Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers
Co-regulation and interdependence of the mammalian epidermal permeability and antimicrobial barriers
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DOI：
10.1038/sj.jid.5701099
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发表时间：
2008-04-01
影响因子：
6.5
通讯作者：
Elias, Peter M.
中科院分区：
文献类型：
--
作者：
Aberg, Karin M.;Man, Mao-Qiang;Elias, Peter M.
人表皮产生两种小的阳离子、高疏水性抗微生物肽（AMP）β-防御素2（hBD 2）和人凯萨林菌素（hCAP 18）的羧基肽裂解产物LL- 37，它们在分泌前与脂质一起沿着包装在表皮板层体（LB）内.由于它们的共定位，我们假设AMP和屏障脂质的产生可以通过改变渗透性屏障的要求来共同调节。mBD 3和导管蛋白相关抗菌肽（CRAMP）（分别为hBD 2和LL- 37的小鼠同源物）的mRNA和免疫蛋白水平在急性渗透性屏障破坏后1 - 8小时增加，并在24小时内恢复正常，动力学反映了脂质代谢对渗透性屏障破坏的反应。抑制脂质合成反应导致屏障恢复的人工渗透性屏障恢复阻断AMP mRNA/蛋白质表达的增加，进一步证明AMP表达与渗透性屏障功能相关。相反，LB衍生的AMP对于渗透性屏障稳态也是重要的。尽管mBD 3蛋白明显增加，但CRAMP -/-小鼠延迟了渗透性屏障恢复，这归因于LB含量缺陷和调节渗透性屏障功能的层状膜结构异常。这些研究表明：（1）渗透性屏障要求协调调节渗透性和抗菌屏障;（2）渗透性屏障稳态需要CRAMP。
Human epidermis elaborates two small cationic, highly hydrophobic antimicrobial peptides ( AMP), beta- defensin 2 ( hBD2), and the carboxypeptide cleavage product of human cathelicidin ( hCAP18), LL- 37, which are co- packaged along with lipids within epidermal lamellar bodies ( LBs) before their secretion. Because of their colocalization, we hypothesized that AMP and barrier lipid production could be coregulated by altered permeability barrier requirements. mRNA and immunostainable protein levels for mBD3 and cathelin- related antimicrobial peptide ( CRAMP) ( murine homologues of hBD2 and LL- 37, respectively) increase 1 - 8 hours after acute permeability barrier disruption and normalize by 24 hours, kinetics that mirror the lipid metabolic response to permeability barrier disruption. Artificial permeability barrier restoration, which inhibits the lipid- synthetic response leading to barrier recovery, blocks the increase in AMP mRNA/ protein expression, further evidence that AMP expression is linked to permeability barrier function. Conversely, LB- derived AMPs are also important for permeability barrier homeostasis. Despite an apparent increase in mBD3 protein, CRAMP -/- mice delayed permeability barrier recovery, attributable to defective LB contents and abnormalities in the structure of the lamellar membranes that regulate permeability barrier function. These studies demonstrate that ( 1) the permeability and antimicrobial barriers are coordinately regulated by permeability barrier requirements and ( 2) CRAMP is required for permeability barrier homeostasis.