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

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.

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References

  1. 1.

    Kaplan, G. G. The global burden of IBD: from 2015 to 2025. Nat. Rev. Gastroenterol. Hepatol. 12, 720–727 (2015).

  2. 2.

    Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

  3. 3.

    Chen, L. et al. NLRP12 attenuates colon inflammation by maintaining colonic microbial diversity and promoting protective commensal bacterial growth. Nat. Immunol. 18, 541–551 (2017).

  4. 4.

    Gupta, J. et al. Dual function of p38alpha MAPK in colon cancer: suppression of colitis-associated tumor initiation but requirement for cancer cell survival. Cancer Cell 25, 484–500 (2014).

  5. 5.

    Gillen, C. D., Walmsley, R. S., Prior, P., Andrews, H. A. & Allan, R. N. Ulcerative colitis and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 35, 1590–1592 (1994).

  6. 6.

    Coussens, L. M., Zitvogel, L. & Palucka, A. K. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science 339, 286–291 (2013).

  7. 7.

    Antonioli, L., Blandizzi, C., Pacher, P. & Hasko, G. Immunity, inflammation and cancer: a leading role for adenosine. Nat. Rev. Cancer 13, 842–857 (2013).

  8. 8.

    Wu, Y. et al. The role of autophagy in colitis-associated colorectal cancer. Signal Transduct. Target. Ther. 3, 31 (2018).

  9. 9.

    Liu, T., Zhang, L., Joo, D. & Sun, S. C. NF-kappaB signaling in inflammation. Signal Transduct. Target. Ther. 2, 17023 (2017).

  10. 10.

    Chen, T. T., Tsai, M. H. & Kung, J. T. STAT1 regulates marginal zone B cell differentiation in response to inflammation and infection with blood-borne bacteria. J. Exp. Med. 213, 3025–3039 (2016).

  11. 11.

    Ernst, M. et al. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J. Clin. Investig. 118, 1727–1738 (2008).

  12. 12.

    Schreiber, S. et al. Activation of signal transducer and activator of transcription (STAT) 1 in human chronic inflammatory bowel disease. Gut 51, 379–385 (2002).

  13. 13.

    Chiriac, M. T. et al. Activation of epithelial signal transducer and activator of transcription 1 by interleukin 28 controls mucosal healing in mice with colitis and is increased in mucosa of patients with inflammatory bowel disease. Gastroenterology 153, 123–138.e128 (2017).

  14. 14.

    Takahashi, R. et al. SOCS1 is essential for regulatory T cell functions by preventing loss of Foxp3 expression as well as IFN-{gamma} and IL-17A production. J. Exp. Med. 208, 2055–2067 (2011).

  15. 15.

    Choi, S. H. et al. Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis. J. Clin. Investig. 124, 2472–2482 (2014).

  16. 16.

    Su, Z. Z. et al. Cloning and characterization of SARI (suppressor of AP-1, regulated by IFN). Proc. Natl Acad. Sci. USA 105, 20906–20911 (2008).

  17. 17.

    Murphy, T. L., Tussiwand, R. & Murphy, K. M. Specificity through cooperation: BATF-IRF interactions control immune-regulatory networks. Nat. Rev. Immunol. 13, 499–509 (2013).

  18. 18.

    Dash, R. et al. Inhibition of AP-1 by SARI negatively regulates transformation progression mediated by CCN1. Oncogene 29, 4412–4423 (2010).

  19. 19.

    Dash, R. et al. Novel mechanism of MDA-7/IL-24 cancer-specific apoptosis through SARI induction. Cancer Res. 74, 563–574 (2014).

  20. 20.

    Dai, L. et al. SARI inhibits angiogenesis and tumour growth of human colon cancer through directly targeting ceruloplasmin. Nat. Commun. 7, 11996 (2016).

  21. 21.

    Kanemaru, H. et al. Antitumor effect of Batf2 through IL-12p40 up-regulation in tumor-associated macrophages. Proc. Natl Acad. Sci. USA 114, E7331–E7340 (2017).

  22. 22.

    Roy, S. et al. Batf2/Irf1 induces inflammatory responses in classically activated macrophages, lipopolysaccharides, and mycobacterial infection. J. Immunol. 194, 6035–6044 (2015).

  23. 23.

    Kitada, S. & Kayama, H. BATF2 inhibits immunopathological Th17 responses by suppressing Il23a expression during Trypanosoma cruzi infection. J. Exp. Med. 214, 1313–1331 (2017).

  24. 24.

    Wirtz, S. et al. Chemically induced mouse models of acute and chronic intestinal inflammation. Nat. Protoc. 12, 1295–1309 (2017).

  25. 25.

    Xiao, Z. et al. The pivotal role of IKKalpha in the development of spontaneous lung squamous cell carcinomas. Cancer Cell 23, 527–540 (2013).

  26. 26.

    Jenkins, S. J. et al. Local macrophage proliferation, rather than recruitment from the blood, is a signature of TH2 inflammation. Science 332, 1284–1288 (2011).

  27. 27.

    Chen, W. et al. Bindarit, an inhibitor of monocyte chemotactic protein synthesis, protects against bone loss induced by chikungunya virus infection. J. Virol. 89, 12232 (2015).

  28. 28.

    Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).

  29. 29.

    Cooks, T. et al. Mutant p53 prolongs NF-kappaB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell 23, 634–646 (2013).

  30. 30.

    Feng, Z. et al. Fludarabine inhibits STAT1-mediated up-regulation of caspase-3 expression in dexamethasone-induced osteoblasts apoptosis and slows the progression of steroid-induced avascular necrosis of the femoral head in rats. Apoptosis: Int. J. Program. Cell Death 22, 1001–1012 (2017).

  31. 31.

    Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 14, 399–416 (2017).

  32. 32.

    Punkenburg, E. et al. Batf-dependent Th17 cells critically regulate IL-23 driven colitis-associated colon cancer. Gut 65, 1139–1150 (2016).

  33. 33.

    Goto, Y., Uematsu, S. & Kiyono, H. Epithelial glycosylation in gut homeostasis and inflammation. Nat. Immunol. 17, 1244–1251 (2016).

  34. 34.

    Peterson, L. W. & Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141–153 (2014).

  35. 35.

    Nowarski, R., Jackson, R. & Flavell, R. A. The stromal intervention: regulation of immunity and inflammation at the epithelial−mesenchymal barrier. Cell 168, 362–375 (2017).

  36. 36.

    Veldhoen, M. & Brucklacher-Waldert, V. Dietary influences on intestinal immunity. Nat. Rev. Immunol. 12, 696–708 (2012).

  37. 37.

    Tussiwand, R. et al. Compensatory dendritic cell development mediated by BATF-IRF interactions. Nature 490, 502–507 (2012).

  38. 38.

    Nagarsheth, N., Wicha, M. S. & Zou, W. Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat. Rev. Immunol. 17, 559–572 (2017).

  39. 39.

    Qian, B. Z. et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475, 222–225 (2011).

  40. 40.

    Kim, Y. G. et al. The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity 34, 769–780 (2011).

  41. 41.

    Diakos, C. I., Charles, K. A., McMillan, D. C. & Clarke, S. J. Cancer-related inflammation and treatment effectiveness. Lancet Oncol. 15, e493–e503 (2014).

  42. 42.

    Di Paolo, N. C. & Shayakhmetov, D. M. Interleukin 1alpha and the inflammatory process. Nat. Immunol. 17, 906–913 (2016).

  43. 43.

    Hu, X., Park-Min, K. H., Ho, H. H. & Ivashkiv, L. B. IFN-gamma-primed macrophages exhibit increased CCR2-dependent migration and altered IFN-gamma responses mediated by Stat1. J. Immunol. 175, 3637–3647 (2005).

  44. 44.

    Lee, H. Y. et al. Sphingosylphosphorylcholine stimulates CCL2 production from human umbilical vein endothelial cells. J. Immunol. 186, 4347–4353 (2011).

  45. 45.

    Izumi, K. et al. Targeting the androgen receptor with siRNA promotes prostate cancer metastasis through enhanced macrophage recruitment via CCL2/CCR2-induced STAT3 activation. EMBO Mol. Med. 5, 1383–1401 (2013).

  46. 46.

    Bauer, D. et al. Diallyl disulfide inhibits TNFalpha induced CCL2 release through MAPK/ERK and NF-Kappa-B signaling. Cytokine 75, 117–126 (2015).

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Acknowledgements

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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