Authors
Weiwei Liang, Deshu Xu, Li Zhang, Yuhua Qu, Lanying Li, Kanghua Zhong, Meng Yao, Jianheng Zhu, Shang Wang, Liren Tan, Wenjiao Ding, Ruizhong Zhang, Feiyan Wang, Wenhao Zhou, Fan Bai, Hua Jiang, Yuxia Zhang
Published in
Blood. Jun 18, 2026. Epub Jun 18, 2026.
Abstract
Steroid-resistant gastrointestinal graft-versus-host disease (SR-GI-GVHD) is a lethal complication of allogeneic hematopoietic stem cell transplantation with no clear therapeutic target. The role of neutrophil heterogeneity in its pathogenesis remains poorly defined. Through single-cell RNA sequencing of patient blood, we identified a specific neutrophil subset (CD16hiCD177⁺) that is markedly expanded in SR-GI-GVHD. This subset utilizes CD177 to bind endothelial CD31, facilitating transmigration into the intestine. Upon arrival, MyD88-mediated sensing of translocated gut bacteria triggers the release of neutrophil extracellular traps (NETs), directly causing epithelial damage. Mechanistically, we discovered that elevated levels of retinoic acid (RA) in patients drive the expansion and pathogenic programming of these neutrophils via the RARA-SPI1 transcriptional axis. In a murine model of GVHD, genetic deletion of Cd177 or Myd88 in donor cells attenuated disease. Crucially, pharmacological inhibition of the RA receptor with AGN193109 not only ameliorated GI-GVHD and improved survival but also restored sensitivity to corticosteroids. Together, these findings delineate a complete pathogenic circuit-from the metabolic driver retinoic acid and the RARA-SPI1 transcriptional axis to the CD177⁺ neutrophil cellular effector and its NETosis-mediated tissue damage. This establishes the RA-driven CD177⁺ neutrophil subset as a key mediator of SR-GI-GVHD and identifies RARA inhibition as a promising therapeutic strategy.
PMID:
42322118
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.
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