TLR4‐driven Lymphatic Alterations during IBD are driven in PAMP/DAMP Specific Manners
Bibliographic record
Abstract
Background Inflammatory bowel disease (IBD) is characterised by both acute and chronic phase inflammation of the gastro‐intestinal (GI) tract that affect a large and growing number of people worldwide with little to no effective treatments. This is in part due to the lack of understanding of the disease pathogenesis and also the currently poorly described involvement of other systems such as the lymphatics. During DSS induced colitis, mice also develop a severe inflammation of both the colon and terminal ileum with many features similar to IBD. As well as inflammation within the intestinal tract we have previously demonstrated lymphatic remodelling within the mesentery and mesenteric lymph nodes of DSS‐treated mice. The lymphatic remodelling includes lymphangiogenesis, lymphatic vessel dilation and leakiness, as well as cellular infiltration into the surrounding tissue and peripheral draining lymph nodes. The aim of the investigation was to delineate the contribution of PAMP‐ and/or DAMP‐driven lymphatic remodelling and inflammation during disease, in respect to Toll‐like receptor 4 (TLR4) activity. Methods Intestinal inflammation was induced in C57BL/6 mice by administration of 2.5% DSS in drinking water for 7 days. Mice were treated with TLR4 blocker C34 or Polymyxin‐B (PMXB) daily from days 3–7 of DSS treatment via I.P. injection, and their effects on disease activity and lymphatic function were examined. TLR4 activity and subsequent effect on lymphangiogenesis, lymphadenopathy, and mesenteric lymph node (MLN) cellular composition were assessed. Results DSS Mice treated with TLR4 inhibitor, C34, had a significantly improved disease phenotype characterised by reduced ileal and colonic insult. The change correlated with significant reduction in colonic and mesenteric inflammation, resolved mesenteric lymphangiectasia, and CD103 + DC accumulation similar to that of healthy control. PMXB treatment did not resolve inflammation within the colon, or associated mesenteric lymphatic dysfunction, but did however prevent lymphadenopathy within the MLN through alteration of CCL21 gradients and CD103 + DC migration. Conclusions TLR4 appears to mediate several changes within the mesenteric lymphatics, more specifically it is shown to have different outcomes whether stimulation occurs through pathogen derived factors such as LPS or tissue derived DAMPs, a novel phenomenon. Support or Funding Information This study was supported by the Lymphedema Research and Education Program, Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary to P.‐Y.v.d.W. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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 source (direct Gemma or distilled Codex), 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".