Mechanisms of the TNF-α signaling pathway in promoting itch and activating central depressive circuits in psoriasis

Summary: Abstract Body: The compromised skin barrier plays a crucial role in psoriasis and its associated depressive comorbidities, yet the underlying regulatory mechanisms remain unclear. Existing literature indicates that a disrupted skin barrier leads to increased expression of tumor necrosis factor-α (TNF-α). Through immunohistochemical staining, Western blotting, and other experimental techniques, we observed a significant elevation of TNF-α in psoriasis skin lesions (p=0.009). Behavioral tests revealed that psoriasis mice exhibited notable depressive-like behaviors, as evidenced by their reduced preference for sucrose preference test (p=0.0018), performance in the tail suspension test (p<0.001), and results from the forced swimming test (p<0.001). Furthermore, using brain stereotactic injections, optogenetics, and patch-clamp techniques, we identified that central mechanisms of itch and depression are regulated by the PBN→vlPAG and vlPAG→LHA neural circuits, respectively. We also noted a significant increase in TNF-α-overexpressing senescent microglial cells in the vlPAG region of the brain (p<0.001). Based on these findings, we hypothesize that TNF-α activation contributes to the engagement of central depressive circuits by promoting itch. We propose to investigate the mechanisms through which TNF-α enhances itch and inflammatory mediators in skin lesions, activates the PBN→vlPAG→LHA depressive neural circuit, and is modulated by TNF-α-activated senescent microglia. This investigation will employ interdisciplinary approaches from immunology and neurophysiology. Ultimately, we aim to assess the efficacy of drug-delivering microneedles, with the goal of providing a novel therapeutic strategy for managing the comorbidities of cutaneous inflammation and depression in patients with psoriasis. Xin Wang¹ 1. Huazhong University of Science and Technology, Wuhan, Hubei, China. Epidermal Structure and Barrier Function