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Mucosal Immunol. 2019 Jun 10. doi: 10.1038/s41385-019-0178-9. [Epub ahead of print]

SARI attenuates colon inflammation by promoting STAT1 degradation in intestinal epithelial cells.

Author information

1
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan Province, China.
2
West China Biobanks, Department of Clinical Research Management and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
3
Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
4
Department of Gastrointestinal Surgery, West China Hospital and State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan Province, China.
5
Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, Merseyside, UK.
6
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan Province, China. denghongx@scu.edu.cn.

Abstract

SARI functions as a suppressor of colon cancer and predicts survival of colon cancer patients, but its role in regulating colitis has not been characterized. Here we show that SARI-/- mice were highly susceptible to colitis, which was associated with enhanced macrophage infiltration and inflammatory cytokine production. Bone marrow reconstitution experiments demonstrated that disease susceptibility was not dependent on the deficiency of SARI in the immune compartment but on the protective role of SARI in the intestinal epithelial cells (IECs). Furthermore, SARI deficiency enhanced Chemokine (C-C motif) Ligand 2 (CCL2) production and knockout of CCR2 blocks the promoting role of SARI deficiency on colitis. Mechanistically, SARI directly targets and promotes signal transducer and activator of transcription 1 (STAT1) degradation in IECs, followed by persistent inactivation of the STAT1/CCL2 transcription complex. In summary, SARI attenuated colitis in mice by impairing colitis-dependent STAT1/CCL2 transcriptional activation in IECs and macrophages recruitment in colon tissue.

PMID:
31182817
DOI:
10.1038/s41385-019-0178-9

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