Journal of Autoimmunity xxx (xxxx) xxx Please cite this article as: Tanya Sezin, Journal of Autoimmunity, https://doi.org/10.1016/j.jaut.2020.102528 0896-8411/© 2020 Published by Elsevier Ltd. 12/15-Lipoxygenase choreographs the resolution of IgG-mediated skin infammation Tanya Sezin a , Nerea Ferreir´ os b , Malin Jennrich a , Khoroljav Ochirbold a , Malte Seutter a , Claudia Attah a , Sadegh Mousavi a , Detlef Zillikens a, c , Gerd Geisslinger b, d , Christian D. Sadik a, c, * a Department of Dermatology, Allergy, and Venereology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany b Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, Goethe - University, Theodor-Stern-Kai 7, 60590, Frankfurt Am Main, Germany c Center for Research on Infammation of the Skin (CRIS), University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany d Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Branch Translational Medicine & Pharmacology TMP and Fraunhofer Cluster of Excellence for Immune-mediated Diseases CIMD, Theodor-Stern-Kai 7, 60596, Frankfurt Am Main, Germany A R T I C L E INFO Keywords: Autoimmune diseases Pemphigoid diseases Eosinophils Lipid mediators Resolution 12/15-Lipoxygenase ABSTRACT Autoimmune diseases are defned by an immune response against a specifc autoantigen, driven by antigen- specifc T cells or antibodies. While the mechanisms resolving brief episodes of acute infammation elicited by microbial components or tissue injury are well understood, the mechanisms resolving tissue infammation in autoimmune diseases are still largely elusive. We have, therefore, addressed the mechanisms of resolution in IgG-mediated autoimmune diseases using a mouse model of the pemphigoid disease “bullous pemphigoid-like epidermolysis bullosa acquisita” (BP-like EBA) as prototypical example. We found that 12/15-LO is induced in skin lesions of BP-like EBA and is predominantly expressed in eosinophils. Dependent on the expression of 12/15-LO, large amounts of proresolving lipid medi- ators, are biosynthesized in the skin by the point disease peaks. Their production is timely correlated to the gradual reversal of tissue infammation. Genetic defciency in Alox15, the gene encoding 12/15-LO, disrupts this process signifcantly protracting and aggravating disease. This protraction is associated reduced recruitment of regulatory T cells (T regs ) into lesional skin. Intriguingly, Alox15 / mice also exhibit reduced recruitment of eosinophils into the skin, and the chemotaxis of cultured Alox15 / eosinophils towards CCL11/eotaxin-1 is compromised. Finally, we demonstrate that 15-lipoxygenase-1, the human homologue of 12/15-LO is induced in granulocytes in lesional skin of patients suffering from a pemphigoid disease. Collectively, our result uncover key mechanisms resolving IgG-mediated skin infammation. These mecha- nisms are orchestrated by 12/15-LO expressed in eosinophils promoting the recruitment of eosinophils and T regs , which in turn inhibit neutrophils. 1. Introduction Tissue infammation is a hallmark of diverse pathological processes. While the mechanisms initiating and propagating tissue infammation have been investigated for decades, more recently, evidence has accu- mulated that the termination of tissue infammation is also an active process orchestrated by complex regulatory networks. This latter pro- cess has been termed “resolution”. Notably, research on resolution has predominantly focused on models of acute, brief episodes of infam- mation, primarily in models of zymosan- or lipopolysaccharide-induced peritonitis or pouchitis, sepsis, ischemia/reperfusion-induced tissue injury or dextran sulfate sodium (DSS)-induced tissue injury (colitis) [1–4]. The mechanisms resolving other, more chronic types of tissue infammation, such as IgG-mediated tissue infammation in autoimmune diseases, have consequently remained largely elusive [1]. A functional group of bioactive lipid mediators termed “Specialized Proresolving Mediators” (SPMs) has been implicated in regulating the resolution of acute tissue infammation [5]. SPMs are classifed by their chemical structure as lipoxins, D- and E-series resolvins, protectins, and maresins and are cognate ligands at different G protein-coupled * Corresponding author. Department of Dermatology, Allergy, and Venereology, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. E-mail address: Christian.Sadik@uksh.de (C.D. Sadik). Contents lists available at ScienceDirect Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm https://doi.org/10.1016/j.jaut.2020.102528 Received 26 February 2020; Received in revised form 11 July 2020; Accepted 22 July 2020