The Alpha-Melanocyte-Stimulating Hormone Suppresses TLR2-Mediated Functional Responses through IRAK-M in Normal Human Keratinocytes

Abstract

Alpha-melanocyte stimulating hormone (α-MSH) is a highly conserved 13-aa neuropeptide derived from pro-opiomelanocortin by post-translational processing, which has been reported to exhibit potent anti-inflammatory activity and a wide range of immunosuppressive activities in the skin. However, the regulatory effect of α-MSH is not completely clear in cutaneous innate immunity. In this study, we investigate the functional regulation of α-MSH in TLR2-mediated inflammatory responses in normal human keratinocytes (HKs). α-MSH pretreatment down-regulated the Staphylococcus aureus LTA-induced expression of both TLR2 and IL-8 as well as NF-κB nuclear translocation in HK cells. The inhibitory effect of α-MSH was blocked by agouti signaling protein (ASP), an α-MSH receptor-1 antagonist. To investigate the mechanism of this response in more detail, siRNA of IRAK-M, a negative regulator of TLR signaling, was utilized in these studies. The α-MSH suppressive effect on IL-8 production and NF-κB transactivation was inhibited by IRAK-M siRNA transfection in HK cells. These results indicate that α-MSH is capable of suppressing keratinocyte TLR2-mediated inflammatory responses induced by S. aureus-LTA, thus demonstrating another novel immunomodulatory activity of α-MSH in normal human keratinocytes.

Differential cell composition and split epidermal differentiation in human palm, sole, and hip skin

“…This striking enrichment of immune-related genes in hip skin likely accounts for the propensity for many inflammatory skin diseases in non-palmoplantar skin compared with palmoplantar skin. Cluster 3 genes include immune cell-specific markers such as CD3D and CD79A , indicating a higher proportion of immune cells in hip skin, as well as immune-related genes that are expressed by skin tissue cells; these include factors such as TLR2 , involved in innate immune responses, 19 and CCL27 , which drives immune cell recruitment. 20 Cluster 3 also includes genes such as hair keratins KRT31 , KRT74 , and KRT85 related to differences in adnexal structures across the sites, as well as melanocyte markers MLANA , TYR , and TYRP1 and Langerhans cell markers CD1A and CD207 (langerin), corresponding to cell types that are more abundant in non-palmoplantar skin.…”

Resolution pharmacology and the treatment of infectious diseases

“…Several derived peptides and analogue molecules of α ‐MSH have shown effectiveness against E. coli , methicillin‐resistant S. aureus (MRSA) and S. aureus (please refer to Table S1 for specific references). In terms of the molecule's pro‐resolutive effects, research has found that α ‐MSH treatment leads to a decrease in the phagocytosis of unopsonized E. coli and S. aureus , inhibition of nitric oxide (NO) production by RAW 264.7 cells, downregulation of TLR2 expression induced by S. aureus , and a reduction in IL‐6 levels while mitigating fever induced by LPS in rats (Huang et al, 1998; Phan & Taylor, 2013; Ryu et al, 2015; Star et al, 1995). In a mouse peritonitis model, administration of the agonist AP214 (modimelanotide) prior to zymosan injection inhibited cell infiltration via MC3R.…”

Resolution pharmacology and the treatment of infectious diseases.

“…In terms of the molecule's pro-resolutive effects, research has found that α-MSH treatment leads to a decrease in the phagocytosis of unopsonizedE. coli and S. aureus , inhibition of NO production by RAW 264.7 cells, downregulation of TLR2 expression induced by S. aureus , and a reduction in IL-6 levels while mitigating fever induced by LPS in rats (Phan and Taylor, 2013;Star et al, 1995;Ryu et al, 2015;Huang and et al, 1998). In a mouse peritonitis model, administration of the agonist AP214 prior to zymosan injection inhibited cell infiltration via MC3R.…”