The Adaptor Protein Myd88 Is a Key Signaling Molecule in the Pathogenesis of Irinotecan-Induced Intestinal Mucositis

Abstract

Intestinal mucositis is a common side effect of irinotecan-based anticancer regimens. Mucositis causes cell damage, bacterial/endotoxin translocation and production of cytokines including IL–1 and IL–18. These molecules and toll-like receptors (TLRs) activate a common signaling pathway that involves the Myeloid Differentiation adaptor protein, MyD88, whose role in intestinal mucositis is unknown. Then, we evaluated the involvement of TLRs and MyD88 in the pathogenesis of irinotecan-induced intestinal mucositis. MyD88-, TLR2- or TLR9-knockout mice and C57BL/6 (WT) mice were given either saline or irinotecan (75 mg/kg, i.p. for 4 days). On day 7, animal survival, diarrhea and bacteremia were assessed, and following euthanasia, samples of the ileum were obtained for morphometric analysis, myeloperoxidase (MPO) assay and measurement of pro-inflammatory markers. Irinotecan reduced the animal survival (50%) and induced a pronounced diarrhea, increased bacteremia, neutrophil accumulation in the intestinal tissue, intestinal damage and more than twofold increased expression of MyD88 (200%), TLR9 (400%), TRAF6 (236%), IL–1β (405%), IL–18 (365%), COX–2 (2,777%) and NF-κB (245%) in the WT animals when compared with saline-injected group (P<0.05). Genetic deletion of MyD88, TLR2 or TLR9 effectively controlled the signs of intestinal injury when compared with irinotecan-administered WT controls (P<0.05). In contrast to the MyD88-/- and TLR2-/- mice, the irinotecan-injected TLR9-/- mice showed a reduced survival, a marked diarrhea and an enhanced expression of IL–18 versus irinotecan-injected WT controls. Additionally, the expression of MyD88 was reduced in the TLR2-/- or TLR9-/- mice. This study shows a critical role of the MyD88-mediated TLR2 and TLR9 signaling in the pathogenesis of irinotecan-induced intestinal mucositis.

The involvement of mast cells in the irinotecan-induced enteric neurons loss and reactive gliosis

“…The CPT-11-induced intestinal damage is indicated in the current work by shortened villi, loss of crypts architecture, and intense inflammatory cell infiltrate, in accordance with previous studies described in the literature [9, 10, 27, 28]. The participation of neutrophils and macrophages in the pathogenesis of CPT-11-induced intestinal mucositis had been reported [9, 10].…”

Cytokine‐mediated blood brain barrier disruption as a conduit for cancer/chemotherapy‐associated neurotoxicity and cognitive dysfunction

“…Furthermore, TNFα and IL‐1β induce MMP‐1, MMP‐2 and MMP‐3 activation, which is thought to contribute to development of gut toxicity through inflammatory pathways, altered extracellular matrix composition, adhesion molecules and tight junction disruption. Toll‐like receptor (TLR)4‐dependent mechanisms have also been linked to the development of gut toxicity, with increases in its expression seen following chemotherapy as well as improvements in symptomatic parameters seen following genetic manipulation of its downstream signaling molecules ( e.g., MyD88, MD‐2) . This aspect of CIGT has significant implications for BBB maintenance, as it is becoming increasingly clear that TLR4‐dependent signaling pathways are critical for tight junction integrity …”

“…Toll-like receptor (TLR)4-dependent mechanisms have also been linked to the development of gut toxicity, with increases in its expression seen following chemotherapy 81 as well as improvements in symptomatic parameters seen following genetic manipulation of its downstream signaling molecules (e.g., MyD88, MD-2). 82,83 This aspect of CIGT has significant implications for BBB maintenance, as it is becoming increasingly clear that TLR4-dependent signaling pathways are critical for tight junction integrity. 84 TLR4-mediated barrier modulation has been shown in both endothelial and epithelial models.…”

A review of complementary therapies for chemotherapy induced gastrointestinal mucositis

“…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).…”

“…TLRs initiate the innate immune response and the production of proinflammatory mediators including IL-1β, nitric oxide and IL-18, whose role in intestinal GIM is well known (32)(33)(34). 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).…”