# GPER1 reduces skin inflammation by inhibiting keratinocyte proliferation

## TL;DR

This study shows that GPER1 reduces skin inflammation by limiting keratinocyte growth, offering a potential new treatment for psoriasis.

## Contribution

The novel finding is that GPER1 acts as a negative regulator of keratinocyte proliferation and inflammation in psoriasis.

## Key findings

- GPER1 signaling is downregulated in psoriasis lesional skin and correlates with inflammation and keratinocyte proliferation.
- Gper1 deficiency in zebrafish increases keratinocyte proliferation and neutrophil infiltration.
- Gper1 overexpression in keratinocytes rescues skin inflammation independently of immune signaling.

## Abstract

Psoriasis is a chronic inflammatory skin disease characterized by keratinocyte (KC) hyperproliferation and immune cell infiltration, including neutrophils. While estrogens are known to modulate immune responses, the role of the G protein-coupled estrogen receptor 1 (GPER1) in skin inflammation remains poorly understood. Here, we show that GPER1 signaling is downregulated in lesional skin of psoriasis patients and negatively correlates with both inflammation markers and KC proliferation. Using a zebrafish model of chronic skin inflammation (Spint1a-deficient larvae), we demonstrate that Gper1 deficiency leads to increased KC proliferation and enhanced neutrophil infiltration, without directly modulating inflammatory signaling. Pharmacological inhibition of cell proliferation with palbociclib reduced both KC aggregates and neutrophil infiltration, independently of NF-κB activation. Moreover, Gper1 overexpression in basal KCs, but not in neutrophils, rescued skin alterations, indicating a cell-autonomous effect in KCs. Notably, our results also suggest that epithelial cell proliferation facilitates immune cell infiltration into inflamed tissue. Together, our results identify GPER1 as a negative regulator of keratinocyte hyperproliferation and skin inflammation, suggesting that modulation of this pathway may represent a therapeutic strategy for hyperproliferative inflammatory skin diseases such as psoriasis.