Lipid Mediator-orchestrated molecular Mechanisms resolving Skin Inflammation in Pemphigoid Diseases

该范式沉淀了组织炎症被终止，组织稳态的炎症前状态通过一个被称为溶解的积极过程恢复。有人提出，延迟或未能解决是慢性炎症出现的一个原因，而恢复解决的治疗原则有可能彻底改变当前的治疗策略，除其他外，因为解决药物不具有免疫抑制作用。解决组织炎症的机制只被部分理解，而且大多是从急性腹膜炎模型中得出的结论，因此目前的概念在多大程度上也适用于其他组织和类型的炎症，如自身抗体诱导的皮肤炎症，尚不确定。我们已经开始通过研究12/15-脂氧合酶（12/15-LO）在被动EBA小鼠模型中的作用来研究类天疱疮疾病（pd）的消退。12/15-LO生物合成几种特定的促溶物种（SPMs），一类脂质介质，通过几种G蛋白偶联受体调节分辨率。我们发现12/15-LO缺乏会加重和延长PD。与SPMs在解决皮肤炎症中的重要作用一致，12/15- lo来源的SPMs在皮肤病变中上调。更详细的研究指出炎症性皮肤浸润中的pmn群是12/15-LO表达的部位。我们还在人类BP患者的病变皮肤中检测到12/15-LO的人类同源物15-LO-1的显著表达水平。在P9中，我们将以这些初步结果为基础，研究PD诱导12/15-LO的分子机制。我们将仔细检查推定的前列腺素轴和12/15-LO初始解决方案。我们还将揭示12/15-LO用于解决皮肤炎症的分子机制，特别是关注SPM受体ALX/FPR2。我们将进行脂质组学和蛋白质组学分析，分析SPMs及其合成酶和受体在皮肤损伤发展的每个阶段，从临床未受损伤的皮肤到愈合的侵蚀。因此，我们将生成一个解决皮肤病变的模型，并确定潜在的干预点。我们的研究目标是在pd的治疗中引入深入的治疗方法。我们预计BP是最受益于渐进疗法的疾病之一；首先，因为老年BP患者容易出现经典抗炎药物的免疫抑制副作用，这被怀疑是导致BP患者死亡率高的主要原因。其次，典型的BP缓解-复发周期内的急性发作反复需要组织炎症的解决，BP的皮肤组织损伤通常是完全可逆的，因此可以通过药物来完全恢复组织的炎症前结构。

The paradigm has precipitated that tissue inflammation is terminated and the pre-inflammatory state of tissue homeostasis restored by an active process termed resolution. It has been proposed that delayed or failed resolution is one cause of the emergence of chronic inflammation and that therapeutic principles reinstating resolution bear the potential to revolutionize current treatment strategies, among others, because proresolving drugs are not immunosuppressive. The mechanisms resolving tissue inflammation are only partially understood and have mostly been concluded from models of acute peritonitis, thus leaving it uncertain to what extent current concepts also pertain to other tissues and types of inflammation, such as autoantibody-induced skin inflammation. We have started to examine resolution in pemphigoid diseases (PDs) by investigating the role of 12/15-lipoxygenase (12/15-LO) in the passive EBA mouse model. 12/15-LO biosynthesizes several specific proresolving species (SPMs), a class of lipid mediators, regulating resolution via several G protein-coupled receptors. We have found that deficiency in 12/15-LO aggravates and protracts PD. In line with an important role of SPMs in the resolution of skin inflammation, 12/15-LO-derived SPMs were upregulated in skin lesions. More detailed studies pinpointed a population of PMNs in the inflammatory skin infiltrate as site of 12/15-LO expression. We have also detected significant expression levels of 15-LO-1, the human orthologue of 12/15-LO, in lesional skin of human BP patients. In P9, we will build on these preliminary results and will investigate the molecular mechanisms inducing 12/15-LO in PD. We will scrutinize a putative axis of prostaglandins and 12/15-LO initiating resolution. We will also uncover the molecular mechanisms 12/15-LO applies to resolve skin inflammation, particularly focusing on the SPM receptor ALX/FPR2. We will conduct lipidomics and proteomics analyses profiling SPMs, their synthesizing enzymes and receptors in each phase of skin lesion development from clinically uninvolved skin to healing erosions. Thus, we will generate a model of the resolution of skin lesions and identify potential points of intervention.The goal of our research is to introduce proresolving therapies in the treatment of PDs. We anticipate that BP is one of the diseases benefiting the most from the introduction of proresolving therapies; first, because the elderly population suffering from BP is prone to the immunosuppressive side effects of classical antiinflammatory drugs, which are suspected to be a major cause for the high mortality of BP patients. Second, the acute flares within the typical remission-relapse cycles of BP repeatedly require the resolution of tissue inflammation, and the skin tissue damage in BP is usually fully reversible, thus making it possible for proresolving drugs to completely restore the pre-inflammatory architecture of the tissue.