# Dissecting the molecular mechanisms of T cell infiltration in psoriatic lesions via cell-cell communication and regulatory network analysis

## TL;DR

This study explores how T cells infiltrate psoriatic skin by analyzing cell communication and signaling pathways, identifying a potential new treatment for psoriasis.

## Contribution

The study reveals a novel IL-6-STAT3-MDK signaling axis in fibroblast-driven T cell recruitment in psoriasis and proposes CuE as a potential therapeutic.

## Key findings

- Psoriatic skin shows increased T cells and endothelial cells with reduced melanocytes.
- CuE treatment reduces psoriasis-like symptoms by inhibiting the IL-6-STAT3-MDK signaling pathway.
- Fibroblasts upregulate MDK signaling, enhancing T cell recruitment in psoriasis.

## Abstract

This study aims to elucidate the intercellular communication mechanisms underlying T cell infiltration in psoriatic skin. Single-cell RNA sequencing revealed increased proportions of endothelial cells and T cells, alongside a reduction in melanocytes in psoriatic skin. Pseudotime analysis demonstrated dynamic transitions in T cell states, with significant gene expression changes at key branching points. These genes were enriched in pathways related to the ribosome, cytoplasmic translation, and ribosomal structural components. Cell-cell communication analysis showed enhanced interactions, particularly between T cells and fibroblasts in psoriasis. Fibroblasts exhibited upregulated MK signaling, characterized by elevated MDK expression and increased MDK receptor levels on T cells, suggesting MDK-mediated T cell recruitment. Regulatory network analysis identified IL-6 as a primary ligand regulating MDK via STAT3 and AHR, with increased expression of IL-6R, STAT3, and AHR in psoriatic fibroblasts. CuE treatment significantly alleviated psoriasis-like symptoms in a mouse model, as evidenced by reduced PASI scores, epidermal hyperplasia, and inflammatory cytokine levels. Mechanistically, CuE inhibited the STAT3/MDK signaling pathway, indicating its role in modulating fibroblast-driven T cell recruitment in psoriatic inflammation. This study demonstrates that CuE alleviates psoriasis-like symptoms by inhibiting the IL-6-STAT3-MDK signaling axis, positioning it as a potential novel therapeutic targeting fibroblast-mediated immune interactions in psoriasis.