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- W2078892072 abstract "hyaluronate hyaluronate synthase 3 Eczema is one the most common skin diseases. At the histopathological level, epidermal spongiosis is the hallmark of eczema. In spongiosis, keratinocytes lose cohesiveness with a decreased expression of cadherins, as a water influx into the epidermal intercellular spaces occurs together with an accumulation of hyaluronate (HA; Ohtani et al., 2009Ohtani T. Memezawa A. Okuyama R. et al.Increased hyaluronan production and decreased E-cadherin expression by cytokine-stimulated keratinocytes lead to spongiosis formation.J Invest Dermatol. 2009; 129: 1412-1420Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). This observation is in agreement with recent reports in which increased HA production and hyaluronate synthase 3 (HAS3) expression was shown to be associated with inflammation in epithelia, as a result of a positive regulation by inflammatory cytokines in vitro and in vivo (Sayo et al., 2002Sayo T. Sugiyama Y. Takahashi Y. et al.Hyaluronan synthase 3 regulates hyaluronan synthesis in cultured human keratinocytes.J Invest Dermatol. 2002; 118: 43-48Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar; Ohtani et al., 2009Ohtani T. Memezawa A. Okuyama R. et al.Increased hyaluronan production and decreased E-cadherin expression by cytokine-stimulated keratinocytes lead to spongiosis formation.J Invest Dermatol. 2009; 129: 1412-1420Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar; Chow et al., 2010Chow G. Tauler J. Mulshine J.L. Cytokines and growth factors stimulate hyaluronan production: role of hyaluronan in epithelial to mesenchymal-like transition in non-small cell lung cancer.J Biomed Biotechnol. 2010; 2010: 485468Crossref PubMed Scopus (43) Google Scholar; Mack et al., 2011Mack J.A. Feldman R.J. Itano N. et al.Enhanced inflammation and accelerated wound closure following tetraphorbol ester application or full-thickness wounding in mice lacking hyaluronan synthases Has1 and Has3.J Invest Dermatol. 2011Google Scholar). In epidermis, HA is naturally present in the intercellular spaces (Tammi et al., 2005Tammi R. Pasonen-Seppanen S. Kolehmainen E. et al.Hyaluronan synthase induction and hyaluronan accumulation in mouse epidermis following skin injury.J Invest Dermatol. 2005; 124: 898-905Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Among the three known HAS variants, HAS3 is the most evident one in epidermis (Tien and Spicer, 2005Tien J.Y. Spicer A.P. Three vertebrate hyaluronan synthases are expressed during mouse development in distinct spatial and temporal patterns.Dev Dyn. 2005; 233: 130-141Crossref PubMed Scopus (76) Google Scholar; Ohtani et al., 2009Ohtani T. Memezawa A. Okuyama R. et al.Increased hyaluronan production and decreased E-cadherin expression by cytokine-stimulated keratinocytes lead to spongiosis formation.J Invest Dermatol. 2009; 129: 1412-1420Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar; Mack et al., 2011Mack J.A. Feldman R.J. Itano N. et al.Enhanced inflammation and accelerated wound closure following tetraphorbol ester application or full-thickness wounding in mice lacking hyaluronan synthases Has1 and Has3.J Invest Dermatol. 2011Google Scholar). Although several recent data point out HAS3 as a possible key factor in inflammatory processes, its expression pattern at the protein level remains unclear in normal human epidermis (Bai et al., 2005Bai K.J. Spicer A.P. Mascarenhas M.M. et al.The role of hyaluronan synthase 3 in ventilator-induced lung injury.Am J Respir Crit Care Med. 2005; 172: 92-98Crossref PubMed Scopus (102) Google Scholar; Mack et al., 2011Mack J.A. Feldman R.J. Itano N. et al.Enhanced inflammation and accelerated wound closure following tetraphorbol ester application or full-thickness wounding in mice lacking hyaluronan synthases Has1 and Has3.J Invest Dermatol. 2011Google Scholar). In this study we explored the expression of HAS3, HA and its major cell surface receptor, CD44, by immunohistochemistry. We stained paraffin-embedded skin sections of seven spongiotic lesions and seven healthy donors for CD44 and HA. All spongiotic lesions showed a stronger CD44 expression and an accumulation of HA when compared with healthy skin (Figure 1). Whereas eight other cryopreserved spongiotic lesions were stained for HAS3. The HAS3 staining in normal skin revealed a weak but detectable spotty signal at the intercellular junctions. This staining pattern fits well with the known membrane localization of HAS3, as this enzyme extrudes the newly synthesized HA through the cytoplasmic membrane (Itano and Kimata, 2002Itano N. Kimata K. Mammalian hyaluronan synthases.IUBMB Life. 2002; 54: 195-199Crossref PubMed Scopus (305) Google Scholar; Rilla et al., 2005Rilla K. Siiskonen H. Spicer A.P. et al.Plasma membrane residence of hyaluronan synthase is coupled to its enzymatic activity.J Biol Chem. 2005; 280: 31890-31897Crossref PubMed Scopus (87) Google Scholar). In normal epidermis, HAS3 seemed to be expressed in all the layers with a weaker or absent signal in the basal layer, and a stronger signal in the suprabasal layers. This expression pattern is very similar to the one of HA and CD44. In spongiotic epidermis, the HAS3 signal was clearly increased in all spongiotic lesions with spots significantly larger in the suprabasal layers when compared with normal skin (Figure 2).Figure 2Hyaluronate synthase 3 (HAS3) expression is increased in spongiotic epidermis. Cryosections of healthy (a) and spongiotic (b) epidermis were stained for HAS3 (rabbit polyclonal antibody, sc-66917, Santa Cruz Biotechnology, Santa Cruz, CA). An anti-rabbit secondary antibody conjugated with Alexa Fluor 488 dye (Molecular Probes, Life Technologies, Paisley, UK) was used to visualize HAS3. Bar=70μM.View Large Image Figure ViewerDownload (PPT) These results show the unreported expression pattern of HAS3 in normal human epidermis and confirm that HAS3 is strongly induced during inflammation, as recently shown in mouse models (Mack et al., 2011Mack J.A. Feldman R.J. Itano N. et al.Enhanced inflammation and accelerated wound closure following tetraphorbol ester application or full-thickness wounding in mice lacking hyaluronan synthases Has1 and Has3.J Invest Dermatol. 2011Google Scholar). However, although HAS3 is the most evident HAS variant in the epidermis, any role of HAS1 and HAS2 in human epidermal inflammation still remains to be investigated (Sayo et al., 2002Sayo T. Sugiyama Y. Takahashi Y. et al.Hyaluronan synthase 3 regulates hyaluronan synthesis in cultured human keratinocytes.J Invest Dermatol. 2002; 118: 43-48Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar; Ohtani et al., 2009Ohtani T. Memezawa A. Okuyama R. et al.Increased hyaluronan production and decreased E-cadherin expression by cytokine-stimulated keratinocytes lead to spongiosis formation.J Invest Dermatol. 2009; 129: 1412-1420Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). HAS3 probably has a specific role in human epidermis and in epidermal inflammation. Its expression pattern shows a stronger signal in the suprabasal layers, suggesting that HAS3 may be one of the key factors in the keratinocyte terminal differentiation. In spongiosis, HAS3 expression was already shown to be increased but only by in situ hybridization detecting the HAS3 RNA (Ohtani et al., 2009Ohtani T. Memezawa A. Okuyama R. et al.Increased hyaluronan production and decreased E-cadherin expression by cytokine-stimulated keratinocytes lead to spongiosis formation.J Invest Dermatol. 2009; 129: 1412-1420Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar). Here we confirm that the expression of the HAS3 protein is also significantly increased in spongiosis. We also found a strong HA accumulation and a strong CD44 expression in spongiotic epidermis, a result consistent with such an increased HAS3 expression. HA accumulation has been shown to be associated with a stronger expression of CD44 (Kaya et al., 2005Kaya G. Grand D. Hotz R. et al.Upregulation of CD44 and hyaluronate synthases by topical retinoids in mouse skin.J Invest Dermatol. 2005; 124: 284-287Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, Kaya et al., 2006Kaya G. Tran C. Sorg O. et al.Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism.PLoS Med. 2006; 3: e493Crossref PubMed Scopus (102) Google Scholar; Barnes et al., 2010Barnes L. Tran C. Sorg O. et al.Synergistic effect of hyaluronate fragments in retinaldehyde-induced skin hyperplasia which is a Cd44-dependent phenomenon.PLoS One. 2010; 5: e14372Crossref PubMed Scopus (34) Google Scholar). It seems that increased CD44 expression is necessary as a feedback mechanism to uptake the excess of HA in tissue (Culty et al., 1992Culty M. Nguyen H.A. Underhill C.B. The hyaluronan receptor (CD44) participates in the uptake and degradation of hyaluronan.J Cell Biol. 1992; 116: 1055-1062Crossref PubMed Scopus (352) Google Scholar; Kaya et al., 1997Kaya G. Rodriguez I. Jorcano J.L. et al.Selective suppression of CD44 in keratinocytes of mice bearing an antisense CD44 transgene driven by a tissue-specific promoter disrupts hyaluronate metabolism in the skin and impairs keratinocyte proliferation.Genes Dev. 1997; 11: 996-1007Crossref PubMed Scopus (219) Google Scholar). This HA uptake is probably crucial for the resolution of inflammation, as shown in lung models (Teder et al., 2002Teder P. Vandivier R.W. Jiang D. et al.Resolution of lung inflammation by CD44.Science. 2002; 296: 155-158Crossref PubMed Scopus (571) Google Scholar). This HA accumulation may obviously explain a water influx into the epidermal intercellular spaces due to the high water-retention properties of this polysaccharide. We assume that a transcriptional activation of the has3 gene causes the increased expression of HAS3. Several lines of evidence indicate that HA production and HAS3 expression are upregulated by proinflammatory factors (Sayo et al., 2002Sayo T. Sugiyama Y. Takahashi Y. et al.Hyaluronan synthase 3 regulates hyaluronan synthesis in cultured human keratinocytes.J Invest Dermatol. 2002; 118: 43-48Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar; Bai et al., 2005Bai K.J. Spicer A.P. Mascarenhas M.M. et al.The role of hyaluronan synthase 3 in ventilator-induced lung injury.Am J Respir Crit Care Med. 2005; 172: 92-98Crossref PubMed Scopus (102) Google Scholar; Mack et al., 2011Mack J.A. Feldman R.J. Itano N. et al.Enhanced inflammation and accelerated wound closure following tetraphorbol ester application or full-thickness wounding in mice lacking hyaluronan synthases Has1 and Has3.J Invest Dermatol. 2011Google Scholar). In lung epithelia, HAS3 has also been shown to be strongly involved in the development of inflammation (Bai et al., 2005Bai K.J. Spicer A.P. Mascarenhas M.M. et al.The role of hyaluronan synthase 3 in ventilator-induced lung injury.Am J Respir Crit Care Med. 2005; 172: 92-98Crossref PubMed Scopus (102) Google Scholar). Thus, even if no direct positive regulation by proinflammatory transcription factors of has3 gene promoter has been shown to date, such a regulation is highly suspected. In total, our results demonstrate the HAS3 expression pattern in normal epidermis and in spongiosis, and underline a probable crucial role for HA in epidermal homeostasis. This work was supported by Swiss National Science Foundation grant 310030-122322 to GK and JHS." @default.
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- W2078892072 title "Increased Expression of CD44 and Hyaluronate Synthase 3 Is Associated with Accumulation of Hyaluronate in Spongiotic Epidermis" @default.
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