# Keratinocyte HIF-1α Orchestrates Imiquimod-Induced Psoriasiform Inflammation by Promoting Type 3 Inflammation

## TL;DR

This study shows that HIF-1α in skin cells plays a key role in causing psoriasis-like inflammation by promoting specific immune responses.

## Contribution

The study identifies keratinocyte HIF-1α as a novel central regulator of psoriasiform inflammation.

## Key findings

- HIF-1α deficiency reduced epidermal hyperplasia and type 3 inflammation in the IMQ-induced psoriasiform model.
- HIF-1α deficiency decreased IL-17, IL-23, and neutrophil-attracting chemokine levels and neutrophil infiltration in IMQ-treated skin.
- HIF-1α-deficient mice showed reduced frequencies of inflammatory cells like IL-17-producing γδ T cells.

## Abstract

Psoriasis is a chronic inflammatory skin disease driven by the IL-23/IL-17 axis and characterized by keratinocyte hyperproliferation, epidermal thickening, and immune infiltration. While immune cell-intrinsic roles of hypoxia-inducible factor-1α (HIF-1α) have been reported, the contribution of keratinocyte HIF-1α remains less clear. In this study, we investigated epithelial HIF function in murine models of skin inflammation using keratinocyte-specific HIF-1α knockout (K14-Cre Hif1afl/fl) mice. HIF-1α deficiency attenuated epidermal hyperplasia and type 3 inflammation in the imiquimod (IMQ)-induced psoriasiform model but had little effect in DNFB-induce contact hypersensitivity and MC903-induced atopic dermatitis model. Flow cytometry of draining lymph nodes revealed reduced frequencies of inflammatory cells including IL-17-producing γδ T cells in HIF-1α-deficient mice. In IMQ-treated skin, HIF-1α deficiency led to reduced Il17, Il23 and neutrophil-attracting chemokine transcript levels and diminished Ly6G+ neutrophil infiltration. These findings identify keratinocyte HIF-1α as a central regulator of psoriasiform inflammation and suggest that epithelial HIF signaling could be a potential therapeutic target for psoriasis.