NF-κB perturbation reveals unique immunomodulatory functions in Prx1+ fibroblasts that promote development of atopic dermatitis

Skin is composed of diverse cell populations that cooperatively maintain homeostasis. Up-regulation of the nuclear factor κB (NF-κB) pathway may lead to the development of chronic inflammatory disorders of the skin, but its role during the early events remains unclear. Through analysis of single-cell RNA sequencing data via iterative random forest leave one out prediction, an explainable artificial intelligence method, we identified an immunoregulatory role for a unique paired related homeobox-1 (Prx1)+ fibroblast subpopulation. Disruption of Ikkb–NF-κB under homeostatic conditions in these fibroblasts paradoxically induced skin inflammation due to the overexpression of C-C motif chemokine ligand 11 (CCL11; or 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 human AD skin samples and found that human AD fibroblasts also overexpressed CCL11 and that perturbation of Ikkb–NF-κB in primary human dermal fibroblasts up-regulated CCL11. Monoclonal antibody treatment against CCL11 was effective in reducing the eosinophilia and TH2 inflammation in a mouse model. 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 and suggest that targeting CCL11 may be a way to treat AD-like skin lesions. Description Disruption of the Ikkb–NF-κB axis in Prx1+ fibroblasts alters skin homeostasis, causing an inflammatory disorder that mimics human atopic dermatitis. Prx1+ fibroblasts prime AD The early events of atopic dermatitis (AD) are not fully elucidated, but immunomodulatory fibroblast subsets may contribute to disease. Here, Ko and colleagues deleted Ikkb in fibroblastic cells in mice to block NF-κB activation, finding that these mice developed AD-like skin lesions. Single-cell RNA sequencing identified the presence of paired related homeobox-1–positive (Prx1+) fibroblasts that overexpressed C-C motif chemokine ligand 11 (CCL11), leading to myeloid cell infiltration in the skin and a type 2 immune response that preceded development of the lesions. Treatment of young Ikkb-deleted mice with a monoclonal antibody blocking CCL11 resulted in decreased eosinophil skin infiltration and type 2 immune response, suggesting that CCL11 may be a target to treat early atopic dermatitis.