Role of the Parasite-Derived Prostaglandin D2 in the Inhibition of Epidermal Langerhans Cell Migration during Schistosomiasis Infection

Abstract

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.

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

“…During murine schistosomiasis, parasite-derived eicosanoids may play important roles in the cutaneous immune response [15,28]. Immunolabeling with highly specific Ab indicated that Sm28GST is massively excreted in the epidermis of infected mice ( Fig.…”

“…Since DP1 activation appears to be important in the control of LC motility in vivo [15], WT or DP1 KO mice were i.d. injected with rSm28GST before TNF- § treatment, and LC density was determined (Fig.…”

“…been shown to synthesize PGD 2 that in turn may modulate the host inflammatory and immune responses [13,14]. During murine schistosomiasis, we recently demonstrated that the production of PGD 2 by the skin stage of Schistosoma mansoni inhibits the migration of epidermal Langerhans cells (LC) and the subsequent accumulation of DC in the draining lymph nodes (DLN) [15]. However, the enzyme responsible for this biological effect was not identified.…”

Prostaglandin D2 affects the differentiation and functions of human dendritic cells: impact on the T cell response

“…We have reported that PGD 2 inhibits the migration of maturing DC via DP1 [9,14,15] whereas it increases the chemokinetic activity of DC precursors through DP2 [11]. Moreover, PGD 2 profoundly modulates the immunoregulatory capacity of DC via DP1 [11,16].…”

“…In addition to the genetic background, it is likely that the tissue environment also determines the capacity of DC to induce Th2 responses consecutively to allergen exposure. For instance, among the main mediators released early during the allergic reaction, histamine and PGD 2 are important for DC functions [8][9][10][11].…”