Guabiraba, Rodrigo, Besnard, Anne-Gaëlle, Menezes, Gustavo Batista, Secher, Thomas, Jabir, M. S., Amaral, S. S., Braun, Harald, Lima-Junior, Roberto C.P., Ribeiro, R. A., Cunha, Fernando de Queiroz, Teixeira, Mauro M., Beyaert, Rudi, Graham, Gérard J., Liew, Foo Yew, Infectiologie et Santé Publique (UMR ISP), Institut National de la Recherche Agronomique (INRA)-Université de Tours (UT), University of Glasgow, Universidade Federal de Minas Gerais, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Technology, Department of Biomedical Molecular Biology, Universiteit Gent = Ghent University (UGENT), Universidade Federal do Ceará = Federal University of Ceará (UFC), Universidade de São Paulo = University of São Paulo (USP), King Abdulaziz University, Welcome Trust and the Medical Research Council, the Belgian Federation against Cancer, CNPq, FAPEMIG and CAPES, European Project: 281608,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,TIMER(2012), Institut National de la Recherche Agronomique (INRA)-Université de Tours, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universiteit Gent = Ghent University [Belgium] (UGENT), and Universidade de São Paulo (USP)
Guabiraba, R Besnard, A G Menezes, G B Secher, T Jabir, M S Amaral, S S Braun, H Lima-Junior, R Cp Ribeiro, R A Cunha, F Q Teixeira, M M Beyaert, R Graham, G J Liew, F Y Mucosal Immunol. 2014 Jan 15. doi: 10.1038/mi.2013.124.; International audience; Intestinal damage and severe diarrhea are serious side effects of cancer chemotherapy and constrain the usage of most such therapies. Here we show that interleukin-33 (IL-33) mediates the severe intestinal mucositis in mice treated with irinotecan (CPT-11), a commonly used cancer chemotherapeutic agent. Systemic CPT-11 administration led to severe mucosal damage, diarrhea, and body weight loss concomitant with the induction of IL-33 in the small intestine (SI). This mucositis was markedly reduced in mice deficient in the IL-33R (ST2-/-). Moreover, recombinant IL-33 exacerbated the CPT-11-induced mucositis, whereas IL-33 blockade with anti-IL-33 antibody or soluble ST2 markedly attenuated the disease. CPT-11 treatment increased neutrophil accumulation in the SI and adhesion to mesenteric veins. Supernatants from SI explants treated with CPT-11 enhanced transmigration of neutrophils in vitro in an IL-33-, CXCL1/2-, and CXCR2-dependent manner. Importantly, IL-33 blockade reduced mucositis and enabled prolonged CPT-11 treatment of ectopic CT26 colon carcinoma, leading to a beneficial outcome of the chemotherapy. These results suggest that inhibition of the IL-33/ST2 pathway may represent a novel approach to limit mucositis and thus improve the effectiveness of chemotherapy.