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

皮肤持续暴露于环境中，导致皮肤免疫应答的诱导。TNF/TNF受体家族成员参与皮肤免疫系统的调节，我们证明上调的CD 40 L信号转导导致SLE样自身免疫的诱导，而皮肤RANKL过表达控制耐受。此外，皮肤炎症依赖于免疫细胞与皮肤神经纤维的通讯，这可以是直接的或由包括IL-31和神经肽在内的可溶性因子介导的。与TNF家族的其他受体-配体对相反，4 - 1BB和4-1BBL由神经元细胞以及免疫细胞表达，并且在细胞活化时上调。为了研究4 1BB/4 1BBL信号传导是否通过控制外周神经纤维与皮肤免疫细胞的通讯而促进皮肤炎症的进展，我们产生了在皮肤中过表达4 1BB的转基因小鼠（K14-4 1BB tg小鼠）。在4月龄时，K14 4 1BB tg小鼠自发地发展出组织学上类似于人类特应性皮炎（AD）的慢性皮炎性皮肤炎症。值得一提的是，4 1BB也在AD患者的皮损中增强，表明4 1BB/4 1BBL信号传导可能参与神经源性皮肤炎症的控制。包括AD在内的神经源性炎症需要T细胞与外周感觉神经纤维的相互作用，而后者在结合T细胞分泌的IL-31后刺激瘙痒相关受体IL-31 ra后产生电流。因此，IL-31及其受体的表达在来自K14-4-1BB tg小鼠的病变皮肤中显著增加，特别是CD 8 + T细胞的特征在于高IL-31水平。有趣的是，感觉神经元或CD 8 + T细胞的耗竭显著降低了疾病的严重程度和IL-31水平，表明4 1BB/4 1BBL信号传导确实与AD样皮肤炎症的发展和进展密切相关，可能是通过控制神经免疫通讯。然而，4 - 1BB/4-1BBL信号在外周感觉神经元与免疫细胞相互作用中的潜在机制和确切作用尚不清楚。因此，我们打算表征4-1BB/4-1BBL信号传导与神经源性皮肤炎症的发展和进展的相关性，以及该信号传导途径对AD样皮肤病发展过程中免疫和神经元细胞串扰的影响。为此，我们将解决三个中心问题：（1）在K14-4-1BB tg小鼠中，4-1BB/4-1BBL相互作用下游的哪些分子机制和信号通路控制AD样皮炎皮肤病？(2)4-1BB/4-1BBL信号传导如何控制慢性皮炎皮肤炎症（如AD）发展过程中的细胞-细胞相互作用？(3)4 - 1BB/4-1BBL信号传导在AD患者的人体细胞或皮肤样本中起什么作用？

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?