GSE172226
NF-kB Perturbation Reveals Unique Immunomodulatory Functions in Prx1+ Fibroblasts that Promote Atopic Dermatitis
Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Upregulation of the NF-kB pathway may lead to the development of chronic inflammatory disorders of the skin, but the early events in situ are not well understood. Through analysis of single cell RNA sequencing (scRNA-seq) data via iterative Random Forest Leave One Out Prediction (iRF-LOOP), an explainable artificial intelligence (X-AI) method, we identified an immunoregulatory role for a unique Prx1+ fibroblast subpopulation. Disruption of Ikkb/NFkB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the over-expression of CCL11 (eotaxin-1) characterized by eosinophil infiltration and a subsequent Th2 immune response. Because the inflammatory phenotype resembled that seen in human atopic dermatitis (AD), we examined validated human AD skin samples and found that human AD fibroblasts also over-expressed CCL11 compared to control skin. Importantly, we demonstrate that monoclonal antibody treatment against CCL11 was therapeutically effective in reducing the eosinophilia and Th2 inflammation in vivo. Taken together, the murine model and human AD specimens point to dysregulated Prx1+ fibroblasts as a previously unrecognized etiologic factor that may contribute to the pathogenesis of AD-like lesions and suggest targeting CCL11 as a novel way to treat AD-like lesions. Overall design: Ventral skin single-cell mRNA profiles of 4 week old wild type (WT) and Prx1Cre+Ikkbf/f (Ikkb-deleted) mice.