Inhibition of Ephrin receptor signaling in the paraventricular nucleus attenuates psoriasis-like dermatitis via synaptic plasticity and immune homeostasis modulation.

Abstract

Psoriasis pathophysiology involves dysregulated neuroimmune crosstalk, yet the central mechanisms involved remain incompletely understood. Here, we show that the hypothalamic paraventricular nucleus (PVN) orchestrates cutaneous inflammation via a transsynaptic brain-skin circuit. Using neural tracing and chemogenetic approaches, we revealed functional connectivity between the PVN and both sympathetic neurons and psoriatic skin. Reactivation of imiquimod (IMQ)-induced PVN-transgenic targeted recombination in active population (TRAP) neurons (which form a specific "inflammatory memory") is essential for psoriasis progression and can drive chronic inflammation. Single-nucleus RNA sequencing (snRNA-seq) identified ephrin receptor A7 (Epha7) as a critical mediator of synaptic plasticity in PVN inflammatory engram neurons. The inhibition of Ephrin receptor and ligand binding in the PVN normalized dendritic spine remodelling, suppressed sympathetic nerve hyperactivity, and restored the balance of Th17/Treg cells in psoriatic-like mice. Mechanistically, blockade of the Ephrin receptor attenuated sympathetic norepinephrine overflow, thereby mitigating Th17-driven inflammation. This study identifies a PVN-sympathetic-skin axis in which the inhibition of Epha7 in the PVN restores skin immune homeostasis. Furthermore, this study elucidates the central neural mechanisms of skin inflammation and promotes the transition of psoriasis treatment from single-target approaches to a synergistic neuroimmune strategy involving "brain-skin" interactions.