Stanley Alanna, Pedersen Esben, Brakebusch Cord, Quondamatteo Fabio
Skin and ECM Research Group, Anatomy NUI Galway, Galway, Ireland.
BRIC, University of Copenhagen, Copenhagen, Denmark.
J Anat. 2016 May;228(5):826-37. doi: 10.1111/joa.12442. Epub 2016 Feb 18.
Keratinocytes, in response to irritants, secrete pro-inflammatory mediators which recruit and activate immune and mesenchymal cells, including fibroblasts, to repair the skin. Fibroblasts respond by synthesising collagen and promoting the crosslinking extracellular matrix (ECM). We recently showed that the deletion of Rac1 in keratinocytes causes heightened inflammation due to aberrant crosstalk with immune cells. Indeed, the skin of these mice shows a higher inflammatory response to the induction of irritant contact dermatitis (ICD), and also even to treatment with a vehicle alone, compared with controls. As inflammation is intimately linked with fibrotic disease in the skin, this raised the question as to whether this deletion may also affect the deposition and arrangement of the dermal ECM. This study assessed the effects of Rac1 deletion in keratinocytes and of the heightened inflammatory status by induction of ICD on the tissue localisation and arrangements of dermal collagen. Qualitative analysis did not reveal evidence for the formation of pathologies in the dermis. However, quantitative analysis did reveal some perturbations in the dermal matrix, namely that only the combination of the lack of Rac1 and ICD affects the architectural organisation of the dermal collagen, and that a higher inflammatory state in the tissue (i.e. when Rac1 is deleted in the keratinocytes or ICD is induced in the skin, or a combination of both) influences the diameter of the collagen fibrils. It is proposed that this increase in the diameter of collagen fibrils due to inflammation may serve as pre-fibrotic marker enabling earlier determination of fibrosis and earlier treatment. This study has revealed previously unknown effects on the ECM due to the deletion of Rac1 in keratinocytes.
角质形成细胞在受到刺激时会分泌促炎介质,这些介质会募集并激活免疫细胞和间充质细胞(包括成纤维细胞)来修复皮肤。成纤维细胞通过合成胶原蛋白和促进细胞外基质(ECM)交联来做出反应。我们最近发现,角质形成细胞中Rac1的缺失会由于与免疫细胞的异常串扰而导致炎症加剧。事实上,与对照组相比,这些小鼠的皮肤对刺激性接触性皮炎(ICD)的诱导表现出更高的炎症反应,甚至对单独使用赋形剂治疗也有更高反应。由于炎症与皮肤纤维化疾病密切相关,这就提出了一个问题,即这种缺失是否也会影响真皮ECM的沉积和排列。本研究评估了角质形成细胞中Rac1缺失以及通过诱导ICD导致的炎症加剧状态对真皮胶原蛋白的组织定位和排列的影响。定性分析未发现真皮中形成病变的证据。然而,定量分析确实揭示了真皮基质中的一些扰动,即只有Rac1缺失和ICD的组合会影响真皮胶原蛋白的结构组织,并且组织中较高的炎症状态(即角质形成细胞中Rac1缺失或皮肤中诱导ICD,或两者结合)会影响胶原纤维的直径。有人提出,由于炎症导致的胶原纤维直径增加可能作为纤维化前标志物,有助于更早地确定纤维化并进行早期治疗。本研究揭示了角质形成细胞中Rac1缺失对ECM产生的前所未知的影响。
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