A14 ACTIVATION OF STROMAL CELL-EXPRESSED NOD2 MODULATES SYSTEMIC DENDRITIC CELL FUNCTION VIA THE PRODUCTION OF GM-CSF
Bibliographic record
Abstract
Polymorphisms in the gene encoding for the pattern-recognition receptor NOD2 confer genetic risk of developing Crohn’s disease (CD). However, the mechanisms by which these mutations contribute to the onset of overt inflammation are at this point unclear. Previous studies have shown that dendritic cells (DC) express among the highest levels of NOD2 of any cell type, yet the effects of NOD2 activation on DC function have not been thoroughly assessed. With this in mind, we chose to assess the effects of in vivo administration of purified NOD2 ligand on the function and prevalence of specific DC subtype populations. C57Bl/6 mice were injected i.p. with ligands for NOD2 (MDP), NOD1 (FK156), TLR4 (LPS) or TLR2/1 (Pam3CSK4). 24h later, tissues were collected and the populations of DCs present assessed by flow cytometry. Injection of MDP led to a significant increase in the proportion of dendritic cells in the spleen expressing the surface marker CD103 (MDP: 25.4 ± 2.5%, Vehicle: 7.9 ± 0.5%). Closer examination of these cells revealed this to be restricted to a specific subset of splenic DCs (CD205+, XCR1+, CLEC9a+, and CD8α+, also known as cDC1) - a cell type that is known to be an efficient cross-presenter of injested antigens to CD8 T cells. This phenotype was replicated by injection of FK156, a synthetic ligand of the closely related receptor NOD1, while injection of the toll-like receptor ligands LPS and Pam3CSK4 resulted conversely in the significant decrease in the total numbers of cDC1s in the spleen, indicating that this phenomenon is specific to activation of Nod-like receptors (NLRs). Suprisingly, Cre-Lox mouse models indicated that this phenomenon was not dependent on expression of Nod2 by these DCs themselves. Accordingly, bone marrow chimera experiments indicated that a radioresitant cell was responsible for the detection of MDP in this model. Thus, we examined by qPCR the expression of various immunomodulatory factors within membrane surrounding the peritoneal cavity following MDP adminstration and found a significant increase in the expression of the gene encoding for GM-CSF (15.9 ± 5.2 fold increase over vehicle control), a growth factor known to modulate expression of CD103 on DCs. Further, we found that the injection of recombinant GM-CSF resulted in an increase in CD103 expression on spleen cDC1s in the same manner as MDP injection, while Csf2-/- mice did not respond to MDP, indicating that these two factors are part of the same pathway. Interestingly, deficiencies in GM-CSF signaling has also been implicated in CD pathogenesis. This study is the first to identify a shared biological pathway between GM-CSF and NOD2, suggesting that this pathway might be of vital importance for intestinal immune homeostasis, and could give us insight into the etiology and potential therapy of CD. CIHR
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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 | 0.001 |
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".