Toll-like receptor 4 signaling: A common biological mechanism of regimen-related toxicities

Wardill, Hannah R.; Sebille, Ysabella Z.A. Van; Mander, Kimberley A.; Gibson, Rachel J.; Logan, Richard M.; Bowen, Joanne M.; Sonis, Stephen T.

doi:10.1016/j.ctrv.2014.11.005

Cited by 36 publications

(28 citation statements)

References 85 publications

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“…TLR4 has been hypothesised to play a key role in the development of both chemotherapy-induced gut toxicity and pain (9,17). Results from the current study support this newly proposed hypothesis, highlighting significant improvements in symptomatic parameters of gut toxicity and histopathological markers in BALB/c-Tlr4 -/-billy mice treated with irinotecan.…”

Section: Discussionsupporting

confidence: 78%

“…It is becoming increasingly recognised that TLR4, expressed on centrally located glia, is able to recognise and respond to peripherally derived LPS and inflammatory mediators (9). We have shown translocation of LPS to systemic circulation following chemotherapy treatment, reflecting the swing towards a gram-negative, pathogenic gut microbiome profile following chemotherapy.…”

Section: Discussionmentioning

confidence: 78%

“…TLR4 has also been hypothesised to mediate chemotherapy-induced pain through central glial activation (9), with strong clinical evidence showing chemotherapy-induced gut toxicity is often paralleled by the symptom of pain (16,17). This is suggestive of common underlying mechanisms.…”

Section: Introductionmentioning

confidence: 99%

“…In light of these findings, the interaction between the gut microbiome and innate mucosal immune system has also gained interest, with particular emphasis on the impact of toll-like receptor (TLR) signaling (8)(9)(10). TLRs are a family of transmembrane protein receptors recognising a diverse range of signals on exogenous and endogenous substances considered to be 'dangerous', and hence warranting activation of the innate immune system for host survival (11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

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

Wardill

Gibson

Sebille

et al. 2016

Molecular Cancer Therapeutics

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123

124

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Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (−/−) BALB/c mice weighing between 18 and 25 g (10–13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P < 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4−/−billy mice (P < 0.0001), correlating with lower mucosal injury scores (P < 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4−/−billy (P = 0.01 and P < 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4−/−billy mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376–86. ©2016 AACR.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Wardill

Gibson

Sebille

et al. 2016

Molecular Cancer Therapeutics

Self Cite

123

124

View full text Add to dashboard Cite

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“…TLR2 and TLR4 are membrane bound surface receptors that sense extracellular DAMPs, whereas TLR9 is located intracellular that sense intracellular DAMP ligand such as DNA [94]. Interestingly, peripheral tissue damage (e.g., following cytotoxic treatment) also possesses TLR-mediated glial activation capacity [147, 148]. Moreover, TLRs involved in signaling DAMPs may interact at several levels, but almost all converge into the activation of NF- κ B [149].…”

Section: Pattern-recognition Receptorsmentioning

confidence: 99%

Sterile Neuroinflammation and Strategies for Therapeutic Intervention

Banjara

Ghosh

2017

International Journal of Inflammation

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Sterile neuroinflammation is essential for the proper brain development and tissue repair. However, uncontrolled neuroinflammation plays a major role in the pathogenesis of various disease processes. The endogenous intracellular molecules so called damage-associated molecular patterns or alarmins or damage signals that are released by activated or necrotic cells are thought to play a crucial role in initiating an immune response. Sterile inflammatory response that occurs in Alzheimer's disease (AD), Parkinson's disease (PD), stroke, hemorrhage, epilepsy, or traumatic brain injury (TBI) creates a vicious cycle of unrestrained inflammation, driving progressive neurodegeneration. Neuroinflammation is a key mechanism in the progression (e.g., AD and PD) or secondary injury development (e.g., stroke, hemorrhage, stress, and TBI) of multiple brain conditions. Hence, it provides an opportunity for the therapeutic intervention to prevent progressive tissue damage and loss of function. The key for developing anti-neuroinflammatory treatment is to minimize the detrimental and neurotoxic effects of inflammation while promoting the beneficial and neurotropic effects, thereby creating ideal conditions for regeneration and repair. This review outlines how inflammation is involved in the pathogenesis of major nonpathogenic neuroinflammatory conditions and discusses the complex response of glial cells to damage signals. In addition, emerging experimental anti-neuroinflammatory drug treatment strategies are discussed.

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

Wardill

Mander

Sebille

et al. 2016

Intl Journal of Cancer

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132

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Publishing in a subscription based journal Accepted (peer-reviewed) VersionThe accepted version of an article is the version that incorporates all amendments made during the peer review process, but prior to the final published version (the Version of Record, which includes; copy and stylistic edits, online and print formatting, citation and other linking, deposit in abstracting and indexing services, and the addition of bibliographic and other material.Self-archiving of the accepted version is subject to an embargo period of 12-24 months. The embargo period is 12 months for scientific, technical, and medical (STM) journals and 24 months for social science and humanities (SSH) journals following publication of the final article.• the author's personal website • the author's company/institutional repository or archive • not for profit subject-based repositories such as PubMed Central Articles may be deposited into repositories on acceptance, but access to the article is subject to the embargo period. The version posted may not be updated or replaced with the final published version (the Version of Record). Authors may transmit, print and share copies of the accepted version with colleagues, provided that there is no systematic distribution, e.g. a posting on a listserve, network or automated delivery.There is no obligation upon authors to remove preprints posted to not for profit preprint servers prior to submission. and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterised by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy-associated toxicities. This review therefore aims to explore the hypothesis that peripherally-derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity. 60

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Toll-like receptor 4 signaling: A common biological mechanism of regimen-related toxicities

Cited by 36 publications

References 85 publications

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

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

Sterile Neuroinflammation and Strategies for Therapeutic Intervention

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

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