Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration.
Cutaneous leishmaniasis (CL) is caused by Leishmania infection of dermal macrophages and is associated with chronic inflammation of the skin. L. aethiopica infection displays two clinical manifestations, firstly ulcerative disease, correlated to a relatively low parasite load in the skin, and second...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-01-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | http://europepmc.org/articles/PMC2953481?pdf=render |
| _version_ | 1819129414141607936 |
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| author | Geremew Tasew Susanne Nylén Thorsten Lieke Befekadu Lemu Hailu Meless Nicolas Ruffin Dawit Wolday Abraham Asseffa Hideo Yagita Sven Britton Hannah Akuffo Francesca Chiodi Liv Eidsmo |
| author_facet | Geremew Tasew Susanne Nylén Thorsten Lieke Befekadu Lemu Hailu Meless Nicolas Ruffin Dawit Wolday Abraham Asseffa Hideo Yagita Sven Britton Hannah Akuffo Francesca Chiodi Liv Eidsmo |
| author_sort | Geremew Tasew |
| collection | DOAJ |
| description | Cutaneous leishmaniasis (CL) is caused by Leishmania infection of dermal macrophages and is associated with chronic inflammation of the skin. L. aethiopica infection displays two clinical manifestations, firstly ulcerative disease, correlated to a relatively low parasite load in the skin, and secondly non-ulcerative disease in which massive parasite infiltration of the dermis occurs in the absence of ulceration of epidermis. Skin ulceration is linked to a vigorous local inflammatory response within the skin towards infected macrophages. Fas ligand (FasL) and Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expressing cells are present in dermis in ulcerative CL and both death ligands cause apoptosis of keratinocytes in the context of Leishmania infection. In the present report we show a differential expression of FasL and TRAIL in ulcerative and non-ulcerative disease caused by L. aethiopica. In vitro experiments confirmed direct FasL- and TRAIL-induced killing of human keratinocytes in the context of Leishmania-induced inflammatory microenvironment. Systemic neutralisation of FasL and TRAIL reduced ulceration in a model of murine Leishmania infection with no effect on parasitic loads or dissemination. Interestingly, FasL neutralisation reduced neutrophil infiltration into the skin during established infection, suggesting an additional proinflammatory role of FasL in addition to direct keratinocyte killing in the context of parasite-induced skin inflammation. FasL signalling resulting in recruitment of activated neutrophils into dermis may lead to destruction of the basal membrane and thus allow direct FasL mediated killing of exposed keratinocytes in vivo. Based on our results we suggest that therapeutic inhibition of FasL and TRAIL could limit skin pathology during CL. |
| first_indexed | 2024-12-22T08:43:20Z |
| format | Article |
| id | doaj.art-95283ef4731c4cb098c92a31621b17de |
| institution | Directory Open Access Journal |
| issn | 1935-2735 |
| language | English |
| last_indexed | 2024-12-22T08:43:20Z |
| publishDate | 2010-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-95283ef4731c4cb098c92a31621b17de2022-12-21T18:32:10ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27352010-01-01410e84410.1371/journal.pntd.0000844Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration.Geremew TasewSusanne NylénThorsten LiekeBefekadu LemuHailu MelessNicolas RuffinDawit WoldayAbraham AsseffaHideo YagitaSven BrittonHannah AkuffoFrancesca ChiodiLiv EidsmoCutaneous leishmaniasis (CL) is caused by Leishmania infection of dermal macrophages and is associated with chronic inflammation of the skin. L. aethiopica infection displays two clinical manifestations, firstly ulcerative disease, correlated to a relatively low parasite load in the skin, and secondly non-ulcerative disease in which massive parasite infiltration of the dermis occurs in the absence of ulceration of epidermis. Skin ulceration is linked to a vigorous local inflammatory response within the skin towards infected macrophages. Fas ligand (FasL) and Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expressing cells are present in dermis in ulcerative CL and both death ligands cause apoptosis of keratinocytes in the context of Leishmania infection. In the present report we show a differential expression of FasL and TRAIL in ulcerative and non-ulcerative disease caused by L. aethiopica. In vitro experiments confirmed direct FasL- and TRAIL-induced killing of human keratinocytes in the context of Leishmania-induced inflammatory microenvironment. Systemic neutralisation of FasL and TRAIL reduced ulceration in a model of murine Leishmania infection with no effect on parasitic loads or dissemination. Interestingly, FasL neutralisation reduced neutrophil infiltration into the skin during established infection, suggesting an additional proinflammatory role of FasL in addition to direct keratinocyte killing in the context of parasite-induced skin inflammation. FasL signalling resulting in recruitment of activated neutrophils into dermis may lead to destruction of the basal membrane and thus allow direct FasL mediated killing of exposed keratinocytes in vivo. Based on our results we suggest that therapeutic inhibition of FasL and TRAIL could limit skin pathology during CL.http://europepmc.org/articles/PMC2953481?pdf=render |
| spellingShingle | Geremew Tasew Susanne Nylén Thorsten Lieke Befekadu Lemu Hailu Meless Nicolas Ruffin Dawit Wolday Abraham Asseffa Hideo Yagita Sven Britton Hannah Akuffo Francesca Chiodi Liv Eidsmo Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration. PLoS Neglected Tropical Diseases |
| title | Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration. |
| title_full | Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration. |
| title_fullStr | Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration. |
| title_full_unstemmed | Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration. |
| title_short | Systemic FasL and TRAIL neutralisation reduce leishmaniasis induced skin ulceration. |
| title_sort | systemic fasl and trail neutralisation reduce leishmaniasis induced skin ulceration |
| url | http://europepmc.org/articles/PMC2953481?pdf=render |
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