The role of noncanonical NF-κB signaling in chronic inflammatory skin diseases and premalignant inflammation and tumorigenesis

• Applicants: Privatdozent Dr. Manfred Kneilling; Professorin Dr. Bettina Weigelin
• Subject Area: Dermatology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 556020868

NF-κB is crucial transaction factor involved in the regulation of immune responses. While the role of canonical NF-κB signaling in inflammation, particularly in initiating innate and adaptive immune responses, is well-established, the exact function of noncanonical NF-κB signaling in T cell mediated inflammatory skin diseases like atopic dermatitis and psoriasis vulgaris, remains largely unexplored. Our preliminary findings demonstrated that noncanonical NF-κB signaling in skin-resident cells, including keratinocytes, significantly influences the transition from acute to chronic inflammation in an experimental model of cutaneous delayed-type hypersensitivity reactions (DTHR) by controlling angiogenesis and the expression of endothelial adhesion molecules, cytokines and chemokines involved in neutrophil and T-cell recruitment and activation. However, this pathway appears to affect inflammation differently depending on the underlying pathomechanism and disease stage. Therefore, understanding the specific role of noncanonical NF-κB signaling in various chronic inflammatory conditions is essential for developing new and effective therapies targeting this pathway. In this project, we aim to elucidate how noncanonical NF-κB signaling in skin-resident cells, such as keratinocytes and endothelial cells, coordinate inflammatory responses in T cell-mediated and T cell-independent inflammatory skin diseases. Thus, we will employ longitudinal non-invasive in vivo positron emission tomography (PET)/magnetic resonance imaging (MRI), optical imaging and intravital microscopy, together with ex vivo multiplexed tissue analysis using 3D light-sheet microscopy and CO-Detection by indEXing (CODEX). To understand the underlying regulatory and compensatory mechanisms in NF-κB2 deficiency we will analyze the expression patterns of the NF-κB subunits and their target genes through extensive chromatin immunoprecipitation DNA-Sequencing (Chip-Seq) analysis. Additionally, we will investigate whether noncanonical NF-κB signaling contributes to the transition to premalignant inflammation, potentially leading to carcinogenesis.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Roman Mehling, Ph.D.