TLR Signaling Modulates Side Effects of Anticancer Therapy in the Small Intestine

Magdalena Frank, Eva Maria Hennenberg, Annette Eyking, Michael Rünzi, Guido Gerken, Paul Scott, Julian Parkhill, Alan W Walker, Elke Cario

Research output: Contribution to journalArticlepeer-review

77 Citations (Scopus)


Intestinal mucositis represents the most common complication of intensive chemotherapy, which has a severe adverse impact on quality of life of cancer patients. However, the precise pathophysiology remains to be clarified, and there is so far no successful therapeutic intervention. In this study, we investigated the role of innate immunity through TLR signaling in modulating genotoxic chemotherapy-induced small intestinal injury in vitro and in vivo. Genetic deletion of TLR2, but not MD-2, in mice resulted in severe chemotherapy-induced intestinal mucositis in the proximal jejunum with villous atrophy, accumulation of damaged DNA, CD11b(+)-myeloid cell infiltration, and significant gene alterations in xenobiotic metabolism, including a decrease in ABCB1/multidrug resistance (MDR)1 p-glycoprotein (p-gp) expression. Functionally, stimulation of TLR2 induced synthesis and drug efflux activity of ABCB1/MDR1 p-gp in murine and human CD11b(+)-myeloid cells, thus inhibiting chemotherapy-mediated cytotoxicity. Conversely, TLR2 activation failed to protect small intestinal tissues genetically deficient in MDR1A against DNA-damaging drug-induced apoptosis. Gut microbiota depletion by antibiotics led to increased susceptibility to chemotherapy-induced mucosal injury in wild-type mice, which was suppressed by administration of a TLR2 ligand, preserving ABCB1/MDR1 p-gp expression. Findings were confirmed in a preclinical model of human chemotherapy-induced intestinal mucositis using duodenal biopsies by demonstrating that TLR2 activation limited the toxic-inflammatory reaction and maintained assembly of the drug transporter p-gp. In conclusion, this study identifies a novel molecular link between innate immunity and xenobiotic metabolism. TLR2 acts as a central regulator of xenobiotic defense via the multidrug transporter ABCB1/MDR1 p-gp. Targeting TLR2 may represent a novel therapeutic approach in chemotherapy-induced intestinal mucositis.

Original languageEnglish
Pages (from-to)1983-1995
Number of pages13
JournalThe Journal of Immunology
Issue number4
Early online date6 Feb 2015
Publication statusPublished - 15 Feb 2015

Bibliographical note

Copyright © 2015 by The American Association of Immunologists, Inc.

This work was supported by Deutsche Forschungsgemeinschaft Grants CA226/8-1, CA226/9-1, and CA226/4-3 (to E.C.) and intramural funding from the Interne Forschungsförderung Essen (to E.C.). Funding for P.S., J.P., A.W.W. and 16S rRNA gene sequencing was provided by Wellcome Trust Grant 098051; A.W.W. and the Rowett Institute of Nutrition and Health, University of Aberdeen receive core funding support from the Scottish Government Rural and Environmental Science and Analysis Service.


  • TLR signalling
  • Anticancer therapy
  • Side Effects
  • Small Intestine


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