Differential expression of inflammatory cytokines and chemokines in lipopolysaccharide‐stimulated melanocytes from lightly and darkly pigmented skin

Abstract

Increasing evidence suggests that human epidermal melanocytes play an important role in the skin immune system; however, a role of their pigmentation in immune and inflammatory responses is poorly examined. In the study, the expression of Toll‐like receptor 4 (TLR4) and inflammatory cytokines and chemokines by cultured normal melanocytes derived from lightly and darkly pigmented skin was investigated after cell stimulation with lipopolysaccharide (LPS). The basal TLR4 mRNA level in heavily pigmented cells was higher as compared to their lightly pigmented counterparts. Melanocyte exposure to LPS upregulated the expression of TLR4 mRNA and enhanced the DNA‐binding activity of NF‐κB p50 and p65. We found substantial differences in the LPS‐stimulated expression of numerous genes encoding inflammatory cytokines and chemokines between the cells with various melanin contents. In lightly pigmented melanocytes, the most significantly upregulated genes were nicotinamide phosphoribosyltransferase (NAMPT/visfatin), the chemokines CCL2 and CCL20, and IL6, while the genes for CXCL12, IL‐16 and the chemokine receptor CCR4 were the most significantly upregulated in heavily pigmented cells. Moreover, the lightly pigmented melanocytes secreted much more NAMPT, CCL2 and IL‐6. The results of our study suggest modulatory effect of melanogenesis on the immune properties of normal epidermal melanocytes.

Melanogenesis Connection with Innate Immunity and Toll-Like Receptors

“…It has been reported that the melanin pigment itself may play a role in controlling the immune response. Compared to melanocytes that contain a large amount of melanin, melanocytes containing little melanin produce a higher number of cytokines such as IL-6 and IL-10 [41,42]. l-DOPA, the intermediate product of melanin synthesis, and its oxidation products function as potent immunosuppressive agents that inhibit lymphocyte proliferation and abrogate inflammatory cytokine production by activated lymphocytes [41,42].…”

“…Compared to melanocytes that contain a large amount of melanin, melanocytes containing little melanin produce a higher number of cytokines such as IL-6 and IL-10 [41,42]. l-DOPA, the intermediate product of melanin synthesis, and its oxidation products function as potent immunosuppressive agents that inhibit lymphocyte proliferation and abrogate inflammatory cytokine production by activated lymphocytes [41,42]. Mohagheghpour et al have shown that non-toxic concentrations of synthetic melanin suppress the production of cytokines such as TNF, IL-1β, IL-6, and IL-10 by reducing the efficiency of mRNA translation [43].…”

“…In human melanocytes, Candida albicans induces pigment production via TLR4, by which melanocytes reduce the infectivity of Candida albicans [95]. Dark-colored melanocytes have higher levels of TLR4 expression and different levels of inflammatory response compared to light-colored melanocytes [41]. This suggests that the melanocyte pigment levels influence the magnitude of the inflammatory response in human skin.…”

Fostering a healthy culture: Biological relevance of in vitro and ex vivo skin models

“…This is not surprising, considering that humans and rodents are separated by an estimated 96 million years of evolution 21 . Addressing this fact, many studies are being conducted on patient‐derived primary skin cells, including human keratinocytes, 22‐25 melanocytes, 26‐30 fibroblasts 31‐34 and cell co‐cultures 35‐37 . However, typical in vitro culture conditions fail to replicate and, in fact, do not come close to imitating the biomechanical and biochemical complexity of the microenvironment in which cells exist and to which they respond to in native tissues.…”

The role of melanocytes in the human choroidal microenvironment and inflammation: Insights from the transcriptome

“…Previous reports indicated that LPS stimulation of epidermal (skin) melanocytes may increase pigmentation (Ahn et al, 2008;Tam et al, 2019). We therefore explored the expression of melanogenesis-related genes including MLANA, TYR, TYRP1 and PMEL, melanocyte-inducing transcription factor (MITF), dopachrome tautomerase (DCT) and melanocortin receptor 1 (MC1R) (reviewed by D'Mello et al, 2016), but found no differential expression of these genes after LPS stimulation (Figure 4a) and no visible change in HCM pigmentation (Figure 4b) within the timeframe of our experiments.…”