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

这一范式促使组织炎症被终止，并通过一种称为消解的活跃过程恢复组织内稳态的炎症前状态。有人提出，延迟或失败的解决是慢性炎症出现的一个原因，恢复解决的治疗原则有可能彻底改变当前的治疗策略，其中，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有部分了解，大部分是从急性腹膜炎的模型中得出的，因此不确定当前的概念在多大程度上也适用于其他组织和类型的炎症，如自身抗体引起的皮肤炎症。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检查类天疱疮(PDs)的分辨率。12/15-LO生物合成几种特定的前分解物(SPM)，这是一类脂类介体，通过几个G蛋白偶联受体调节拆分。我们发现12/15-LO的缺陷会加重和延长帕金森病。根据SPM在缓解皮肤炎症中的重要作用，12/15-LO来源的SPM在皮肤病变中上调。更详细的研究明确了炎性皮肤浸润处的大量中性粒细胞是12/15-LO表达的部位。我们还检测到人类12/15-LO的同源基因15-LO-1在人类BP患者皮损中的显著表达水平。在P9，我们将在这些初步结果的基础上，研究在PD中诱导12/15-LO的分子机制。我们将仔细研究前列腺素的推定轴和12/15-LO的启动决议。我们还将揭示12/15-LO应用于解决皮肤炎症的分子机制，特别是SPM受体ALX/FPR2。我们将进行脂质组学和蛋白质组学分析，分析SPM及其合成酶和受体在皮肤损伤发展的每个阶段，从临床未受影响的皮肤到愈合的侵蚀。因此，我们将建立一个皮损消退的模型，并确定潜在的干预点。我们的研究目标是在PDS的治疗中引入预消解疗法。我们预计BP是最能从解决方案的引入中获益的疾病之一；首先，因为患有BP的老年人群容易出现经典抗炎药物的免疫抑制副作用，这被怀疑是BP患者高死亡率的主要原因。其次，BP典型缓解-复发周期内的急性红斑反复要求组织炎症消退，而BP中的皮肤组织损伤通常是完全可逆的，从而使延缓药物完全恢复组织的炎症前架构成为可能。

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.