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. Here, 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/MDR1 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 wildtype 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.

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

“…Similar results have also been demonstrated in methotrexate-induced gut toxicity, with MD-2 (TLR4 accessory protein) deletion improving clinical and histological parameters of toxicity (36). Importantly, this study showed that TLR4 and TLR2 appear to have opposing roles, with both genetic deletion and pharmacological inhibition of TLR2 worsening methotrexate-induced damage (36). It appears that TLR2 has paradoxical roles in chemotherapy-induced gut toxicity, with improvements seen in Tlr2 -/-mice treated with irinotecan.…”

“…For example, significant improvements in acute inflammation have been shown in the absence of TLR4 and MyD88, a downstream signaling molecule of TLR, following acute infection with Citrobacter rodentium (35). Similar results have also been demonstrated in methotrexate-induced gut toxicity, with MD-2 (TLR4 accessory protein) deletion improving clinical and histological parameters of toxicity (36). Importantly, this study showed that TLR4 and TLR2 appear to have opposing roles, with both genetic deletion and pharmacological inhibition of TLR2 worsening methotrexate-induced damage (36).…”

“…This study also showed that Myd88 -/-mice were also protected from developing severe irinotecaninduced gut toxicity, reiterating the importance of TLR4-dependent signaling (36). Despite support for TLR4 deletion providing protection against chemotherapy-induced gut toxicity, this does not appear to be the case for acute and chronic colitis, with Tlr4 -/-mice more susceptible to ulceration and bleeding (35).…”

A review of complementary therapies for chemotherapy induced gastrointestinal mucositis

“…Recently, TLR/MyD88/NF-κB pathway has been implicated in the mechanisms of damage involved in chemotherapy-related GIM (27). It has also been reported that TLR-2 acts as a central regulator of xenobiotic defense and targeting TLR2 may represent a novel therapeutic approach in chemotherapy-induced GIM (26).…”

“…These overlapping steps are thought to be largely driven by the activation of NFκB, subsequently promoting key pro-inflammatory cytokines. Furthermore, apoptosis, pathogenic bacteria, inflammation, matrix metalloproteinases (MMPs), loss of mucosal barrier integrity and toll like receptors (TLRs) have also been reported to play an important role in GIM (21)(22)(23)(24)(25)(26)(27)(28).…”