Pivotal roles of the parasite PGD₂ synthase and of the host D prostanoid receptor 1 in schistosome immune evasion

Abstract

Prostaglandins (PG) are important modulators of immune and inflammatory responses. We recently demonstrated that the production of PGD 2 by the helminthic parasite Schistosoma mansoni inhibits the migration of epidermal Langerhans cells (LC) to the draining lymph nodes (DLN). Here, we identify the responsible parasite enzyme as being a 28-kDa glutathione-S-transferase (termed Sm28GST). Intradermal injection of Sm28GST in wildtype (WT), but not in D prostanoid receptor (DP) 1-deficient mice abrogates the departure of LC from the epidermis after TNF- § or FITC treatment. During infection, DP1 deficiency restores LC migration, but does not enhance the rate of T cell proliferation in the skin DLN. However, relative to WT mice, DLN cells from DP1-deficient infected mice produce dramatically less IFN-+ and IL-10, but equal amount of IL-4. Interestingly, infected DP1-deficient mice develop a more Th2-biased humoral immune response, a significantly reduced parasitemia and a decreased egg-induced inflammatory response in the liver and intestines. Taken together, we propose that DP1 activation by the Sm28GST-derived PGD 2 could represent a strategy for the schistosome to evade host immune defenses. We also suggest that DP1 is important in the Th1/Th2 balance of the immune response and in inflammatory reactions during infection.

Helminth Antigens Modulate TLR-Initiated Dendritic Cell Activation

“…Strikingly, as is the case for SEA, some of these ligands additionally augment TLR-initiated IL-10 production. In this vein, it was reported that larval schistosomes, and therefore perhaps schistosome eggs, produce PGD 2 , which significantly inhibits DC activation (28). Finally, we have also considered the possibility that SEA contains a molecule that is capable of interacting with Fc␥R, because the effects of SEA on LPS-stimulated DC are reminiscent of the modulatory effects of Fc␥R ligation on macrophage activation (29,30).…”

International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress

“…They further showed that this retention can be mimicked by administration of a DP 1 agonist, BW 245C, during local TNF-␣ treatment and that the retention of LCs in the skin by S. mansoni infection or by BW 245C was impaired in DP 1 -deficient PROSTAGLANDIN RECEPTORS mice. In DP 1 -deficient mice, LCs migrated to draining lymph nodes and triggered a Th2 response (Hervé et al, 2003). Such inhibitory modulation of dendritic cell (DC) function by DP stimulation is also found in DCs in the lung.…”

Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination intwitcher

“…It augments vascular permeability (Flower et al, 1976), chemotaxis (Hirai et al, 2001), and antigen presentation (Herve et al, 2003), inhibits platelet aggregation (Whittle et al, 1978), and induces vasodilatation and bronchoconstriction (Wasserman et al, 1980). Hematopoietic PGD synthase (HPGDS) is responsible for the production of PGD 2 , including that linked to immune and inflammatory responses (Kanaoka and Urade, 2003).…”