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


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.

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Writing assistance was obtained from the Editage Company. This study was supported by the National Natural Science Foundation of China Programme grant (No. 81772939) and the National Key R&D Programme of China grant (No. 2017YFA0105702) and the National Key R&D Programme of China (2016YFC1201700) and the Fundamental Research Funds for the Central Universities (2017SCU12033) and the Special Foundation of China Postdoctoral Science (2018T110980).

Author information

H.D. and L.D. designed the study; L.D. and H.D. analyzed and interpreted data, drafted and critically revised the manuscript. L.D., Y.L., L.C., H.W. performed most of the experiments with assistance from Y.L., G.S., Z.D., J.L.; P.F., X.H. and Z.Z. collected human colon cancer tissue; Q.W. and X.S. were involved in animal study. S.Z. and Y.Y. provided assistance in technical support, data analysis and interpretation. W.H. and C.P. critically revised the manuscript. L.D., D.Y., Y.W. and H.D. obtained funding and supervised students; all authors read and approved the manuscript.

Competing interests

The authors declare no competing interests.

Correspondence to Hongxin Deng.

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