Keratinocyte-derived CXCL-CXCR2 ligand-receptor axis by MED1 orchestrates neutrophil phenotypes during psoriasis
5 affiliations
- 1Health Science Center, Ningbo University , , ,
- 2Immunology Department, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University , ,
- 3Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer , ,
- 4Department of Dermatology, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital , ,
- 5Department of Ophthalmology, Second Hospital of Tianjin Medical University , ,
Abstract
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 ⁺ Ly6G ⁺ neutrophils were found to be the most pronounced decreased relative to the other immune cells in cKO mice after IMQ. To further explore the dynamic changes of neutrophils in psoriasis, three novel neutrophil subtypes were identified, among which Cluster Nb exhibited a prominent chemotactic phenotype and was substantially diminished in cKO mice. Cell-cell communication analysis further identified the keratinocyte-derived CXCL-CXCR2 ligand-receptor axis as a key mediator of neutrophil recruitment. Mechanistically, keratinocyte-derived Med1 transcriptionally bound to CXCL1/2/3, thereby promoting CXCR2-dependent neutrophil chemotaxis during psoriasis.
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.
Related
- Gut microbiota-induced perturbation in bile acids alter keratinocyte lipid metabolism via FXR-NQO1 signaling in psoriasis
- L-Citrulline Attenuates Keratinocyte Activation and Modulates ASS1 Expression in Psoriasis-Like Mice.
- High-altitude exercise orchestrates a divergent immune landscape: cytotoxic suppression, humoral compensation, and neutrophil functional reprogramming.
- Single-cell profiling reveals stromal niche and α5β1 regulation of neutrophil phenotypes in ulcerative colitis
- Activation of α7 Nicotinic Acetylcholine Receptor Inhibits Neutrophil ex vivo Swarming and Pulmonary Recruitment in Inflamed Mice through an Integrin αMβ2-dependent Mechanism
BibTeX
@article{li2026keratinocytederived,
title = {{Keratinocyte-derived CXCL-CXCR2 ligand-receptor axis by MED1 orchestrates neutrophil phenotypes during psoriasis}},
author = {Yingxi Li and Junkai Huang and Guixin Wang and Jing Luo and Zhikai Cao and Lin Li and Qi Guo and Qianshu Yuan and Mingwei Li and Ziyu Zhang and Weibin Xing and Long Su and Lizhi Hu},
journal = {Frontiers in immunology},
year = {2026},
month = sep,
doi = {10.3389/fimmu.2026.1935554},
url = {https://europepmc.org/article/PMC/PMC13661492},
note = {CC BY},
}
RIS
TY - JOUR
TI - Keratinocyte-derived CXCL-CXCR2 ligand-receptor axis by MED1 orchestrates neutrophil phenotypes during psoriasis
AU - Yingxi Li
AU - Junkai Huang
AU - Guixin Wang
AU - Jing Luo
AU - Zhikai Cao
AU - Lin Li
AU - Qi Guo
AU - Qianshu Yuan
AU - Mingwei Li
AU - Ziyu Zhang
AU - Weibin Xing
AU - Long Su
AU - Lizhi Hu
PY - 2026
DA - 2026/09/30
JO - Frontiers in immunology
DO - 10.3389/fimmu.2026.1935554
UR - https://europepmc.org/article/PMC/PMC13661492
AB - 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 ⁺ Ly6G ⁺ neutrophils were found to be the most pronounced decreased relative to the other immune cells in cKO mice after IMQ. To further explore the dynamic changes of neutrophils in psoriasis, three novel neutrophil subtypes were identified, among which Cluster Nb exhibited a prominent chemotactic phenotype and was substantially diminished in cKO mice. Cell-cell communication analysis further identified the keratinocyte-derived CXCL-CXCR2 ligand-receptor axis as a key mediator of neutrophil recruitment. Mechanistically, keratinocyte-derived Med1 transcriptionally bound to CXCL1/2/3, thereby promoting CXCR2-dependent neutrophil chemotaxis during psoriasis. 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.
SN - 1664-3224
ER -