IL-6-Mediated Neurogenic Inflammation Regulated by the Dorsal Root Ganglion Macrophages Exacerbates Imiquimod-Induced Psoriasis-Like Skin Lesions in Mice.

Abstract

Neuroimmunological mechanisms are essential for maintaining bodily homeostasis. Abnormal activation of these mechanisms is significantly linked to various skin disorders and constitutes a significant component in the development of these diseases. However, the involvement of neuroimmunological interactions in psoriasis pathogenesis is not yet fully understood. In this study, we identify the peripheral nervous system as a significant source of IL-6, which contributes to skin inflammation and acts as a key regulator in the onset and progression of psoriasis. Through single-cell sequencing analysis of mouse dorsal root ganglia tissue, we identified a specific group of neurons that secrete IL-6. These neurons exhibited elevated levels of IL-6 expression after treatment with imiquimod. In addition, we observed a reciprocal regulatory relationship between the peripheral nervous system and immune cells. Neuronal activity is tightly controlled by surrounding macrophages. The expression of IL-6 is regulated by the secreted IL-1β upon M1 polarization and is dependent on MAPK signaling. Consequently, IL-6 is secreted from neurons into the skin, exacerbating the development and progression of psoriasis. This study reveals the mechanisms through which sensory neurons regulate psoriasis through IL-6, further clarifying the neuropsychiatric factors involved in the pathogenesis of psoriasis. It offers previously unreported insights for the clinical treatment of psoriasis.