Bourguignon Lilly Y W, Ramez Mohamed, Gilad Eli, Singleton Patrick A, Man Mao-Qiang, Crumrine Debra A, Elias Peter M, Feingold Kenneth R
Department of Medicine, University of California San Francisco and VA Medical Center, San Francisco, California, USA. lilly.bourguignon.ucsf.edu
J Invest Dermatol. 2006 Jun;126(6):1356-65. doi: 10.1038/sj.jid.5700260.
In this study we investigated whether hyaluronan (HA)-CD44 interaction influences epidermal structure and function. Our data show that CD44 deficiency is accompanied by reduction in HA staining in CD44 knockout (k/o) mouse skin leading to a marked thinning of epidermis versus wild-type mouse skin. A significant delay in the early barrier recovery (following acute barrier disruption) occurs in CD44 k/o versus wild-type mouse skin. To assess the basis for these alterations in CD44 k/o mouse epidermis, we determined that differentiation markers are greatly reduced in the epidermis of CD44 k/o versus wild-type mice, while conversely HA binding to CD44 triggers differentiation in cultured human keratinocytes. CD44 downregulation (using CD44 small interfering RNAs) also inhibits HA-mediated keratinocyte differentiation. Slower barrier recovery in CD44 k/o mice could be further attributed to reduced lamellar body formation, loss of apical polarization of LB secretion, and downregulation of cholesterol synthesis. Accordingly, HA-CD44 binding stimulates both LB formation and secretion. Together, these observations demonstrate new roles for HA-CD44 interaction in regulating both epidermal differentiation and lipid synthesis/secretion, which in turn influence permeability barrier homeostasis. HA-CD44 signaling could comprise a novel approach to treat skin disorders characterized by abnormalities in differentiation, lipid synthesis, and/or barrier function.
在本研究中，我们调查了透明质酸（HA）-CD44相互作用是否会影响表皮结构和功能。我们的数据表明，CD44基因敲除（k/o）小鼠皮肤中的CD44缺陷伴随着HA染色减少，导致与野生型小鼠皮肤相比表皮明显变薄。与野生型小鼠皮肤相比，CD44基因敲除小鼠皮肤在早期屏障恢复（急性屏障破坏后）方面出现显著延迟。为了评估CD44基因敲除小鼠表皮中这些改变的基础，我们确定与野生型小鼠相比，CD44基因敲除小鼠表皮中的分化标志物大大减少，而相反，HA与CD44的结合会触发培养的人角质形成细胞的分化。CD44下调（使用CD44小干扰RNA）也会抑制HA介导的角质形成细胞分化。CD44基因敲除小鼠中屏障恢复较慢可能进一步归因于板层小体形成减少、板层小体分泌顶端极化丧失以及胆固醇合成下调。因此，HA-CD44结合会刺激板层小体的形成和分泌。总之，这些观察结果证明了HA-CD44相互作用在调节表皮分化和脂质合成/分泌方面的新作用，进而影响通透性屏障稳态。HA-CD44信号传导可能构成一种治疗以分化、脂质合成和/或屏障功能异常为特征的皮肤疾病的新方法。
