Primary sensory neuron-derived miR-let-7b underlies stress-elicited psoriasis

• Published in: Brain, behavior, and immunity Vol. 123; pp. 997 - 1010
• Main Authors: Yang, Huan, Wang, Yun-Yun, Chang, Weiqi, Zhai, Mengying, Du, Wan-Jie, Jiang, Wencheng, Xiang, Yan-Wei, Qin, Guoyou, Yu, Jin, Gong, Ye, Han, Qingjian
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-01-2025
• Subjects: CSDS; DRG; Macrophage; miR-let-7b; Psoriasis; TLR7; CSDS; DRG; TLR7; miR-let-7b; Psoriasis; Macrophage
• ISSN: 0889-1591; 1090-2139; 1090-2139
• DOI: 10.1016/j.bbi.2024.11.005

•Mice exposed to chronic social defeat stress (CSDS) show worsened imiquimod (IMQ)-induced psoriasis symptoms.•Depolarization significantly elevates the expression and release of miR-let-7b from DRG neurons in CSDS mice.•miR-let-7b activates skin-resident macrophages via TLR7 expressed on these immune cells.•Activated macrophages secrete more immune mediators, driving macrophage recruitment and activating the IL-23/IL-17 axis.
Psoriasis, a chronic autoimmune skin condition with significant global morbidity, badly impairs patients’ quality of life. Stress has been identified as a prominent trigger for psoriasis, and effectively management of stress can ameliorate its pathological manifestations. However, the precise mechanisms by which stress influences psoriasis remain elusive. In this study, we found that mice subjected to chronic social defeat stress (CSDS) exhibit severer imiquimod (IMQ)-induced psoriasis with increased epidermal scaling, epidermal hyperplasia, number of epidermal ridges, itch, and skin inflammation than control mice. Mechanistic study reveals that CSDS leads to an elevated release of miR-let-7b, an endogenous ligand of Toll-like receptor 7 (TLR7), from the peripheral terminal of dorsal root ganglia (DRG) neurons into the skin. This process can stimulate skin-resident macrophages to release cytokines (such as IL-6 and TNF-a) and chemokines (such as MCP-1), subsequently promoting the recruitment of additional macrophages into the skin. Notably, the specific blockade of miR-let-7b in DRG neurons effectively relieve stress-induced exacerbations of psoriasis. Furthermore, intradermal injection of synthetic miR-let-7b can induce a psoriasis-like phenotype in wildtype mice, a phenomenon that can be countered by the application of a TLR7 antagonist. Additionally, microfluidic chamber coculture assays demonstrated that miR-let-7b released by DRG neurons activates macrophages via TLR7 expressed on these immune cells. Totally, this study found that stress-induced upregulation and release of miR-let-7b from DRG neurons stimulates macrophages to secrete more inflammatory cytokines and chemokines, thereby exacerbating skin inflammation and the psoriatic phenotype. These findings provide a potential therapeutic strategy targeting the miR-let-7b/TLR7 pathway to alleviate stress-induced exacerbation of psoriasis.