A88 NLRP3 DRIVES INTESTINAL INFLAMMATION-ASSOCIATED FIBROSIS
Bibliographic record
Abstract
Fibrosis is one of the most common causes of surgery in inflammatory bowel disease (IBD) and the mechanisms of fibrosis in IBD are not well understood. Nucleotide-binding oligomerization domain (NOD)- like receptors, including NLRP3, are cytosolic protein sensors involved in inflammatory pathways and implicated in IBD pathogenesis. We have shown NLRP3 drives fibrosis in the heart and kidney; however, its role in intestinal fibrosis is unknown. We hypothesize that NLRP3 drives inflammation associated with intestinal fibrosis. 1) To determine, in vitro, if intestinal fibroblasts lacking NLRP3 are phenotypically distinct from wild type fibroblasts. 2) To assess intestinal fibrosis of NLRP3-deficient and wild type mice in a model of chronic colitis. 3) To investigate intestinal NLR expression in IBD patients and healthy controls. Primary colonic myofibroblasts were isolated from wild-type (WT) and Nlrp3-/- mice. Cells were treated with pro-fibrogenic cytokine TGF-beta and downstream signalling was assessed by western blot. To investigate the role of NLRP3 in intestinal fibrosis in vivo, WT and Nlrp3-/- mice were given 3 cycles of low percent (w/v) dextran sulfate sodium (DSS) in water for 5 days, followed by a two-week recovery period. In addition, we investigated the expression of NLRP3 transcripts in patients with IBD by qPCR of cDNA from mucosal biopsies. TGF-beta signalling is attenuated in Nlrp3-/- colonic myofibroblasts as phosphorylation of Smad2, a downstream TGF-beta signalling protein, was reduced in Nlrp3-/- myofibroblasts compared to WT. Nlrp3-/- myofibroblasts also had lower TGF-beta-induced connective tissue growth factor (CTGF) compared to WT. Nlrp3-/- mice are more susceptible to cyclical DSS treatment with significantly greater weight loss and mortality compared to WT. Marked intestinal fibrosis was induced with the cyclical DSS protocol and those with most severe fibrosis were Nlpr3-/- mice. NLRP3 transcript levels were significantly increased in Crohn’s Disease (CD) patients compared to normal controls, but not in ulcerative colitis (UC) patients. Our data suggest that loss of NLRP3 leads to reduced response to TGF-beta in colonic myofibroblasts. Similar to its role in the kidney and heart, NLRP3 may potentiate TGF-beta signalling in the gut. Further insights into the mechanisms of intestinal fibrosis will significantly impact the development of new tools that will help with assessing and treating patients with IBD complications. CIHR
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.001 |
| 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".