title: FasL and TRAIL induce epidermal apoptosis and skin ulceration upon exposure to Leishmania major.
abstract: Receptor-mediated apoptosis is proposed as an important regulator of keratinocyte homeostasis in human epidermis. We have previously reported that Fas/FasL interactions in epidermis are altered during cutaneous leishmaniasis (CL) and that keratinocyte death through apoptosis may play a pathogenic role for skin ulceration. To further investigate the alterations of apoptosis during CL, a keratinocyte cell line (HaCaT) and primary human epidermal keratinocytes were incubated with supernatants from Leishmania major-infected peripheral blood mononuclear cells. An apoptosis-specific microarray was used to assess mRNA expression in HaCaT cells exposed to supernatants derived from L. major-infected cultures. Fas and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mRNA and protein expression were significantly up-regulated, and apoptosis was detected in both HaCaT and human epidermal keratinocyte cells. The keratinocyte apoptosis was partly inhibited through blocking of Fas or FasL and even more efficiently through TRAIL neutralization. Up-regulation of Fas on keratinocytes in epidermis and the presence of FasL-expressing macrophages and T cells in dermis were previously reported by us. In this study, keratinocytes expressing TRAIL, as well as the proapoptotic receptor TRAIL-R2, were detected in skin biopsies from CL cases. We propose that activation of Fas and TRAIL apoptosis pathways, in the presence of inflammatory mediators at the site of infection, leads to tissue destruction and ulceration during CL.
authors.affiliation: Department of Microbiology, Karolinska Institutet, MTC, 171 77 Stockholm, Sweden. liv.eidsmo@mtc.ki.se
authors.forename: Liv
authors.initials: L
authors.lastname: Eidsmo
authors.forename: Caroline
authors.initials: C
authors.lastname: Fluur
authors.forename: Bence
authors.initials: B
authors.lastname: Rethi
authors.forename: Sofia
authors.initials: S
authors.lastname: Eriksson Ygberg
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ruffin
authors.forename: Angelo
authors.initials: A
authors.lastname: De Milito
authors.forename: Hannah
authors.initials: H
authors.lastname: Akuffo
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiodi
mesh_terms: D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D053222:Fas Ligand Protein / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D015398:Signal Transduction; D012883:Skin Ulcer / Q000378:metabolism / Q000469:parasitology / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D053222:Fas Ligand Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D020169:Caspases