Systemic FasL and TRAIL Neutralisation Reduce Leishmaniasis Induced Skin Ulceration

Abstract

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.

Epidermal Th22 and Tc17 Cells Form a Localized Disease Memory in Clinically Healed Psoriasis

“…Epidermis was cut and incubated in trypsin (0.025%)/EDTA (0.01%) (Life Technologies) for 15 min, and single-cell suspension was prepared by pipetting. Dermis was incubated in collagenase III (3 mg/ml; Worthington) for 90 min with DNAse (5 mg/ml) in 10% FBS RPMI 1640 medium and further processed by Medicon tissue disruptor (BD Biosciences) as described previously (17). For cytokine stimulation and CD103, CCR6 and IL-23R staining epidermis was treated with collagenase, and for IL-23R staining, the samples were incubated 18 h prior to staining.…”

Chronic Gastrointestinal Nematode Infection Mutes Immune Responses to Mycobacterial Infection Distal to the Gut

“…To determine the burden of Leishmania parasites, tissue homogenates were prepared as previously described (25) and cultured in limiting dilutions in 96-well plates using M199 medium supplemented with 20% FCS, 2 mM L-glutamine, 100 U/ml penicillin, and 200 mM streptomycin.…”

Activity of synthetic chalcones in hamsters experimentally infected with Leishmania (Viannia) braziliensis

“…Similarly, the reduction of apoptosis of cells of the epidermis and dermis in the lesion leads to a reduction of tissue damage and ulceration, which makes research on apoptosis in leishmaniasis extremely important to improve disease pathology (Eidsmo et al 2005;Tasew et al 2010;WHO 2010). The identification of apoptosis by TUNEL staining in the lesions showed a decrease in apoptosis of cells of the dermis and epidermis in animals treated with chalcone 2 intraperitoneally and amphotericin B at 16 and 18 weeks PI compared with the control group.…”