW245C treatment strongly reduces the recruitment of inflammatory cells into the dermis and disrupts the Th1/Th2 balance, probably through the increased production of the immunoregulatory cytokine IL-10, in the skin of sensitized mice. Taken together, our results suggest a new function for DP1 in the regulation of the immune and inflammatory responses. We propose that DP1 activation by specific agonists may represent a strategy to control cutaneous inflammatory Th2-associated diseases.