scRNA-seq identifies atopic dermatitis development marked by early neutrophils and T cell shifts in filaggrin-null mice with environmental sensitivity

Summary: Abstract Body: Filaggrin (Flg) deficiency is a major risk factor for atopic dermatitis (AD) with epicutaneous sensitization and increased permeability shown in filaggrin-null (Flg-/-) mice. Flg loss-of-function variants are semipenetrant for AD suggesting a role for environmental effects. We hypothesize differential AD-like, skin inflammation induced by MC903 in Flg-/- adult mice housed in two different animal facilities. Flg-/- mice in facility A developed normally yet with increased Streptococcus dysbiosis and higher overall rate of MC903-induced inflammation but was not significant (vs. wild-type [wt] mice). Flg-/- mice in facility B exhibited a perinatal flaky tail that resolved yet with a significant increase in the overall rate of MC903-inflammation (p<0.05). Flow cytometry revealed neutrophil infiltration in the early (days 1-6) and not in the late phase (days 7-12) with notable TCRb+ cell influx in Flg-/- mice. scRNA-seq of treated ear skin further identified 22 distinct clusters and validated the observed increased neutrophils yet with additional myeloid and lymphoid immune cells in Flg-/- mice in the early and late phases, respectively. Tslp was specific to suprabasal KCs that persisted in both phases whereas IL2/CD101 T cells predominated the early phase and shifted to CD8+, Treg, and Th2 by the late phase with higher inflammation. In summary, our MC903 Flg-/- study identifies environmental sensitivity and longitudinal development of AD with early neutrophil infiltration and late T cell shifts that offers insights into potential therapeutic targets to modulate specific immune cell subsets in treating AD. Autumn Hicks^{5, 4}, Mohammed Barmal², Alina Schmidt³, Qi Zheng¹, Congcong Yin⁵, Peter Dimitrion⁵, Qing-Sheng Mi^{5, 4}, Aimin Jiang^{5, 4}, Elizabeth Grice¹, Indra Adrianto², Cristina de Guzman Strong^{5, 4} 1. Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States. 2. Public Health Sciences, Henry Ford Health System, Detroit, MI, United States. 3. Washington University in St Louis School of Medicine, St. Louis, MO, United States. 4. Medicine, Michigan State University College of Human Medicine, East Lansing, MI, United States. 5. Dermatology, Henry Ford Health System, Detroit, MI, United States. Epidermal Structure and Barrier Function