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.
- Sezin, T.
- Krajewski, M.
- Wutkowski, A.
- Mousavi, S.
- Chakievska, L.
- Bieber, K.
- Ludwig, R. J.
- Dahlke, M.
- Rades, D.
- Schulze, F. S.
- Schmidt, E.
- Kalies, K.
- Gupta, Y.
- Schilf, P.
- Ibrahim, S. M.
- Konig, P.
- Schwudke, D.
- Zillikens, D.
- Sadik, C. D.
Keywords
- Animals
- Arachidonate 5-Lipoxygenase/genetics
- Chromatography, Liquid/methods
- Disease Models, Animal
- Eosinophils/metabolism
- Epidermolysis Bullosa Acquisita/*pathology
- Female
- Inflammation/pathology
- Leukotriene B4/*metabolism
- Male
- Mass Spectrometry/methods
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Neutrophil Infiltration
- Neutrophils/metabolism
- Pemphigoid, Bullous/*pathology
- Receptors, Leukotriene B4/*metabolism
- Skin/*pathology