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

Ko, Kang I.; Merlet, Jean J.; DerGarabedian, Brett P.; Zhen, Huang; Suzuki-Horiuchi, Yoko; Hedberg, Matthew L.; Hu, Eileen; Nguyen, Anh T.; Prouty, Stephen; Alawi, Faizan; Walsh, Matthew C.; Choi, Yongwon; Millar, Sarah E.; Cliff, Ashley; Romero, Jonathon; Garvin, Michael R.; Seykora, John T.; Jacobson, Daniel; Graves, Dana T.

doi:10.1126/scitranslmed.abj0324

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

Journal Article · 01 February 2022 · Science Translational Medicine

DOI: https://doi.org/10.1126/scitranslmed.abj0324 · OSTI ID:1872872

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^[2]; DerGarabedian, Brett P. ^[1];

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^[1]; Alawi, Faizan ^[1]; Walsh, Matthew C. ^[1]; Choi, Yongwon ^[1];

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Univ. of Pennsylvania, Philadelphia, PA (United States)
Univ. of Tennessee, Knoxville, TN (United States)
Univ. of Pennsylvania, Philadelphia, PA (United States); Peking Univ., Beijing (China)
Icahn School of Medicine at Mount Sinai, New York, NY (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

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. Here, 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 T_H2 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 T_H2 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.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1872872

Journal Information:: Science Translational Medicine, Journal Name: Science Translational Medicine Journal Issue: 630 Vol. 14; ISSN 1946-6234

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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

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