title: TLR signaling modulates side effects of anticancer therapy in the small intestine.
abstract: 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.
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital of Essen, D-45147 Essen, Germany; Medical School, University of Duisburg-Essen, D-45122 Essen, Germany;
authors.forename: Magdalena
authors.initials: M
authors.lastname: Frank
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital of Essen, D-45147 Essen, Germany; Medical School, University of Duisburg-Essen, D-45122 Essen, Germany;
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Hennenberg
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital of Essen, D-45147 Essen, Germany; Medical School, University of Duisburg-Essen, D-45122 Essen, Germany;
authors.forename: Annette
authors.initials: A
authors.lastname: Eyking
authors.affiliation: Medical School, University of Duisburg-Essen, D-45122 Essen, Germany; Division of Gastroenterology and Metabolic Diseases, Kliniken Essen Süd, D-45239 Essen, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Rünzi
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital of Essen, D-45147 Essen, Germany; Medical School, University of Duisburg-Essen, D-45122 Essen, Germany;
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.affiliation: Pathogen Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; and.
authors.forename: Paul
authors.initials: P
authors.lastname: Scott
authors.affiliation: Pathogen Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; and.
authors.forename: Julian
authors.initials: J
authors.lastname: Parkhill
authors.affiliation: Pathogen Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United Kingdom; and Microbiology Group, Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen AB21 9SB, United Kingdom.
authors.forename: Alan W
authors.initials: AW
authors.lastname: Walker
authors.affiliation: Division of Gastroenterology and Hepatology, University Hospital of Essen, D-45147 Essen, Germany; Medical School, University of Duisburg-Essen, D-45122 Essen, Germany; elke.cario@uni-due.de.
authors.forename: Elke
authors.initials: E
authors.lastname: Cario
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D015151:Immunoblotting; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D064307:Microbiota; D052016:Mucositis / Q000139:chemically induced / Q000276:immunology* / Q000382:microbiology*; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000276:immunology / Q000378:metabolism*
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D051195:Toll-Like Receptor 2