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CCL11 exacerbates colitis and inflammation-associated colon tumorigenesis

Abstract

CCL11, also known as eotaxin-1, is described as an eosinophil chemoattractant, which has been implicated in allergic and Th2 inflammatory diseases. We have reported that CCL11 is significantly increased in the serum of inflammatory bowel disease (IBD) patients, colonic eosinophils are increased and correlate with tissue CCL11 levels in ulcerative colitis patients, and CCL11 is increased in dextran sulfate sodium (DSS)-induced murine colitis. Here, we show that CCL11 is involved in the pathogenesis of DSS-induced colitis and in colon tumorigenesis in the azoxymethane (AOM)-DSS model of colitis-associated carcinogenesis (CAC). Ccl11−/− mice exposed to DSS then allowed to recover had significantly less body weight loss and a decrease in histologic injury versus wild-type (WT) mice. In the AOM-DSS model, Ccl11−/− mice exhibited decreased colonic tumor number and burden, histologic injury, and colonic eosinophil infiltration versus WT mice. Ccl11 is expressed by both colonic epithelial and lamina propria immune cells. Studies in bone marrow chimera mice revealed that hematopoietic- and epithelial-cell-derived CCL11 were both important for tumorigenesis in the AOM-DSS model. These findings indicate that CCL11 is important in the regulation of colitis and associated carcinogenesis and thus anti-CCL11 antibodies may be useful for treatment and cancer chemoprevention in IBD.

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Fig. 1: Ccl11 deletion is protective in DSS-induced colitis.
Fig. 2: Ccl11−/− mice exhibit decreased tumorigenesis after exposure to the AOM-DSS model of CAC.
Fig. 3: Ccl11−/− mice exhibit altered tumor chemokine and cytokine levels.
Fig. 4: Loss of both hematopoietic and epithelial CCL11 is required for protection from tumorigenesis.

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Acknowledgements

LAC was supported by NIH training grant 5T32DK007673, a Vanderbilt Physician Scientist Development Award, a Veterans Affairs Career Development Award 1IK2BX002126, and a Veterans Affairs Merit Award 1I01BX004366. This work was also funded by National Institutes of Health (NIH) grants R01DK128200, R01CA190612, P01CA116087, and P01CA028842 (KTW), Veterans Affairs Merit Review grant I01CX002171 (KTW), Crohn’s and Colitis Foundation Senior Research Award 703003 (KTW), the Thomas F. Frist Sr. Endowment (KTW), and the Vanderbilt Center for Mucosal Inflammation and Cancer (KTW). DMH was supported by T32GM008554 and F31DK10715. Additional support was provided by the Tissue Morphology Subcore of NIH Grant P30DK058404 (Vanderbilt Digestive Disease Research Center). The Translational Pathology Shared Resource was supported by NCI/NIH Cancer Center Support Grant P30CA068485 and the Vanderbilt Mouse Metabolic Phenotyping Center Grant U24DK059637.

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Study concept and design: LAC and KTW. Data acquisition: DP, KS, MA, DPB, MMA, DMH, MBP, MKW, and LAC. Analysis and interpretation of the data: DP, KS, MMA, DMH, MBP, APG, KTW, and LAC. Paper preparation: DP and LAC. Critical review: DP, MBP, APG, KTW, and LAC.

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Correspondence to Lori A. Coburn.

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Polosukhina, D., Singh, K., Asim, M. et al. CCL11 exacerbates colitis and inflammation-associated colon tumorigenesis. Oncogene 40, 6540–6546 (2021). https://doi.org/10.1038/s41388-021-02046-3

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  • DOI: https://doi.org/10.1038/s41388-021-02046-3

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