Authors
Victoriano Mulero, Joaquin Canton-Sandoval, Francisco Martinez-Morcillo, Natalia Perez-Escudero, Isabel Cabas, Beatriz Bernal-Bermudez, Anna Luciano, Juan Lozano-Gil, Alicia Martinez-Lopez, Cassia Michael, Teresa Martinez Menchon, Raul Corbalan-Velez, Belén Ferri, Maria Luisa Cayuela, Raquel Espin Palazon, Sofia de Oliveira, Diana García-Moreno
Published in
Research square. Aug 11, 2026. Epub Aug 11, 2026.
Abstract
Neutrophils are the most abundant leukocytes and key regulators of tissue homeostasis and disease. Here we show that inhibiting Gapdh nuclear translocation limits neutrophil infiltration into inflamed skin, reduces their motility, and decreases keratinocyte hyperproliferation and cell death in a zebrafish model of skin inflammation. Wild-type Gapdh expression in neutrophils, but not a nuclear-translocation-deficient mutant, exacerbated inflammation. Pharmacological inhibition of GAPDH nuclear translocation also attenuated pathology-associated markers in human organotypic 3D skin models of inflammation. In psoriasis lesions, GAPDH levels were elevated with altered localization. Single-cell RNA-seq revealed that Gapdh nuclear translocation regulates a subset of inflammation-induced genes in neutrophils, including il4. Mechanistically, Gapdh enhances il4 transcription by promoting H3K27 acetylation at its promoter, whereas pharmacological inhibition of this pathway restores basal levels. Consistently, Il4 deficiency alleviated inflammation. These findings identify a conserved, non-canonical GAPDH signaling pathway that orchestrates chronic skin inflammation and represents a potential therapeutic target.
PMID:
42845787
Bibliographic data and abstract were imported from PubMed on 08 Oct 2026.
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