Differential susceptibility of Cx26 mutations associated with epidermal dysplasias to peptidoglycan derived from Staphylococcus aureus and Staphylococcus epidermidis
Differential susceptibility of Cx26 mutations associated with epidermal dysplasias to peptidoglycan derived from Staphylococcus aureus and Staphylococcus epidermidis
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DOI：
10.1111/j.1600-0625.2012.01521.x
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发表时间：
2012-08-01
影响因子：
3.6
通讯作者：
Martin, Patricia E.
中科院分区：
文献类型：
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作者：
Donnelly, Steven;English, Grant;Martin, Patricia E.
连接蛋白26（Cx 26）的突变引起一系列显性遗传的过度增殖性皮肤病，最常见的是角膜炎性鱼鳞病性耳聋（KID）综合征，这是一种炎性皮肤病，患者容易发生机会性感染。我们比较了从皮肤表皮葡萄球菌和条件致病菌金黄色葡萄球菌中提取的肽聚糖（PGN）对HaCaT细胞（角质形成细胞系）中白细胞介素-6和connexin表达以及转染表达KID和非KID Cx 26突变的HaCaT和HeLa（connexin缺陷）细胞中connexin通道活性的影响。在两种细胞中，S.金黄色葡萄球菌在表达KID突变体的细胞中诱导半通道活性，如在15分钟攻击后通过ATP释放测定监测的，而来自S. epidermidis引起HeLa细胞的反应。在表达KID突变体的细胞中，ATP释放显著高于用野生型Cx 26转染的细胞。在非KID突变体转染的细胞中或在存在甘珀酸（一种连接蛋白通道阻断剂）的情况下，未观察到ATP释放。PGN分离自S.金黄色葡萄球菌，而不是S.在HaCaT细胞中，表皮葡萄球菌刺激6小时后诱导白细胞介素-6和Cx 26的表达。来自S.金黄色葡萄球菌在表达KID突变体的细胞中比在表达wtCx 26或非KID突变体的细胞中诱发更大的白细胞介素-6应答。如果急性KID半通道信号传导在PGN激发前被阻断，则该反应返回到基础水平。因此，KID突变体形成的通道，可以触发促炎介质PGN从机会病原体，但不是皮肤的真菌，提供了进一步的洞察Cx 26疾病的基因型表型关系。
Mutations in Connexin26 (Cx26) give rise to a spectrum of dominantly inherited hyperproliferating skin disorders, the severest being keratitisichthyosisdeafness (KID) syndrome, an inflammatory skin disorder, with patients prone to opportunistic infections. We compared the effects of peptidoglycan (PGN) extracted from the skin commensal Staphylococcus epidermidis and the opportunistic pathogen Staphylococcus aureus on interleukin-6 and connexin expression in HaCaT cells (a keratinocyte cell line) and connexin channel activity in HaCaT and HeLa (connexin deficient) cells transfected to express KID and non-KID Cx26 mutations. In both cell types, PGN from S. aureus induced hemichannel activity in cells expressing KID mutants as monitored by ATP release assays following 15-min challenge, while that from S. epidermidis evoked a response in HeLa cells. In KID mutant expressing cells, ATP release was significantly higher than in cells transfected with wild-type Cx26. No ATP release was observed in non-KID mutant transfected cells or in the presence of carbenoxolone, a connexin channel blocker. PGN isolated from S. aureus but not S. epidermidis induced interleukin-6 and Cx26 expression in HaCaT cells following 6-h challenge. Challenge by PGN from S. aureus evoked a greater interleukin-6 response in cells expressing KID mutants than in cells expressing wtCx26 or non-KID mutants. This response returned to basal levels if acute KID hemichannel signalling was blocked prior to PGN challenge. Thus, KID mutants form channels that can be triggered by the pro-inflammatory mediator PGN from opportunistic pathogens but not skin commensals, providing further insight into the genotypephenotype relationship of Cx26 disorders.