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NF-kB Perturbation Reveals Unique Immunomodulatory Functions in Prx1+ Fibroblasts that Promote Atopic Dermatitis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE172226 | GEO | 2021/04/17

REPOSITORIES: GEO

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Project description:Atopic dermatitis (AD) is a common disease, with an increasing prevalence. The primary pathogenesis of the disease is still elusive, resulting in lack of specific treatments. The prevailing view is that AD is a biphasic, T-cell polarized disease, with Th2 predominating acute AD, and a switch to Th1 characterizing chronic disease. Identification of factors that participate in onset of lesions and maintenance of chronic lesions is critical for development of targeted therapeutics. We performed global genomic, molecular and cellular profiling of paired non-lesional, acute, and chronic skin biopsies from ten AD patients. Onset of acute lesions is associated with a striking increase in a subset of terminal differentiation proteins, specifically the IL-22-modulated S100A7-9. Correspondingly, acute disease is associated with significant increases in gene expression levels of the major Th22- (IL-22) and Th2- (IL-4, IL-31) cytokines and Th17-regulated genes (CCL20, PI3/Elafin), without significant changes in IL-17. A lesser induction of Th1- (IFNγ, MX-1, CXCL9-11) associated genes was detected in acute disease. Chronic skin lesions are characterized by significantly intensified activation of Th22, Th2 and Th1. Our data establish increased expression of S100A7-9 and other epidermal genes at onset of acute AD, with parallel activation of Th2 and Th22 cytokines. Our findings suggest an absence of switch mechanism in chronic disease and instead indicate that progression to chronic lesions is associated with intensified activation of immune axes that initiate onset of acute lesions, particularly Th22 and Th2. This alters the prevailing view of pathogenesis, with important therapeutic implications. Acute, chronic, and non-lesional skin samples were collected from ten patients with moderate-to-severe AD that met our inclusion criteria, under an institutional review board–approved protocol. The following criteria were employed to define acute AD and distinguish true acute from “acute on chronic” skin lesions: a) new lesions of <72 hours duration, as previously defined;14 b) lack of skin lichenification; c) lack of regenerative hyperplasia, as defined by epidermal thickness ≤150μ [hematoxylin and eosin (H&E)] and basal or confluent supra-basal Keratin 16 (K16) positivity. No systemic or topical treatments were allowed for ≥4 weeks prior to biopsies. Biopsy specimens were frozen in optimal cutting temperature (OCT) for immunohistochemistry (IHC) and liquid nitrogen for RNA extraction.

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NF-kB Perturbation Reveals Unique Immunomodulatory Functions in Prx1+ Fibroblasts that Promote Atopic Dermatitis

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