Keratinocyte-derived CXCL-CXCR2 ligand-receptor axis by MED1 orchestrates neutrophil phenotypes during psoriasis.

Background: Psoriasis is a chronic inflammatory skin disease characterized by aberrant keratinocyte proliferation and dysregulated immune responses. Increasing evidence suggests that reciprocal communication between tissue-resident keratinocytes and infiltrating immune cells shapes the inflammatory microenvironment and governs disease progression. However, the molecular mechanisms underlying this immune-parenchymal crosstalk remain incompletely understood. Methods: Here, we generate epidermal-specific Med1 conditional knockout (cKO) mice using the Cre-loxP system and induce psoriasis model with imiquimod (IMQ). To characterize immune-parenchymal interactions, single-cell RNA sequencing (scRNA-seq) was performed on lesional skin from cKO and wild-type (WT) mice. The underlying mechanisms governing keratinocyte-neutrophil communication were further investigated using flow cytometry, CellChat analysis, dual-luciferase reporter assays, transwell migration assays, and qRT-PCR. Results: Epidermal deficiency of Med1 markedly alleviated IMQ-induced psoriasis, as evidenced by reduced epidermal thickness and diminished inflammatory cytokine production. The scRNA-seq result showed epithelial cells were reduced, accompanied with the significantly diminished neutrophil accumulation in cKO mice. Flow cytometry analysis also showed that CD45 Conclusions: Collectively, our findings identify previously unrecognized neutrophil subtypes and demonstrates that epithelial Med1 regulates neutrophil phenotypes through the keratinocyte-derived CXCL-CXCR2 ligand-receptor axis. These findings uncover a microenvironmental mechanism governing neutrophil reprogramming and provide new insights into immune-parenchymal ligand-receptor communication in psoriasis.