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Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection.

Angeli V, Faveeuw C, Roye O, Fontaine J, Teissier E, Capron A, Wolowczuk I, Capron M, Trottein F - J. Exp. Med. (2001)

Bottom Line: The inhibitory effect is mediated by soluble lipophilic factors released by the parasites and not by host-derived antiinflammatory cytokines, such as interleukin-10.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.

View Article: PubMed Central - PubMed

Affiliation: Centre d'Immunologie et de Biologie Parasitaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U547, Lille, France.

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)-alpha, 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-alpha-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.

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(A) RT-PCR analysis of mRNAs specific for pro- and antiinflammatory cytokines in the epidermis of S. mansoni–infected mice. Epidermal sheets were prepared from noninfected (0 h) or infected (1, 6, 24, and 120 h) mice, total RNA extracted, and RT-PCR was carried out using the primers shown in Table . Representative results of three independent experiments are shown. (B) Role of IL-10 in the inhibition of LC migration. IL-10 KO or WT mice were infected (or not) and 24 h after infection, epidermal sheets were prepared and the number of LCs/mm2 determined by immunohistochemistry. Before infection, WT mice were treated with neutralizing anti–IL-10 or isotype-matched mAbs (IgG1). As a positive control, TNF-α was intradermally injected 1 h before the analysis. Significant differences are designated by * (P < 0.001).
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Figure 4: (A) RT-PCR analysis of mRNAs specific for pro- and antiinflammatory cytokines in the epidermis of S. mansoni–infected mice. Epidermal sheets were prepared from noninfected (0 h) or infected (1, 6, 24, and 120 h) mice, total RNA extracted, and RT-PCR was carried out using the primers shown in Table . Representative results of three independent experiments are shown. (B) Role of IL-10 in the inhibition of LC migration. IL-10 KO or WT mice were infected (or not) and 24 h after infection, epidermal sheets were prepared and the number of LCs/mm2 determined by immunohistochemistry. Before infection, WT mice were treated with neutralizing anti–IL-10 or isotype-matched mAbs (IgG1). As a positive control, TNF-α was intradermally injected 1 h before the analysis. Significant differences are designated by * (P < 0.001).

Mentions: To determine the mechanism by which S. mansoni inhibits LC migration, we first investigated by reverse transcription (RT)-PCR the presence of mRNAs for cytokines known to control LC mobility at various times after infection (1 to 120 h). As shown in Fig. 4 A, compared with noninfected mice (0 h), we observed a rapid and sustained increase in TNF-α and IL-1β mRNA levels in the epidermis of infected mice suggesting that the signals required for LC departure may be present. We then tested the hypothesis that the observed inhibitory effect could be associated with the expression of antiinflammatory cytokines. Interestingly, we detected a marked up-regulation of IL-10 mRNA, particularly between 6 and 24 h after infection. In contrast, we found that infection did not significantly affect the basal level of IL-1ra mRNA expression. In infected mice, the level of IL-4 mRNA increased progressively between 1 to 120 h after infection and this change was accompanied by a gradual decrease in mRNA levels of TNFR-II, but not by a total disappearance of the signal, in infected mice. Altogether, based on recent findings 17, our data suggest that IL-10 might be involved in the control of LC migration after S. mansoni infection. To test this hypothesis, IL-10 KO mice were infected and the density of LCs on epidermal sheets was assessed by immunohistochemistry 24 h after infection. As shown in Fig. 4 B, the number of LC/mm2 was identical in the epidermis of noninfected and infected IL-10–deficient mice, whereas TNF-α dramatically depleted the population of LCs by >60%. It is worth mentioning that in IL-10 KO mice, LCs exhibited an activated phenotype after parasite infection. Similar results were obtained in WT mice by using anti–IL-10 neutralizing mAbs injected intradermally before infection (Fig. 4 B). These data indicate that the inhibition of LC migration in S. mansoni–infected skin probably involve other factors than antiinflammatory host-derived cytokines.


Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection.

Angeli V, Faveeuw C, Roye O, Fontaine J, Teissier E, Capron A, Wolowczuk I, Capron M, Trottein F - J. Exp. Med. (2001)

(A) RT-PCR analysis of mRNAs specific for pro- and antiinflammatory cytokines in the epidermis of S. mansoni–infected mice. Epidermal sheets were prepared from noninfected (0 h) or infected (1, 6, 24, and 120 h) mice, total RNA extracted, and RT-PCR was carried out using the primers shown in Table . Representative results of three independent experiments are shown. (B) Role of IL-10 in the inhibition of LC migration. IL-10 KO or WT mice were infected (or not) and 24 h after infection, epidermal sheets were prepared and the number of LCs/mm2 determined by immunohistochemistry. Before infection, WT mice were treated with neutralizing anti–IL-10 or isotype-matched mAbs (IgG1). As a positive control, TNF-α was intradermally injected 1 h before the analysis. Significant differences are designated by * (P < 0.001).
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Related In: Results  -  Collection

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Figure 4: (A) RT-PCR analysis of mRNAs specific for pro- and antiinflammatory cytokines in the epidermis of S. mansoni–infected mice. Epidermal sheets were prepared from noninfected (0 h) or infected (1, 6, 24, and 120 h) mice, total RNA extracted, and RT-PCR was carried out using the primers shown in Table . Representative results of three independent experiments are shown. (B) Role of IL-10 in the inhibition of LC migration. IL-10 KO or WT mice were infected (or not) and 24 h after infection, epidermal sheets were prepared and the number of LCs/mm2 determined by immunohistochemistry. Before infection, WT mice were treated with neutralizing anti–IL-10 or isotype-matched mAbs (IgG1). As a positive control, TNF-α was intradermally injected 1 h before the analysis. Significant differences are designated by * (P < 0.001).
Mentions: To determine the mechanism by which S. mansoni inhibits LC migration, we first investigated by reverse transcription (RT)-PCR the presence of mRNAs for cytokines known to control LC mobility at various times after infection (1 to 120 h). As shown in Fig. 4 A, compared with noninfected mice (0 h), we observed a rapid and sustained increase in TNF-α and IL-1β mRNA levels in the epidermis of infected mice suggesting that the signals required for LC departure may be present. We then tested the hypothesis that the observed inhibitory effect could be associated with the expression of antiinflammatory cytokines. Interestingly, we detected a marked up-regulation of IL-10 mRNA, particularly between 6 and 24 h after infection. In contrast, we found that infection did not significantly affect the basal level of IL-1ra mRNA expression. In infected mice, the level of IL-4 mRNA increased progressively between 1 to 120 h after infection and this change was accompanied by a gradual decrease in mRNA levels of TNFR-II, but not by a total disappearance of the signal, in infected mice. Altogether, based on recent findings 17, our data suggest that IL-10 might be involved in the control of LC migration after S. mansoni infection. To test this hypothesis, IL-10 KO mice were infected and the density of LCs on epidermal sheets was assessed by immunohistochemistry 24 h after infection. As shown in Fig. 4 B, the number of LC/mm2 was identical in the epidermis of noninfected and infected IL-10–deficient mice, whereas TNF-α dramatically depleted the population of LCs by >60%. It is worth mentioning that in IL-10 KO mice, LCs exhibited an activated phenotype after parasite infection. Similar results were obtained in WT mice by using anti–IL-10 neutralizing mAbs injected intradermally before infection (Fig. 4 B). These data indicate that the inhibition of LC migration in S. mansoni–infected skin probably involve other factors than antiinflammatory host-derived cytokines.

Bottom Line: The inhibitory effect is mediated by soluble lipophilic factors released by the parasites and not by host-derived antiinflammatory cytokines, such as interleukin-10.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.

View Article: PubMed Central - PubMed

Affiliation: Centre d'Immunologie et de Biologie Parasitaire, Institut National de la Santé et de la Recherche Médicale (INSERM) U547, Lille, France.

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)-alpha, 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-alpha-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.

Show MeSH
Related in: MedlinePlus