CD47 fuels intestinal fibrosis by inducing fibroblast phagocytic evasion and represents a therapeutic target
- 1Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China
- 2Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
Abstract
Intestinal fibrosis is a major complication of Crohn’s disease, for which targeted therapies remain unavailable. Fibrosis is defined by excess matrix deposition, which may result from inadequate phagocytic clearance, yet how phagocytosis shifts here is unclear. Using single-cell and spatial transcriptomics, we identify fibrosis-associated CD47hi fibroblasts coupled to SIRPAhi macrophages in fibrotic regions. Cell-cell communication analyses and neutralizing-antibody experiments identify interleukin-1β as a mediator of their crosstalk, forming a profibrotic niche characterized by phagocytic evasion. Genetic disruption of fibroblast Cd47 or macrophage Sirpa enhances fibroblast clearance and attenuates fibrosis. Mechanistically, checkpoint disruption reprograms macrophages toward an NRF2-associated pro-phagocytic state, linking enhanced clearance to the antifibrotic response. Furthermore, therapeutic antibody blockade of this checkpoint attenuates intestinal fibrosis in mouse models with schedule-dependent efficacy. Collectively, these findings support CD47-mediated phagocytic evasion as a key pathogenic mechanism in intestinal fibrosis and identify CD47-SIRPα blockade as a promising therapeutic target.
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BibTeX
@article{zhao2026cd47,
title = {{CD47 fuels intestinal fibrosis by inducing fibroblast phagocytic evasion and represents a therapeutic target}},
author = {Xiangyu Zhao and Yingman Wang and Danshu Wang and Xinyu Wang and Sishen Sun and Mingji Li and Jia Song and Haiming Zhuang and Jiaxin Wang and Qidi Yang and Yizhou Zhao and Youqiong Ye and Liwen Hong and Taojing Ran and Yao Zhang and Duowu Zou},
journal = {Cell Reports Medicine},
year = {2026},
month = oct,
doi = {10.1016/j.xcrm.2026.103103},
url = {https://doi.org/10.1016/j.xcrm.2026.103103},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - CD47 fuels intestinal fibrosis by inducing fibroblast phagocytic evasion and represents a therapeutic target
AU - Xiangyu Zhao
AU - Yingman Wang
AU - Danshu Wang
AU - Xinyu Wang
AU - Sishen Sun
AU - Mingji Li
AU - Jia Song
AU - Haiming Zhuang
AU - Jiaxin Wang
AU - Qidi Yang
AU - Yizhou Zhao
AU - Youqiong Ye
AU - Liwen Hong
AU - Taojing Ran
AU - Yao Zhang
AU - Duowu Zou
PY - 2026
DA - 2026/10/20
JO - Cell Reports Medicine
DO - 10.1016/j.xcrm.2026.103103
UR - https://doi.org/10.1016/j.xcrm.2026.103103
AB - Intestinal fibrosis is a major complication of Crohn’s disease, for which targeted therapies remain unavailable. Fibrosis is defined by excess matrix deposition, which may result from inadequate phagocytic clearance, yet how phagocytosis shifts here is unclear. Using single-cell and spatial transcriptomics, we identify fibrosis-associated CD47hi fibroblasts coupled to SIRPAhi macrophages in fibrotic regions. Cell-cell communication analyses and neutralizing-antibody experiments identify interleukin-1β as a mediator of their crosstalk, forming a profibrotic niche characterized by phagocytic evasion. Genetic disruption of fibroblast Cd47 or macrophage Sirpa enhances fibroblast clearance and attenuates fibrosis. Mechanistically, checkpoint disruption reprograms macrophages toward an NRF2-associated pro-phagocytic state, linking enhanced clearance to the antifibrotic response. Furthermore, therapeutic antibody blockade of this checkpoint attenuates intestinal fibrosis in mouse models with schedule-dependent efficacy. Collectively, these findings support CD47-mediated phagocytic evasion as a key pathogenic mechanism in intestinal fibrosis and identify CD47-SIRPα blockade as a promising therapeutic target.
SN - 2666-3791
ER -