TNF-α promotes psoriasis-related keratinocytes dedifferentiation by inactivating NOTCH1 signaling

Summary: Abstract Body: The pathogenesis of psoriasis remains elusive, yet anti-TNF-α and IL-17A biologics have proven highly effective, highlighting the crucial role of these cytokines. TNF-α exhibits a broader range of responsive gene signatures in keratinocytes, suggesting its significant impact on keratinocyte fate. NOTCH1 signaling, a critical regulator of cell proliferation and differentiation, has not been thoroughly studied in the context of TNF-α interaction in psoriasis. Our study observed inactivated NOTCH1 signaling in psoriasis skin samples and TNF-α-induced mouse epidermis, accompanied by downregulated keratinocyte differentiation markers (KRT1, KRT10). Using a TNF-α-induced NHEK model, we found significant downregulation of differentiation-related genes, including KRT1 and KRT10, and upregulation of the stemness marker CD44. Knockdown of TNFR1 blocked TNF-α's impact on NOTCH1 signaling and differentiation marker expression. Our results further revealed that TNF-α upregulated ADAM8 expression and activated ADAM10 in an ADAM8-dependent manner, leading to NOTCH1 cleavage and NICD1 release. TNF-α also activated TNFR1 signaling, causing ubiquitination-mediated degradation of NICD1, thereby inactivating NOTCH1 signaling. To validate our findings, we employed cell and animal models. Administration of ADAM8 or ADAM10 inhibitors blocked NICD1 degradation, restored KRT1 and KRT10 expression, and alleviated epidermal thickening in psoriasis-like mice. These results suggest that TNF-α inhibits keratinocyte differentiation by inactivating NOTCH1 signaling through ubiquitination-mediated NICD1 degradation. In summary, our study identifies a novel mechanism by which TNF-α regulates keratinocyte differentiation in psoriasis, providing insights into the disease's pathogenesis and potential new therapeutic targets. Zengyang Yu^{1, 2}, Yuling Shi^{3, 2} 1. Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. 2. Institute of Psoriasis, Tongji University School of Medicine, Shanghai, China. 3. Shanghai Skin Disease Hospital, Tongji University School of Medicine, Shanghai, China. Epidermal Structure and Barrier Function