The Leukotriene B4 and its Receptor BLT1 Act as Critical Drivers of Neutrophil Recruitment in Murine Bullous Pemphigoid-Like Epidermolysis Bullosa Acquisita

Tanya Sezin, Matthias Krajewski, Adam Wutkowski, Sadegh Mousavi, Lenche Chakievska, Katja Bieber, Ralf J. Ludwig, Markus Dahlke, Dirk Rades, Franziska S. Schulze, Enno Schmidt, Kathrin Kalies, Yask Gupta, Paul Schilf, Saleh M. Ibrahim, Peter König, Dominik Schwudke, Detlef Zillikens, Christian D. Sadik

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

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 LTB4 and 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 LTB4 biosynthesis, 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 LTB4 and 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.

Original languageBritish English
Pages (from-to)1104-1113
Number of pages10
JournalJournal of Investigative Dermatology
Volume137
Issue number5
DOIs
StatePublished - May 2017

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