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• W2017009423 abstract "It is well established that hyperkeratosis, acanthosis, and sprouting of peripheral nerve branches of sensory fibres occur in the epidermis of inflamed skin [[1]Mihm Jr., M.C. Soter N.A. Dvorak H.F. Austen K.F. The structure of normal skin and the morphology of atopic eczema.J Invest Dermatol. 1976; 67: 305-312Abstract Full Text PDF PubMed Scopus (318) Google Scholar]. Nerve growth factor (NGF) is thought to play an important role in this mechanism as its expression increases both in keratinocytes and cutaneous innervation in the epidermis of inflamed skin [[2]Dou Y.C. Hagstromer L. Emtestam L. Johansson O. Increased nerve growth factor and its receptors in atopic dermatitis.Arch Dermatol Res. 2006; 298: 31-37Crossref PubMed Scopus (110) Google Scholar]. Furthermore, we have established that NGF and its low affinity receptor, p75, induce hyperkeratosis, acanthosis, and sprouting of sensory fibres in the epidermis [[3]Taniguchi M. Matsuzaki S. Tohyama M. P75 plays a key role in the induction of the sprouting of sensory nerve fibers in inflamed skin.J Invest Dermatol. 2007; 127: 2062-2065Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. Recently, we found that hyperkeratosis and acanthosis in sodium lauryl sulphate (SLS: a detergent used to irritate the skin and induce inflammation)-stimulated skin were markedly inhibited in neuropsin KO mice [[4]Shingaki K. Matsuzaki S. Taniguchi M. Kubo T. Fujiwara T. Kanazawa S. et al.Molecular mechanism of kallikrein-related peptidase 8/neuropsin-induced hyperkeratosis in inflamed skin.Br J Dermatol. 2010; 163: 466-475Crossref PubMed Scopus (11) Google Scholar]. In addition, we have elucidated the downstream pathway of neuropsin and its human homologue, kallikrein-related peptidase 8 (KLK8) [[4]Shingaki K. Matsuzaki S. Taniguchi M. Kubo T. Fujiwara T. Kanazawa S. et al.Molecular mechanism of kallikrein-related peptidase 8/neuropsin-induced hyperkeratosis in inflamed skin.Br J Dermatol. 2010; 163: 466-475Crossref PubMed Scopus (11) Google Scholar]. The findings, i.e., both NGF and neuropsin/KLK8 are involved in hyperkeratosis and acanthosis in inflamed skin strongly suggest a close relationship between the NGF and neuropsin/KLK8 pathways. Thus, we hypothesised that NGF and neuropsin/KLK8 pathways would stimulate each other to cause hyperkeratosis and acanthosis in inflamed skin. The present study provides evidence that neuropsin/KLK8 and NGF are mutual enhancers of expression. Quantitative real-time PCR analysis revealed that neuropsin expression in the epidermis of p75 KO mice was significantly lower than that found in the wild-type (WT) C57BL/6 mice (Fig. 1A CTR). Furthermore, a marked increase of neuropsin mRNA was detected in the epidermis of WT mice at 48 h after SLS treatment (Fig. 1A cf. black bars). However, such upregulation of neuropsin mRNA after SLS treatment was dramatically inhibited in p75 KO mice (Fig. 1A SLS). Subsequent immunohistochemistry confirmed these results at the protein level. SLS treatment on the WT mice skin increased neuropsin protein expression, particularly in the spinous layer (Fig. 1B). However, such upregulation of neuropsin protein in the SLS-treated p75 KO mice skin could not be confirmed (Fig. 1B). Moreover, acanthosis and hyperkeratosis determined in the WT mice skin were markedly inhibited in p75 KO mice (Fig. 1B), as we previously described [[3]Taniguchi M. Matsuzaki S. Tohyama M. P75 plays a key role in the induction of the sprouting of sensory nerve fibers in inflamed skin.J Invest Dermatol. 2007; 127: 2062-2065Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar]. On the other hand, quantitative real-time PCR analysis showed that NGF mRNA expression was inhibited in the epidermis of neuropsin KO mice compared with WT C57BL/6 mice (Fig. 2A) . In the neuropsin KO mice, there was a 76% inhibition of NGF mRNA expression in the epidermis compared to that in WT mice (Fig. 2A). In accordance with the results of real-time PCR analysis, NGF expression after SLS treatment was much lower in the epidermis of neuropsin KO mice (Fig. 2B) than in WT mice (Fig. 2B). Furthermore, SLS treatment on neuropsin KO mice skin showed reduced acanthosis and hyperkeratosis compared to WT mice (Fig. 2B). To confirm the in vivo finding, we performed in vitro experiments using human keratinocyte–HaCaT cells that express endogenous KLK8, a human homologue of neuropsin. HaCaT cells were transfected with siRNA to KLK8 or control siRNA. Quantitative real-time PCR analysis showed that decrease in KLK8 in the HaCaT cells caused a 96% decrease in KLK8 at 72 h after transfection with siRNA compared to control siRNA (Fig. 2C). NGF expression in these KLK8 siRNA-transfected cells decreased to 79% (Fig. 2D). Additionally, an application of recombinant human KLK8 to the medium of the reconstructed human epidermis model upregulated NGF mRNA expression 2-fold compared with the PBS-treated epidermis model (Fig. 2E). These findings show that neuropsin/KLK8 accelerates NGF expression both in vivo and in vitro. These findings have shown that the NGF and neuropsin/KLK8 pathways activate each other to promote hyperkeratosis and acanthosis more effectively. Two possible mechanisms could be responsible: direct and indirect effects of neuropsin/KLK8 on NGF expression. Because neuropsin/KLK8 is a serine protease, it may be involved in processing of pro-NGF, and increased neuropsin from inflammatory stimulation produces NGF from pro-NGF by cleaving pro-NGF. Another mechanism for enhancing NGF expression might be an indirect mechanism. In this study, stronger influence of neuropsin/KLK8 on NGF expression has been determined in stratified cells than in cells in monolayer culture (Figs. 2A, D and E). Furthermore, it has been demonstrated that neuropsin released from presynaptic sites cuts an adherent molecule, L1, depending on the activation of the NMDA receptor in hippocampus [[5]Matumoto-Miyai K. Ninomiya A. Yamasaki H. Tamura H. Nakamura Y. Shiosaka S. NMDA-dependent proteolysis of presynaptic adhesion molecule L1 in the hippocampus by neuropsin.J Neurosci. 2003; 23: 7727-7736Crossref PubMed Google Scholar]. Therefore, it is likely that the neuropsin/KLK8 released in the epidermis regulates NGF expression by activating adhesion molecules of the epidermis and neuroactivator receptors. In recent studies, it has been suggested that both NGF and KLK are involved in innate immune response. Namely, NGF induces innate immune receptor, toll-like receptor (TLR), overexpression in conjunctival epithelial cells [[6]Micera A. Stampachiacchiere B. Normando E.M. Lambiase A. Bonini S. Bonini S. Nerve growth factor modulates toll-like receptor (TLR) 4 and 9 expression in cultured primary VKC conjunctival epithelial cells.Mol Vis. 2009; 15: 2037-2044PubMed Google Scholar] and TLR signalling increases the expression of KLK to produce antimicrobial peptides via enhanced intracellular Ca influx in keratinocytes [[7]Yamasaki K. Kanada K. Macleod D.T. Borkowski A.W. Morizane S. Nakatsuji T. et al.TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes.J Invest Dermatol. 2011; 131: 688-697Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar]. Consequently, up-regulation of neuropsin/KLK8 expression via NGF pathway in inflamed skin might be involved in activation of TLR. The close relationship among KLK, NGF and innate immune receptor may play an important role that induce essential responses to external stimulus rapidly and definitely in inflamed skin. The NGF intracellular transduction pathway has been well established in nervous system. NGF stimulates neurite outgrowth from embryonic neurons [[8]Roux P.P. Barker P.A. Neurotrophin signaling through the p75 neurotrophin receptor.Prog Neurobiol. 2002; 67: 203-233Crossref PubMed Scopus (602) Google Scholar]. These effects have been accounted for by p75-mediated modulation of Rho-activity [[8]Roux P.P. Barker P.A. Neurotrophin signaling through the p75 neurotrophin receptor.Prog Neurobiol. 2002; 67: 203-233Crossref PubMed Scopus (602) Google Scholar]. Additionally, it has been shown that the p75 receptor acts as a displacement factor that releases Rho from Rho-guanine nucleotide dissociation inhibitor (Rho-GDI) [[9]Yamashita T. Tohyama M. The p75 receptor acts as a displacement factor that releases Rho from Rho-GDI.Nat Neurosci. 2003; 6: 461-467Crossref PubMed Scopus (398) Google Scholar]. In addition to Rho, several signalling molecules have been shown to exist downstream of p75, e.g., JNK (c-Jun amino-terminal kinase)-p53, Rac, ceramide, nuclear factor-κB (NF-κB), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3-kinase (PI3K) [[8]Roux P.P. Barker P.A. Neurotrophin signaling through the p75 neurotrophin receptor.Prog Neurobiol. 2002; 67: 203-233Crossref PubMed Scopus (602) Google Scholar]. Therefore, it is probable that the downstream molecules of these pathways regulate the neuropsin/KLK8 gene. In conclusion, NGF-p75 and neuropsin/KLK8 pathways may cooperate in regulation of epidermal homeostasis in inflamed skin. As NGF and neuropsin/KLK8 pathways have been reported to be involved in many skin diseases such as atopic dermatitis and psoriasis [2Dou Y.C. Hagstromer L. Emtestam L. Johansson O. Increased nerve growth factor and its receptors in atopic dermatitis.Arch Dermatol Res. 2006; 298: 31-37Crossref PubMed Scopus (110) Google Scholar, 4Shingaki K. Matsuzaki S. Taniguchi M. Kubo T. Fujiwara T. Kanazawa S. et al.Molecular mechanism of kallikrein-related peptidase 8/neuropsin-induced hyperkeratosis in inflamed skin.Br J Dermatol. 2010; 163: 466-475Crossref PubMed Scopus (11) Google Scholar, 10Komatsu N. Saijoh K. Toyama T. Ohka R. Otsuki N. Hussack G. et al.Multiple tissue kallikrein mRNA and protein expression in normal skin and skin diseases.Br J Dermatol. 2005; 153: 274-281Crossref PubMed Scopus (123) Google Scholar], downregulation of NGF or neuropsin/KLK8 pathway via inactivation of the other pathway could be a novel therapy for these diseases. The 21st Century COE project and Health Science Research Grants from the Ministry of Health Science, Welfare, and Labour of Japan supported this study." @default.
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• W2017009423 title "NGF-p75 and neuropsin/KLK8 pathways stimulate each other to cause hyperkeratosis and acanthosis in inflamed skin" @default.
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