Abstract
Mucous membrane pemphigoid (MMP) is a mucocutaneous autoimmune blistering disease affecting diverse mucous membranes and the skin with inflammatory blisters and erosions. The pathogenesis of MMP is only poorly understood, but inflammation in MMP is triggered by specific binding of autoantibodies directed to different proteins of the dermal-epidermal/-epithelial junction, subsequently leading to the influx of inflammatory cells, particularly neutrophils, into the dermis. Using the anti-laminin 332 antibody transfer model of MMP, we addressed the molecular mechanisms of neutrophil infiltration and its significance for the eruption of mucocutaneous lesions. Mice deficient in 5-lipoxygenase (Alox5–/–) or in the leukotriene B4 (LTB4) receptor BLT1 (Ltb4r1–/–) were resistant to skin inflammation and exhibited substantially fewer mucosal lesions, with deficiency in either gene compromising the recruitment of neutrophils to the lesion. Furthermore, neutrophil-specific genetic deficiency in Ltb4r1 similarly protected from MMP. Hence, BLT1 was required on neutrophils, and neutrophil recruitment was indispensable for the eruption of lesions in MMP. In line with these findings, the BLT1 inhibitor CP-105,606 ameliorated MMP dose-dependently. Collectively, our results highlight neutrophils and LTB4/BLT1 as key drivers of inflammation in MMP and as promising therapeutic targets.
Authors
Tabea Bremer, Sripriya Murthy, Sabrina Patzelt, Paul Schilf, Mareike Neumann, Sina Gonther, Jasper Pruessmann, Wiebke Pruessmann, Enno Schmidt, Thomas Rülicke, Christian D. Sadik
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