Suppressing Ephrin Receptor Signaling in the Paraventricular Nucleus Attenuates Psoriasis by Modulating Synaptic Plasticity and Immunity Homeostasis
Psoriasis pathophysiology involves dysregulated neuroimmune crosstalk, yet the central mechanisms remain incompletely understood. Here, we demonstrate 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-TRAPed neurons (forms a specific "inflammatory memory") are essential for psoriasis progression and can be activated to 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. Inhibition of PVN Ephrin receptor and ligand binding normalized dendritic spine remodeling, suppressed sympathetic nerve hyperactivity, and restored the balance of Th17/Treg cells in psoriatic-like mice. Mechanistically, blockade of Ephrin receptor attenuated sympathetic norepinephrine overflow, thereby rescuing Treg depletion and mitigating Th17-driven inflammation. This study identifies a PVN-sympathetic-skin axis, wherein the inhibition of PVN Epha7 restores skin immune homeostasis. Furthermore, this study elucidated the central neural mechanisms encoding skin inflammation, and promotes the transition of psoriasis treatment from single-target approaches to a neuroimmune synergistic strategy encompassing "brain-skin" interactions. Overall design: Single-cell RNA-sequencing  of male mice smeared IMQ on the back (IMQ group).