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 journalArticle

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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.

Original languageEnglish
Pages (from-to)1983-1995
Number of pages13
JournalThe Journal of Immunology
Volume194
Issue number4
Early online date14 Jan 2015
DOIs
Publication statusPublished - 15 Feb 2015

Fingerprint

Small Intestine
Mucositis
Drug Therapy
Glycoproteins
Xenobiotics
Myeloid Cells
Innate Immunity
Therapeutics
Pharmaceutical Preparations
Poisons
DNA
Wounds and Injuries
Multiple Drug Resistance
Jejunum
Atrophy
Quality of Life
Apoptosis
Anti-Bacterial Agents
Ligands
Biopsy

Keywords

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

Cite this

Frank, M., Hennenberg, E. M., Eyking, A., Rünzi, M., Gerken, G., Scott, P., ... Cario, E. (2015). TLR Signaling Modulates Side Effects of Anticancer Therapy in the Small Intestine. The Journal of Immunology, 194(4), 1983-1995. https://doi.org/10.4049/jimmunol.1402481

TLR Signaling Modulates Side Effects of Anticancer Therapy in the Small Intestine. / Frank, Magdalena; Hennenberg, Eva Maria; Eyking, Annette; Rünzi, Michael; Gerken, Guido; Scott, Paul; Parkhill, Julian; Walker, Alan W; Cario, Elke.

In: The Journal of Immunology, Vol. 194, No. 4, 15.02.2015, p. 1983-1995.

Research output: Contribution to journalArticle

Frank, M, Hennenberg, EM, Eyking, A, Rünzi, M, Gerken, G, Scott, P, Parkhill, J, Walker, AW & Cario, E 2015, 'TLR Signaling Modulates Side Effects of Anticancer Therapy in the Small Intestine' The Journal of Immunology, vol. 194, no. 4, pp. 1983-1995. https://doi.org/10.4049/jimmunol.1402481
Frank M, Hennenberg EM, Eyking A, Rünzi M, Gerken G, Scott P et al. TLR Signaling Modulates Side Effects of Anticancer Therapy in the Small Intestine. The Journal of Immunology. 2015 Feb 15;194(4):1983-1995. https://doi.org/10.4049/jimmunol.1402481
Frank, Magdalena ; Hennenberg, Eva Maria ; Eyking, Annette ; Rünzi, Michael ; Gerken, Guido ; Scott, Paul ; Parkhill, Julian ; Walker, Alan W ; Cario, Elke. / TLR Signaling Modulates Side Effects of Anticancer Therapy in the Small Intestine. In: The Journal of Immunology. 2015 ; Vol. 194, No. 4. pp. 1983-1995.
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N2 - 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.

AB - 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.

KW - TLR signalling

KW - Anticancer therapy

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JO - The Journal of Immunology

JF - The Journal of Immunology

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