Melanocytes and melanin represent a first line of innate immunity against Candida albicans

Abstract

Melanocytes are dendritic cells located in the skin and mucosae that synthesize melanin. Some infections induce hypo- or hyperpigmentation, which is associated with the activation of Toll-like receptors (TLRs), especially TLR4. Candida albicans is an opportunist pathogen that can switch between blastoconidia and hyphae forms; the latter is associated with invasion. Our objectives in this study were to ascertain whether C. albicans induces pigmentation in melanocytes and whether this process is dependent on TLR activation, as well as relating this with the antifungal activity of melanin as a first line of innate immunity against fungal infections. Normal human melanocytes were stimulated with C. albicans supernatants or with crude extracts of the blastoconidia or hyphae forms, and pigmentation and TLR2/TLR4 expression were measured. Expression of the melanosomal antigens Melan-A and gp100 was examined for any correlation with increased melanin levels or antifungal activity in melanocyte lysates. Melanosomal antigens were induced earlier than cell pigmentation, and hyphae induced stronger melanization than blastoconidia. Notably, when melanocytes were stimulated with crude extracts of C. albicans, the cell surface expression of TLR2/TLR4 began at 48 h post-stimulation and peaked at 72 h. At this time, blastoconidia induced both TLR2 and TLR4 expression, whereas hyphae only induced TLR4 expression. Taken together, these results suggest that melanocytes play a key role in innate immune responses against C. albicans infections by recognizing pathogenic forms of C. albicans via TLR4, resulting in increased melanin content and inhibition of infection.

Differential Antifungal Activity of Human and Cryptococcal Melanins with Structural Discrepancies

“…In addition, this antifungal activity against the clinical isolates, obtained from patients, was higher than the reference strains ( Figure 3 ). In previous work (Tapia et al, 2014), we demonstrated that melanin participates in a first line of the innate immune response of melanocytes stimulated with Candida extracts, by cell melanisation, which is related to the expression of Toll Like Receptor 4 (TLR4). Therefore, these results support the idea that human melanin can represent a mechanism of antimicrobial defense against fungi.…”

Skin Immunity to Candida albicans

“…Melanin has also been demonstrated to have antimicrobial properties[50]. While early studies demonstrated that C. albicans negatively regulates transcription of melanogenesis genes, more recent study has shown that melanocytes may recognize C. albicans via Toll Like Receptor 4 to increase melanization and inhibit infection (Figure 1)[51,52]. …”

“…IL-23 acts on dermal γδ T cells to drive IL-17 production in the skin, leading to anti- C. albicans resistance through the presumed activation of neutrophils and antimicrobial peptides such as β-defensins[14]. In addition, melanocytes in the basal epidermis can also recognize C. albicans via TLR-4 to drive production and release of melanin granules, which are antimicrobial in nature[52]. Finally, Langerhans cells of the epidermis can suppress liver derived CD49a+ NK cells in response to C. albicans through unknown mechanisms[73].…”

Enhanced antifungal effects of amphotericin B-TPGS-b-(PCL-ran-PGA) nanoparticles in vitro and in vivo

“…1,2 Most of these infections are caused by Candida albicans, non-albicans Candida spp., Candida tropicalis, Candida glabrata, and Candida Krusei. 3,4 Echinocandins, polyenes, pyrimidine, allylamine, and azoles are the most common antifungal agents available for the treatment of topical Candida spp. infections.…”