Lee Pedro, Lee Dai-Jen, Chan Carol, Chen Shih-Wei, Ch'en Irene, Jamora Colin
Section of Cell and Developmental Biology, Division of Biological Sciences, Natural Science Building, Room 6311, 9500 Gilman Drive, MC 0380, La Jolla, California 92093, USA.
Nature. 2009 Mar 26;458(7237):519-23. doi: 10.1038/nature07687. Epub 2009 Feb 8.
Tissue homeostasis and regeneration are regulated by an intricate balance of seemingly competing processes-proliferation versus differentiation, and cell death versus survival. Here we demonstrate that the loss of epidermal caspase 8, an important mediator of apoptosis, recapitulates several phases of a wound healing response in the mouse. The epidermal hyperplasia in the caspase 8 null skin is the culmination of signals exchanged between epidermal keratinocytes, dermal fibroblasts and leukocytic cells. This reciprocal interaction is initiated by the paracrine signalling of interleukin 1alpha (IL1alpha), which activates both skin stem cell proliferation and cutaneous inflammation. The non-canonical secretion of IL1alpha is induced by a p38-MAPK-mediated upregulation of NALP3 (also known as NLRP3), leading to inflammasome assembly and caspase 1 activation. Notably, the increased proliferation of basal keratinocytes is counterbalanced by the growth arrest of suprabasal keratinocytes in the stratified epidermis by IL1alpha-dependent NFkappaB signalling. Altogether, our findings illustrate how the loss of caspase 8 can affect more than programmed cell death to alter the local microenvironment and elicit processes common to wound repair and many neoplastic skin disorders.
组织稳态和再生受看似相互竞争的过程——增殖与分化、细胞死亡与存活之间复杂平衡的调节。在此，我们证明表皮半胱天冬酶8（一种重要的细胞凋亡介质）的缺失重现了小鼠伤口愈合反应的几个阶段。半胱天冬酶8基因敲除皮肤中的表皮增生是表皮角质形成细胞、真皮成纤维细胞和白细胞之间信号交换的结果。这种相互作用由白细胞介素1α（IL1α）的旁分泌信号启动，它激活皮肤干细胞增殖和皮肤炎症。IL1α的非经典分泌由p38丝裂原活化蛋白激酶介导的NALP3（也称为NLRP3）上调诱导，导致炎性小体组装和半胱天冬酶1激活。值得注意的是，基底角质形成细胞增殖的增加被分层表皮中基底上层角质形成细胞通过IL1α依赖的核因子κB信号传导的生长停滞所抵消。总之，我们的研究结果说明了半胱天冬酶8的缺失如何不仅影响程序性细胞死亡，还能改变局部微环境，并引发伤口修复和许多皮肤肿瘤性疾病共有的过程。
