A293 INFLAMMASOME ACTIVATION INCREASES MACROPHAGE MIGRATION THROUGH EPITHELIAL BARRIER DURING CITROBACTER RODENTIUMINFECTION
Bibliographic record
Abstract
The proinflammatory cytokine interleukin (IL)-1β is released from macrophages and monocytes through a class of protein complexes called inflammasomes. Nod-like receptor protein-3 (NLRP3) inflammasomes have been linked to various inflammatory conditions such as inflammatory bowel diseases (IBD). Conditions associated with the inflammasomes are typically characterized by an overabundance of IL-1β with the exception of IBD, where its dysregulation leads to an IL-1β reduction. The mouse pathogen Citrobacter rodentium, a common mouse model pathogen for enteropathogenic E. coli, is used to understand the dynamic relationship between pathogens, the inflammasome, and the epithelial barrier. We have previously shown that ATP-activated macrophages increase clearance of C. rodentium in vitro. Our hypothesis was that inflammasome activation will increase macrophage recruitment and facilitate migration through the epithelial barrier. To determine the role of the inflammasome in bacterial-epithelial-macrophage interplay Mouse colonic epithelial cells (CMT-93) were seeded on collagen coated transwells until tight junctions were formed [documented using transepithelial electrical resistance (TEER)]. CMT-93 cells were then infected with C. rodentium on the apical membrane. ATP (2.5mM) and LPS (10ng/ml) were used to activate the inflammasome in macrophages and then added to the basolateral membrane for 24hrs. Tight junction permeability was measured every 2 hrs using TEER. Macrophage migration was observed using confocal microcopy with F4/80 as the macrophage stain along with GFP C. rodentium and epithelial ZO-1 staining. The tight junction proteins Claudin-1, Occludin, and ZO-1 were assessed in macrophages. ATP-activated macrophages were recruited to the apical membrane during C. rodentium infection of epithelial cells. C. rodentium adherence to epithelial cells after 24 hours was found to be significantly reduced and there was an increase in epithelial barrier recovery, measured by TEER; these effects were inhibited when YVAD was present. We also documented an increase in macrophage tight junction proteins during C. rodentium infection, suggesting a potential for active interaction with epithelial cells. These data suggest that the inflammasome is an important mediator for pathogen clearance by macrophages. Some individuals with Crohn Disease that have a decreased ability to produce IL-1β may be more susceptible to infection, due to impairments in the ability to clear pathogens. Our multi-cell type models highlights the important relationship between epithelial cells and macrophage inflammasomes in maintaining the epithelial barrier in IBD patients, which could allow development of new treatments. CCCCCA
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".