Impact of 4-1BB/4-1BB ligand signaling on neuroimmune communication and the development of skin inflammation

• Applicant: Professorin Dr. Karin Loser
• Subject Area: Dermatology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 425988903

The skin is constantly exposed to the environment resulting in the induction of cutaneous immune responses. Members of the TNF/TNF receptor family are involved in the regulation of the skin immune system and we demonstrated that up-regulated CD40L signaling resulted in the induction of SLE-like autoimmunity whereas cutaneous RANKL overexpression controlled tolerance. Additionally, skin inflammation is dependent on the communication of immune cells with cutaneous nerve fibers, which can be direct or mediated by soluble factors including IL-31 and neuropeptides. In contrast to other receptor-ligand pairs of the TNF family, 4 1BB and 4-1BBL are expressed by neuronal as well as immune cells and are up-regulated upon cell activation. To investigate whether 4 1BB/4 1BBL signaling contributes to the progression of skin inflammation by controlling the communication of peripheral nerve fibers with cutaneous immune cells, we generated transgenic mice overexpressing 4 1BB in the skin (K14-4 1BB tg mice). At the age of 4 months K14 4 1BB tg mice spontaneously developed a chronic pruritic skin inflammation histologically resembling human atopic dermatitis (AD). Worth mentioning, 4 1BB is also enhanced in lesional skin from individuals with AD, suggesting that 4 1BB/4 1BBL signaling might be involved in the control of neurogenic skin inflammation. Neurogenic inflammation including AD requires the interaction of T cells with peripheral sensory nerve fibers, whereas the latter generate currents following the stimulation of the itch-related receptor IL-31ra after binding T cell-secreted IL-31. Accordingly, the expression of IL-31 and its receptor was significantly increased in lesional skin from K14-4-1BB tg mice and particularly CD8+ T cells were characterized by high IL-31 levels. Interestingly, the depletion of either sensory neurons or CD8+ T cells dramatically reduced disease severity and IL-31 levels, indicating that 4 1BB/4 1BBL signaling is indeed critically involved in the development and progression AD-like skin inflammation, probably via controlling neuroimmune communication. However, the underlying mechanisms and the precise role of 4 1BB/4-1BBL signaling in the interplay of peripheral sensory neurons with immune cells are not clear. Therefore, we intend to characterize the relevance of 4-1BB/4-1BBL signaling for the development and progression of neurogenic skin inflammation and the impact of this signaling pathway on the crosstalk of immune and neuronal cells during the development of AD-like skin disease. To this end, we will address three central questions: (1) Which molecular mechanisms and signaling pathways downstream of 4-1BB/4-1BBL interactions control AD-like pruritic skin disease in K14-4-1BB tg mice? (2) How does 4-1BB/4-1BBL signaling control cell-cell-interaction during the development of chronic pruritic skin inflammation such as AD? (3) Which role does 4 1BB/4-1BBL signaling play in human cells or skin samples from patients with AD?

• DFG Programme: Research Grants