Vitiligo is a depigmentary disorder that develops as a result of the progressive disappearance of epidermal melanocytes. Stress can precipitate or exacerbate a skin disease through psychosomatic mechanisms. Stress exposure induces vitiligo-like symptoms in mice, as cellular damage to melanocytes causes synthetic pigment loss. Stress also increases IL-17, IL-1β, and antimelanocyte IgG in model mouse serum. Up-regulation of the IL-1β transcript in patients suggests its possible role in autoimmune pathogenesis of vitiligo. We demonstrate that IL-17 promoted IL-1β secretion from keratinocytes. Mitochondrial dysfunction, which can induce the excessive production of reactive oxygen species (ROS), is emerging as a mechanism that underlies various inflammatory and autoimmune diseases. In this study, we demonstrate that IL-17 inhibits melanogenesis of zebrafish, normal human epidermal melanocytes, and B16F10 cells. IL-17 increased mitochondrial dysfunction and ROS accumulation, which was related to autophagy induction. Autophagy is needed for autophagic apoptosis of B16F10 cells induced by IL-17. To inhibit ROS generation, B16F10 cells were pretreated with N-acetyl-l-cysteine (NAC), which inhibited autophagy. 3-Methyladenine (3-MA) also had an inhibiting effect on autophagy. NAC or 3-MA pretreatments inhibited IL-17-mediated cell apoptosis. In summary, IL-17 induces the cellular stress microenvironment in melanocytes to promote autophagic cell apoptosis in vitiligo.-Zhou, J., An, X., Dong, J., Wang, Y., Zhong, H., Duan, L., Ling, J., Ping, F., Shang, J. IL-17 induces cellular stress microenvironment of melanocytes to promote autophagic cell apoptosis in vitiligo.

Recent evidence has established that consumption of High-fat diet (HFD)-induced obesity is associated with deficits in hippocampus-dependent memory/learning and mood states. Nevertheless the link between obesity and emotional disorders still remains to be elucidated. This issue is of particular interest during adolescence, which is important period for shaping learning/memory and mood regulation that can be sensitive to the detrimental effects of HFD. Our present study is focused to investigate behavioral and metabolic influences of short-term HFD intake in adolescent C57BL/6 mice. HFD caused weight gain, impaired glucose tolerance (IGT) and depression-like behavior as early as after 3 weeks which was clearly proved by a decrease in number of groomings in the open field test (OFT) and an increase in immobility time in the tail suspension test (TST). In the 4th week HFD induced obese model was fully developed and above behavioral symptoms were more dominant (decrease in number of crossings and groomings and increase in immobility time in both FST and TST). At the end of 6th week hippocampal analysis revealed the differences in morphology (reduced Nissl positive neurons and decreased the 5-HT receptor expression), neuronal survival (increased cleaved caspase-3 expression), synaptic plasticity (down regulation of p-CREB and BDNF), and inflammatory responses (increase in expression of pro-inflammatory cytokines and decrease in expression of anti-inflammatory cyokines) in HFD mice. Our results demonstrate that, high-fat feeding of adolescent mice could provoke "depression-like" behavior as early as 3 weeks and modulate structure, neuron survival and neuroinflammation in hippocampus as early as 6 weeks proving that adolescent age is much prone to adverse effects of HFD, which causes obesity, behavioral differences, memory and learning deficiencies.

Protoporphyrin IX (PPIX) is a heterocyclic organic compound that is the last intermediate in the heme biosynthetic pathway. PPIX, due to its photodynamic effects, is utilized in the treatment of skin diseases. Furthermore, PPIX has been utilized as a melanogenesisstimulating agent in various studies. However, the exact function and mechanism underlying PPIX action in melanocytes remain to be elucidated. In the present study, we sought to further investigate how PPIX affects melanocyte melanogenesis, and whether PPIX is involved in melanin transport. Our findings demonstrated that PPIX increased melanocyte dendricity and melanosome transport, in addition to increasing melanogenesis. PPIX functions primarily by activating the guanylate cyclase (GC) and cyclic guanosine 3', 5'-monophosphate/protein kinase G (cGMP/PKG) signaling pathways. Once activated, these pathways increase tyrosinase activity and the expression of microphthalmiaassociated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 and-2 (TRP-1 and TRP-2), myosin Va, melanophinin, Ras-related protein Rab-27A (Rab27a), and cell division cycle 42 (Cdc42), promoting melanogenesis, melanocyte dendricity, and melanosome transport. Furthermore, the melanogenic effects of PPIX were confirmed in vivo in a zebrafish model system. Our results indicate that PPIX is not cytotoxic and may, thus, be utilized as a pigmentation enhancer.

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Vitiligo is an acquired depigmentary skin inflammatory disorder. The pathogenesis of inflammatory skin disease involves the release of cytokines from keratinocytes, including interleukin (IL)-1β. IL-22 belongs to a family of cytokines structurally related to IL-10, including IL-19, IL-20, IL-24, and IL-26. In contrast to IL-10, IL-22 has proinflammatory activities. Among skin cell populations only keratinocytes are the major targets of IL-22. In the present study, we demonstrated that IL-22 promoting IL-1β secretion from keratinocytes via the Reactive oxygen species (ROS)-NOD-like receptor family, pyrin domain containing 3 (NLRP3)-caspase-1 pathway. It inhibited the expression of protease-activated receptor-2 (PAR-2) of keratinocytes. However, IL-22 had no direct effect on normal human foreskin-derived epidermal melanocytes (NHEM). Considering the closely connection between keratinocytes and melanocytes, and the ability of keratinocytes to produce a plethora of cytokines, in the present work, we examined whether IL-22 could regulate melanocytes functions by keratinocytes participation. Keratinocytes were exposed to IL-22 and the conditional medium was collected. The effect of conditional medium on melanocytes was studied. The expressions of relative proteins were assessed by western blot. Influence of conditional medium on NHEM migration was assessed by Transwell method and the apoptosis by flow cytometry analysis. The IL-22-treating keratinocytes conditional medium inhibited melanogenesis and restrained the expressions of Rab GTPases of NHEM. In addition, the conditional medium suppressed melanocytes migration and induced apoptosis. Our results collectively indicated that IL-22 may potentiate IL-1β-mediated skin inflammation and result in participating in the inflammatory pathogenesis of vitiligo.

The 5-HT2A serotonin receptor (HTR2A) has been reported to be involved in the serotonin- or serotonin receptor 2A agonist-induced melanogenesis in human melanoma cells. However, the molecular mechanisms underlying HTR2A in regulating melanogenesis remain poorly understood. In this research, cultured mouse melanoma cell line B16F10, human skin, and zebrafish embryos were used to elucidate the downstream signaling of HTR2A in regulating melanogenesis and to verify the potential application of HTR2A in the treatment of pigment-associated cutaneous diseases. We demonstrated that HTR2A antagonists (AT1015 and ketanserin) attenuated the melanogenesis induction of serotonin in both mouse melanoma cells and zebrafish embryos. The agonists of HTR2A (DOI and TCB-2) increased melanin synthesis and transfer in B16F10 cells, human skin tissue, and zebrafish embryos. Furthermore, the HTR2A agonists increased the expression of proteins related to melanosome organization and melanocyte dendrites to facilitate the melanocyte migration and melanosome transport. HTR2A antagonists and genetic knockout of zebrafish htr2aa (the homologue of mammalian HTR2A gene) were also used to clarify that HTR2A mediates serotonin and DOI in regulating melanogenesis. Finally, through small scale screening of the candidate downstream pathway, we demonstrated that HTR2A mediates the melanogenesis induction of its ligands by activating the PKA/CREB signaling pathway. In this research, we further confirmed that HTR2A is a crucial protein to mediate melanocyte function. Meanwhile, this research supports that HTR2A could be designed as a drug target for the development of chemicals to treat cutaneous diseases with melanocytes or melanogenesis abnormality.

Substance P (SP) is a candidate mediator along the brain-skin axis and can mimic the effects of stress to regulate melanogenesis. Previously, we and others have found that the regulation of SP for pigmentary function was mediated by neurokinin 1 receptor (NK1R). Emerging evidence has accumulated that psychologic stress can induce dysfunction in the cutaneous serotonin 5-hydroxytryptamine (5-HT)-5-HT1A/1B receptor system, thereby resulting in skin hypopigmentation. Moreover, NK1R and 5-HTR (except 5-HT3) belong to GPCR. The present study aimed at assessing the possible existence of NK1R-5-HTR interactions and related melanogenic functions. Western blot and PCR detection revealed that SP reduced expression of 5-HT1A receptor via the NK1 receptor. Biochemical analyses showed that NK1R and 5-HT1AR could colocalize and interact in a cell and in the skin. When the N terminus of the NK1R protein was removed NK1R surface targeting was prevented, the interaction between NK1R-5-HT1AR decreased, and the depigmentation caused by SP and WAY100635 could be rescued. Importantly, pharmaceutical coadministration of NK1R agonist (SP) and 5-HT1A antagonist (WAY100635) enhanced the NK1-5-HT1A receptor coimmunoprecipitation along with the depigmentary response. SP and WAY100635 cooperation elicited activation of a signaling cascade (the extracellular, regulated protein kinase p-JNK signaling pathway) and inhibition of p70S6K1 phosphorylation and greatly reduced melanin production in vitro and in vivo in mice and zebrafish. Moreover, the SP-induced depigmentation response did not be occur in 5-htr1aa zebrafish embryos. Taken together, the results of our systemic study increases our knowledge of the roles of NK1R and 5-HT1AR in melanogenesis and provides possible, novel therapeutic strategies for treatment of skin hypo/hyperpigmentation.-Wu, H., Zhao, Y., Huang, Q., Cai, M., Pan, Q., Fu, M., An, X., Xia, Z., Liu, M., Jin, Y., He, L., Shang, J. NK1R/5-HT1AR interaction is related to the regulation of melanogenesis.

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