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 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.
Ethiopian Health and Nutrition Research Institute, Parasitology Laboratory, Addis Ababa, Ethiopia.
Geremew
G
Tasew
Susanne
S
Nylén
Thorsten
T
Lieke
Befekadu
B
Lemu
Hailu
H
Meless
Nicolas
N
Ruffin
Dawit
D
Wolday
Abraham
A
Asseffa
Hideo
H
Yagita
Sven
S
Britton
Hannah
H
Akuffo
Francesca
F
Chiodi
Liv
L
Eidsmo
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015603:Keratinocytes / Q000502:physiology; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000276:immunology; D012883:Skin Ulcer / Q000473:pathology* / Q000517:prevention & control*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse