Spontaneous Skin Erosions and Reduced Skin and Corneal Wound Healing Characterize CLIC4NULL Mice
Spontaneous Skin Erosions and Reduced Skin and Corneal Wound Healing Characterize CLIC4NULL Mice
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DOI：
10.1016/j.ajpath.2012.03.025
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发表时间：
2012-07-01
影响因子：
6
通讯作者：
Yuspa, Stuart H.
中科院分区：
文献类型：
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作者：
Padmakumar, V. C.;Speer, Kelsey;Yuspa, Stuart H.
皮肤伤口愈合是一个复杂的过程，涉及血液凝固、炎症、角质形成细胞的迁移、血管生成，并最终涉及组织重塑和伤口愈合。许多这些过程涉及转化生长因子- β (tgf - β)信号通路，缺乏tgf - β信号通路成分的小鼠在伤口愈合中存在缺陷。我们在此表明，作为tgf - β通路的一个组成部分，CLIC4在皮肤伤口中被高度上调。我们从基因上删除了小鼠CLIC4，并在C57Bl/6背景上产生了一个菌落。CLIC4（NULL）小鼠存活且可育，但产仔量小于野生型小鼠。6个月后，高达40%的小鼠出现自发性皮肤糜烂。在CLIC4（NULL）小鼠中，诱导的全层皮肤创面和角膜浅层创面的再上皮化延迟，炎症消退延迟，在构成性和损伤的CLIC4（NULL）皮肤裂解物中β 4整合素和p21的表达降低。在培养的CLIC4（NULL）角质形成细胞中，受tgf - β诱导的磷酸化Smad2水平相对于野生型细胞降低，并且CLIC4（NULL）角质形成细胞的迁移速度比野生型角质形成细胞慢，并且对tgf - β的迁移没有增加。CLIC4（NULL）角质形成细胞在涂有野生型角质形成细胞分泌的基质的板上也较少粘附。这些结果表明，CLIC4通过促进上皮迁移参与皮肤愈合和角膜创面再上皮化，其机制可能涉及受损的tgf - β通路。（中华病理学杂志，2012,181:74-84;http://dx.doi.org/10.1016/j.ajpath.2012.03.025）
Cutaneous wound healing is a complex process involving blood clotting, inflammation, migration of keratinocytes, angiogenesis, and, ultimately, tissue remodeling and wound closure. Many of these processes involve transforming growth factor-beta (TGF-beta) signaling, and mice lacking components of the TGF-beta signaling pathway are defective in wound healing. We show herein that CLIC4, an integral component of the TGF-beta pathway, is highly up-regulated in skin wounds. We genetically deleted murine CLIC4 and generated a colony on a C57Bl/6 background. CLIC4(NULL) mice were viable and fertile but had smaller litters than did wild-type mice. After 6 months of age, up to 40% of null mice developed spontaneous skin erosions. Reepithelialization of induced full-thickness skin wounds and superficial corneal wounds was delayed in CLIC4(NULL) mice, resolution of inflammation was delayed, and expression of beta 4 integrin and p21 was reduced in lysates of constitutive and wounded CLIC4(NULL) skin. The induced level of phosphorylated Smad2 in response to TGF-beta was reduced in cultured CLIC4(NULL) keratinocytes relative to in wild-type cells, and CLIC4(NULL) keratinocytes migrated slower than did wild-type keratinocytes and did not increase migration in response to TGF-beta. CLIC4(NULL) keratinocytes were also less adherent on plates coated with matrix secreted by wild-type keratinocytes. These results indicate that CLIC4 participates in skin healing and corneal wound reepithelialization through enhancement of epithelial migration by a mechanism that may involve a compromised TGF-beta pathway. (Am J Pathol 2012, 181:74-84; http://dx.doi.org/10.1016/j.ajpath.2012.03.025)