https://phaidra.vetmeduni.ac.at/o:2639 C-type lectin receptor expression is a hallmark of neutrophils infiltrating the skin in epidermolysis bullosa acquisita Guerrero-Juarez, Christian F. Christian F. Guerrero-Juarez University of Illinois / Rush University Medical Center Amber, Kyle T. Kyle T. Amber Rush University Medical Center Sadik, Christian D. Christian D. Sadik University of Lübeck Ludwig, Ralf J. Ralf J. Ludwig University of Lübeck Bieber, Katja Katja Bieber University of Lübeck Rülicke, Thomas Thomas Rülicke 0000-0002-2121-9496 University of Veterinary Medicine Vienna Ishii, Norito Norito Ishii Kurume University Hashimoto, Takashi Takashi Hashimoto Osaka Metropolitan University Graduate School of Medicine Frolov, Maxim V. Maxim V. Frolov University of Illinois Sverdlov, Maria Maria Sverdlov University of Illinois Cole, Connor Connor Cole Rush University Medical Center Murthy, Sripriya Sripriya Murthy University of Lübeck Gieseler-Tillmann, Jenny Jenny Gieseler-Tillmann University of Lübeck Patel, Payal M. Payal M. Patel Rush University Medical Center / Massachusetts General Hospital Bao, Lei Lei Bao University of Lübeck Zappia, Maria Paula Maria Paula Zappia University of Illinois Schilf, Paul Paul Schilf University of Lübeck Li, Jing Jing Li Rush University Medical Center Frontiers Media Sa text eng Inflammatory epidermolysis bullosa acquisita (EBA) is characterized by a neutrophilic response to anti-type VII collagen (COL7) antibodies resulting in the development of skin inflammation and blistering. The antibody transfer model of EBA closely mirrors this EBA phenotype.To better understand the changes induced in neutrophils upon recruitment from peripheral blood into lesional skin in EBA, we performed single-cell RNA-sequencing of whole blood and skin dissociate to capture minimally perturbed neutrophils and characterize their transcriptome.Through this approach, we identified clear distinctions between circulating activated neutrophils and intradermal neutrophils. Most strikingly, the gene expression of multiple C-type lectin receptors, which have previously been reported to orchestrate host defense against fungi and select bacteria, were markedly dysregulated. After confirming the upregulation of Clec4n, Clec4d, and Clec4e in experimental EBA as well as in lesional skin from patients with inflammatory EBA, we performed functional studies in globally deficient Clec4e-/- and Clec4d-/- mice as well as in neutrophil-specific Clec4n-/- mice. Deficiency in these genes did not reduce disease in the EBA model.Collectively, our results suggest that while the upregulation of Clec4n, Clec4d, and Clec4e is a hallmark of activated dermal neutrophil populations, their individual contribution to the pathogenesis of EBA is dispensable. Inflammation; Dectin-2 http://creativecommons.org/licenses/by/4.0/ https://phaidra.vetmeduni.ac.at/api/object/o:2639/download 10.3389/fimmu.2023.1266359 https://phaidra.vetmeduni.ac.at/o:605 application/pdf Frontiers in Immunology 14 (2023) Frontiers in Immunology 14 6.26 MB 2023