FasL and TRAIL Induce Epidermal Apoptosis and Skin Ulceration Upon Exposure to Leishmania major

• Published in: The American journal of pathology Vol. 170; no. 1; pp. 227 - 239
• Main Authors: Eidsmo, Liv, Fluur, Caroline, Rethi, Bence, Eriksson Ygberg, Sofia, Ruffin, Nicolas, De Milito, Angelo, Akuffo, Hannah, Chiodi, Francesca
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 2007; ASIP; American Society for Investigative Pathology
• Subjects: Animals; Apoptosis; Biological and medical sciences; Caspases - metabolism; Cells, Cultured; Fas Ligand Protein - metabolism; Humans; Investigative techniques, diagnostic techniques (general aspects); Keratinocytes - metabolism; Keratinocytes - parasitology; Keratinocytes - pathology; Leishmania major; Leishmaniasis, Cutaneous - metabolism; Leishmaniasis, Cutaneous - pathology; Macrophage Activation; Medical sciences; Medicin och hälsovetenskap; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Regular; Signal Transduction; Skin Ulcer - metabolism; Skin Ulcer - parasitology; Skin Ulcer - pathology; TNF-Related Apoptosis-Inducing Ligand - metabolism; Kinetoplastida; Protozoa; Fas ligand; Cytokine; Exposure; Anatomic pathology; Tumor necrosis factor; Cell death; TNF related apoptosis inducing ligand; Skin; Ulceration; Apoptosis; Leishmania major
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2007.060068

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.