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

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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.