title: The Leukotriene B4and its Receptor BLT1 Act as Critical Drivers of Neutrophil Recruitment in Murine Bullous Pemphigoid-Like Epidermolysis Bullosa Acquisita.
abstract: Recruitment of neutrophils and eosinophils into the skin is a hallmark of pemphigoid diseases. The molecular cues regulating granulocyte recruitment into the skin and the individual contributions of neutrophils and eosinophils to pemphigoid diseases are, however, poorly understood. The lipid mediator leukotriene B4(LTB4) is a potent granulocyte chemoattractant and is abundant in the skin blister fluid of bullous pemphigoid (BP) patients, but its pathogenic significance is unknown. Using mouse models of BP-like epidermolysis bullosa acquisita and of BP, we show that LTB4and its receptor BLT1 act as critical drivers of neutrophil entry into the skin upon antibody deposition at the dermal-epidermal junction. Mice deficient in 5-lipoxygenase, a key enzyme in LTB4biosynthesis, or in BLT1 exhibited dramatic resistance to neutrophil recruitment and, consequently, skin inflammation. Accordingly, liquid chromatography-mass spectrometry, used to comprehensively profile lipid mediator generation in the first 48 hours after antibody deposition, showed a pronounced parallel increase in LTB4and in neutrophils in the skin. Subsequent mechanistic studies in BP-like epidermolysis bullosa acquisita uncovered that neutrophils are necessary for skin inflammation, whereas eosinophils are dispensable, thus identifying neutrophils as major culprits of blister formation. Our results highlight LTB4/BLT1 as absolutely critical drivers of murine pemphigoid disease-like skin inflammation.
authors.affiliation: Department of Dermatology, Allergy, and Venereology, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Tanya
authors.initials: T
authors.lastname: Sezin
authors.affiliation: Division of Bioanalytical Chemistry, Research Center Borstel- Leibniz-Center for Medicine and Biosciences, 23845 Borstel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Krajewski
authors.affiliation: Division of Bioanalytical Chemistry, Research Center Borstel- Leibniz-Center for Medicine and Biosciences, 23845 Borstel, Germany.
authors.forename: Adam
authors.initials: A
authors.lastname: Wutkowski
authors.affiliation: Department of Dermatology, Allergy, and Venereology, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Sadegh
authors.initials: S
authors.lastname: Mousavi
authors.affiliation: Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Lenche
authors.initials: L
authors.lastname: Chakievska
authors.affiliation: Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Bieber
authors.affiliation: Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Ralf J
authors.initials: RJ
authors.lastname: Ludwig
authors.affiliation: Department of Radiation Oncology, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Dahlke
authors.affiliation: Department of Radiation Oncology, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Rades
authors.affiliation: Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Franziska S
authors.initials: FS
authors.lastname: Schulze
authors.affiliation: Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Enno
authors.initials: E
authors.lastname: Schmidt
authors.affiliation: Department of Anatomy, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kalies
authors.affiliation: Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Yask
authors.initials: Y
authors.lastname: Gupta
authors.affiliation: Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Schilf
authors.affiliation: Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Saleh M
authors.initials: SM
authors.lastname: Ibrahim
authors.affiliation: Department of Anatomy, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: König
authors.affiliation: Division of Bioanalytical Chemistry, Research Center Borstel- Leibniz-Center for Medicine and Biosciences, 23845 Borstel, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schwudke
authors.affiliation: Department of Dermatology, Allergy, and Venereology, University of Lübeck, 23538 Lübeck, Germany.
authors.forename: Detlef
authors.initials: D
authors.lastname: Zillikens
authors.affiliation: Department of Dermatology, Allergy, and Venereology, University of Lübeck, 23538 Lübeck, Germany. Electronic address: Christian.Sadik@uksh.de.
authors.forename: Christian D
authors.initials: CD
authors.lastname: Sadik
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics; D002853:Chromatography, Liquid / Q000379:methods; D004195:Disease Models, Animal; D004804:Eosinophils / Q000378:metabolism; D016107:Epidermolysis Bullosa Acquisita / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000473:pathology; D007975:Leukotriene B4 / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry / Q000379:methods; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism; D010391:Pemphigoid, Bullous / Q000473:pathology*; D018102:Receptors, Leukotriene B4 / Q000378:metabolism*; D012867:Skin / Q000473:pathology*
chemical_list: C503704:Ltb4r1 protein, mouse; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase