Type 3 inflammation–specific keratinocyte glutaminolysis promotes skin inflammation
- 1Institute of Dermatology and Venereology, Dermatology Hospital, Southern Medical University, Guangzhou, China.
- 2Department of Dermatology, The First Affiliated Hospital of Jinan University & Jinan University Institute of Dermatology, Guangzhou, China.
Abstract
Inflammatory cytokines reprogram keratinocyte metabolism, but the metabolic pathways that couple immune signals to pathological epidermal growth remain incompletely defined. Here, we identify glutaminase 1–mediated (GLS1-mediated) glutaminolysis as a metabolic program preferentially induced in keratinocytes under type 3 inflammatory conditions. Integrated transcriptomic, metabolomic, genetic, and functional analyses showed that IL-17A induced GLS1 expression and glutaminolysis in keratinocytes. Keratinocyte-specific Gls1 deletion reduced the intracellular availability of arginine, proline, and methionine, impaired amino acid–dependent mTORC1 activation, disrupted redox homeostasis, and limited keratinocyte proliferation. Amino acid or antioxidant supplementation partially rescued these defects, whereas rapamycin blocked the amino acid–mediated proliferative rescue. Gls1 deletion did not impair steady-state skin development or homeostasis and did not alter MC903-induced type 2 dermatitis, but it delayed wound re-epithelialization and attenuated imiquimod-induced psoriasiform inflammation. Loss of keratinocyte GLS1 also reduced epidermal chemokine expression and the accumulation of neutrophils and IL-17A–producing γδ T cells, revealing a role for glutaminolysis in amplifying epithelial-immune crosstalk. These findings define GLS1-mediated glutaminolysis as a context-specific metabolic checkpoint linking type 3 inflammation to keratinocyte proliferation and cutaneous immune amplification, and support locally or temporally controlled GLS1 inhibition as a potential therapeutic strategy for psoriasis.
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BibTeX
@article{hu2026type,
title = {{Type 3 inflammation–specific keratinocyte glutaminolysis promotes skin inflammation}},
author = {Yongfei Hu and Hai Yu and Kaiyu Liang and Liyan Yuan and Wenjun Zhang and Zhe Zhuang and Suyun Ji and Xichun Xia},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.203626},
url = {https://doi.org/10.1172/jci.insight.203626},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Type 3 inflammation–specific keratinocyte glutaminolysis promotes skin inflammation
AU - Yongfei Hu
AU - Hai Yu
AU - Kaiyu Liang
AU - Liyan Yuan
AU - Wenjun Zhang
AU - Zhe Zhuang
AU - Suyun Ji
AU - Xichun Xia
PY - 2026
DA - 2026/09/08
JO - JCI Insight
DO - 10.1172/jci.insight.203626
UR - https://doi.org/10.1172/jci.insight.203626
AB - Inflammatory cytokines reprogram keratinocyte metabolism, but the metabolic pathways that couple immune signals to pathological epidermal growth remain incompletely defined. Here, we identify glutaminase 1–mediated (GLS1-mediated) glutaminolysis as a metabolic program preferentially induced in keratinocytes under type 3 inflammatory conditions. Integrated transcriptomic, metabolomic, genetic, and functional analyses showed that IL-17A induced GLS1 expression and glutaminolysis in keratinocytes. Keratinocyte-specific Gls1 deletion reduced the intracellular availability of arginine, proline, and methionine, impaired amino acid–dependent mTORC1 activation, disrupted redox homeostasis, and limited keratinocyte proliferation. Amino acid or antioxidant supplementation partially rescued these defects, whereas rapamycin blocked the amino acid–mediated proliferative rescue. Gls1 deletion did not impair steady-state skin development or homeostasis and did not alter MC903-induced type 2 dermatitis, but it delayed wound re-epithelialization and attenuated imiquimod-induced psoriasiform inflammation. Loss of keratinocyte GLS1 also reduced epidermal chemokine expression and the accumulation of neutrophils and IL-17A–producing γδ T cells, revealing a role for glutaminolysis in amplifying epithelial-immune crosstalk. These findings define GLS1-mediated glutaminolysis as a context-specific metabolic checkpoint linking type 3 inflammation to keratinocyte proliferation and cutaneous immune amplification, and support locally or temporally controlled GLS1 inhibition as a potential therapeutic strategy for psoriasis.
SN - 2379-3708
ER -