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Severity of doxorubicin‐induced small intestinal mucositis is regulated by the TLR‐2 and TLR‐9 pathways
Author(s) -
Kaczmarek Agnieszka,
Brinkman Brigitta M,
Heyndrickx Liesbeth,
Vandenabeele Peter,
Krysko Dmitri V
Publication year - 2012
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.3009
Subject(s) - mucositis , doxorubicin , lamina propria , ileum , apoptosis , chemotherapy , medicine , tunel assay , biology , gastroenterology , cancer research , pharmacology , pathology , immunohistochemistry , epithelium , biochemistry
Intestinal mucositis is a serious complication of cancer chemotherapy and radiotherapy; it frequently compromises treatment and dramatically reduces the quality of life of patients. Different approaches to limit the damage to the intestine during anti‐cancer therapy have been largely ineffective due to insufficient knowledge of the mechanism of mucositis development. This study aimed to define the role of TLR‐2 and TLR‐9 in the modulation of small intestinal damage in a model of doxorubicin‐induced mucositis. Doxorubicin‐induced intestinal damage was verified by a histological score (HS), analysis of leukocyte influx into the lamina propria, and determination of the number of apoptotic cells. Additionally, the activation status of glycogen synthase kinase 3β (GSK‐3β) was assessed. Wild‐type (WT) mice injected with doxorubicin demonstrated severe intestinal damage (HS 8.0 ± 0.81), reduction of villus length to 43.9% ± 13.7% of original length, and increased influx of leukocytes as compared to vehicle‐injected mice (HS 1.33 ± 1.15). The protective effect of TLR‐2 or TLR‐9 deficiency was associated with a significant decrease of the HS as compared to WT mice. In the ileum, a minor reduction of villus length and a decreased number of infiltrating leukocytes and TUNEL‐positive cells was observed. We demonstrate that the TLR‐9 antagonist ODN2088 reduces doxorubicin‐induced intestinal damage. Furthermore, we show that GSK‐3β activity is inhibited in the absence of TLR‐2. The protective capacity of GSK‐3β suppression was observed in WT mice by inhibiting it with the specific inhibitor SB216763. Overall, our findings demonstrate that the TLR‐2/GSK‐3β and TLR‐9 signalling pathways play a central role in the development of intestinal mucositis and we suggest a new therapeutic strategy for limiting doxorubicin‐induced intestinal inflammation. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.