CSF1-dependent macrophage support matrisome and epithelial stress-induced keratin remodeling in Eosinophilic esophagitis
Year: 2024
Type: article
Abstract: Atopic diseases such as Eosinophilic Esophagitis (EoE) often progress into fibrosis (FS-EoE), compromising organ function with limited targeted treatment options. Mechanistic understanding of FS-EoE progression is confounded by the lack of preclinical models and the heavy focus of research on eosinophils themselves. We found that macrophage accumulation precedes esophageal fibrosis in FS-EoE patients. We developed a FS-EoE model via chronic administration of oxazalone allergen, in a transgenic mouse over-expressing esophageal epithelial hIL-5 ( L2-IL5 OXA ). These mice display striking histopathologic features congruent with that found in FS-EoE patients. Unbiased proteomic analysis, using a unique extracellular-matrix (ECM) focused technique, identified an inflammation-reactive provisional basal lamina membrane signature and this was validated in two independent EoE patient RNA-sequencing/proteomic cohorts, supporting model significance. A wound healing signature was also observed involving hemostasis-associated molecules previously unnoted in EoE. We further identified the ECM glycoprotein, Tenascin-C (TNC), and the stress-responsive keratin-16 (KRT16) as IL-4 and IL-13 responsive mediators, acting as biomarkers of FS-EoE. To mechanistically address how the immune infiltrate shapes FS-EoE progression, we phenotyped the major immune cell subsets that coalesce with fibrosis in both the L2-IL5 OXA mice and in FS-EoE patients. We found that macrophage are required for matrisome and cytoskeletal remodeling. Importantly, we show that macrophage accumulation precedes esophageal fibrosis and provide a novel therapeutic target in FS-EoE as their depletion with anti-CSF1 attenuated reactive matrisome and cytoskeletal changes. Thus, macrophage-based treatments and the exploration of TNC and KRT16 as biomarkers may provide novel therapeutic options for patients with fibrostenosis.
Source: Mucosal Immunology
Authors: Taylor M. Benson, Gary E. Markey, Juliet A. Hammer, Luke Simerly, Monika Dzieciatkowska, Kimberly R. Jordan, Kelley E. Capocelli, Kathleen M. Scullion, Louise Crowe, Sinéad Ryan, Jennifer O. Black, Taylor Crue, Rachel Andrews, Cassandra Burger, Eóin N. McNamee, Glenn T. Furuta, Calies Menard-Katcher, Joanne C. Masterson
Language: English
Topic: Eosinophilic Esophagitis
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,800
Funders: Division of Cancer Prevention, National Cancer Institute, Crohn's and Colitis Foundation, Georgia Tech Foundation, Science Foundation Ireland, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, University of Colorado School of Medicine, Anschutz Medical Campus
Awards: G2110478374, G4365586400, G4512425335, Structural and molecular markers for detection and monitoring of pediatric fibrostenotic Eosinophilic Esophagitis, Transcriptional Mechanisms Controling Epithelial Cell Fate Determination during Allergic Esophageal Inflammation in Eosinophilic Esophagitis, G8131669909
OpenAlex ID: W4402910263