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Suppressing Ephrin Receptor Signaling in the Paraventricular Nucleus Attenuates Psoriasis by Modulating Synaptic Plasticity and Immunity Homeostasis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE296150 | GEO | 2025/11/14

REPOSITORIES: GEO

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Project description:IL-20 cytokines are involved in the establishment of psoriasis, a common chronic skin inflammation epidemiologically associated with metabolic syndrome, but molecular mechanisms underlying their over-expression remain to be elucidated. We find that keratinocytes (KCs) expressed IL-20 and lymphocytes expressed IL-22 cytokines up-regulation occurs at post-transcriptional level with stabilization of their RNA messengers. Looking at psoriatic epidermis, we observe that the p38/MK2 pathway is not activated but that the RNA-binding protein (RBP) HuR re-localizes in keratinocytes cytoplasm, suggesting post-transcriptional regulation of numerous mRNAs. HuR ribonucleoprotein immunoprecipitations analyzed by high-throughput sequencing (RIP-Seq) identify potential pre-mature and mature RNA targets for uninvolved and involved skin and confirms that HuR activity is displaced from the nucleus to the cytoplasm. Numerous psoriasis up-regulated transcripts are HuR targets and HuR knockdown reduces expression of transcripts like beta-defensin-2, CXCL-10 or IL-2, suggesting an implication of HuR in pathophysiological processes such as morphological, immune and metabolic inflammatory responses. Finally, metabolic disorders affecting psoriatic keratinocytes are responsible for HuR cytoplasmic localization since a decreased activity of the cellular metabolic sensor AMPK, that is observed in human psoriatic epidermis, is sufficient to promote HuR cytosolic localization as well as IL-20 over-production both in human keratinocytes and in vivo in mouse epidermis where it then initiates psoriasis-like histological changes. These results may provide insights into molecular links between metabolism and post-transcriptional networks during chronic inflammation, as illustrated in psoriasis by mechanisms connecting AMPK, HuR and IL-20. Analysis of HuR-binding RNA in uninvolved versus involved psoriatic samples by RIP-Seq. Samples from five different patients were used for both uninvolved and involved skin. RIP-Seq was also made using a control IgG.

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Suppressing Ephrin Receptor Signaling in the Paraventricular Nucleus Attenuates Psoriasis by Modulating Synaptic Plasticity and Immunity Homeostasis

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