Division of Biological Sciences, Section of Cell and Developmental Biology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Proc Natl Acad Sci U S A. 2010 Dec 21;107(51):22249-54. doi: 10.1073/pnas.1009751108. Epub 2010 Dec 6.
Atopic dermatitis is an inflammatory skin disease that affects approximately 20% of children worldwide. Left untreated, the barrier function of the skin is compromised, increasing susceptibility to dehydration and infection. Despite its prevalence, its multifactorial nature has complicated the unraveling of its etiology. We found that chronic loss of epidermal caspase-8 recapitulates many aspects of atopic dermatitis, including a spongiotic phenotype whereby intercellular adhesion between epidermal keratinocytes is disrupted, adversely affecting tissue architecture and function. Although spongiosis is generally thought to be secondary to edema, we found that suppression of matrix metalloproteinase-2 activity is sufficient to abrogate this defect. p38 MAPK induces matrix metalloproteinase-2 expression to cleave E-cadherin, which mediates keratinocyte cohesion in the epidermis. Thus, the conditional loss of caspase-8, which we previously found to mimic a wound response, can be used to gain insights into how these same wound-healing processes are commandeered in inflammatory skin diseases.
特应性皮炎是一种炎症性皮肤病，影响全球约 20%的儿童。如果不治疗，皮肤的屏障功能会受损，增加脱水和感染的易感性。尽管它很普遍，但它的多因素性质使得其病因的研究变得复杂。我们发现，表皮半胱天冬酶-8 的慢性缺失可再现特应性皮炎的许多方面，包括海绵状表型，其中表皮角质形成细胞之间的细胞间黏附被破坏，从而对组织结构和功能产生不利影响。尽管海绵状变性通常被认为是水肿的继发表现，但我们发现抑制基质金属蛋白酶-2 的活性足以消除这一缺陷。p38 MAPK 诱导基质金属蛋白酶-2 的表达，以切割 E-钙黏蛋白，从而介导表皮中角质形成细胞的黏附。因此，我们之前发现模拟伤口反应的半胱天冬酶-8 的条件性缺失可用于深入了解这些相同的伤口愈合过程是如何在炎症性皮肤病中被利用的。
