Inhibition of the TLR4/RAGE pathway by clearance of extracellular HMGB1 is a potential therapeutic target for radiation-damaged salivary glands
Bibliographic record
Abstract
Introduction: We recently developed a new therapy using effective-mononuclear cells (E-MNCs) and demonstrated its efficacy in treating radiation-damaged salivary glands (SGs). The activity of E-MNCs in part involves constituent immunoregulatory -CD11b/macrophage scavenger receptor 1(Msr1)-positive-M2 macrophages, which exert anti-inflammatory and tissue-regenerating effects via phagocytic clearance of extracellular high mobility group box 1 (HMGB1). Focusing on the phenomena, this study investigated significance of regulating the HMGB1/toll-like receptor 4 (TLR4)/receptor for advanced glycation end products (RAGE) signaling pathway in the treatment of SG dysfunction caused by radiation damage. Methods: E-MNCs were transplanted into radiation-damaged mice SGs, and changes of TLR4/RAGE expression were observed. Furthermore, the activation of downstream signals was investigated in both intact SGs and cultured SG epithelial cells after irradiation. Subsequently, TLR4-knock-out (KO) mice were employed to examine how HMGB1/TLR4/RAGE signaling affected damage progression. Results: Expression of both TLR4 and RAGE was diminished in ductal cells and macrophages/vascular endothelial cells of damaged SGs with E-MNC transplantation, respectively. Meanwhile, expression of TLR2/4 and RAGE in damaged SGs markedly increased in association with extracellular HMGB1 accumulation. Downstream signals were activated, and intranuclear localization of phospho-nuclear factor-kappa B (p-NF-KB) in ductal cells and production of IL-6, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were observed. Additionally, culture supernatant of irradiated cultured SG epithelial cells contained damaged associated molecular pattern (DAMP)/senescence-associated secretory phenotype (SASP) factors. Treatment of cultured SG epithelial cells with this supernatant activated TLR4 signaling pathway and induced cellular senescence. In TLR4-KO mice, onset of radiogenic SG dysfunction was markedly delayed. However, TLR2/RAGE signalings were alternatively activated, and SG function was impaired. Conclusions: Clearance of DAMPs such as HMGB1 may attenuate sterile inflammation in damaged SGs via suppression of the TLR4/RAGE signaling pathway. This cellular mechanism may have significant implications for the development of future cell-based regenerative therapies.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".