A191 THE NEURAL SIGNAL, CALCITONIN GENE-RELATED PEPTIDE (CGRG) ENHANCES A REGULATORY PHENOTYPE IN THE HUMAN IL-4-TREATED MACROPHAGE
Bibliographic record
Abstract
Abstract Background Interlukin-4 activated human macrophages (M(IL4) promote epithelial wound healing and exert an anti-colitic effect in a murine model. Blood monocyte-derived M(IL4)s from healthy donors and individuals with Crohn’s disease had increased mRNA expression of the calcitonin gene-related peptide (CGRP) receptor chain, RAMP1, raising the issue of neural modulation of the M(IL4)s reparative function. Aims To determine if CGRP-RAMP1 signalling in human IL-4 treated macrophages enhances the anti-colitic phenotype. Methods Peripheral blood mononuclear cells from healthy volunteers (HD) and individuals with Crohn’s disease were cultured on plastic (2h, 37°C) and non-adherent cells removed. The adherent cells were cultured with recombinant hM-CSF (10 ng/ml) for 7 days. The resultant macrophages (2.5×105) were differentiated with IL-4 (48h 10 ng/mL). In other cells, CGRP (10 nM) was added 24h after IL-4 and phenotype assessed by qPCR. Rag1-/- mice were treated with M(IL4)±CGRP (1x106 i.p.): 48h later, colitis was induced by oxazolone. FITC dextran was used to evaluate epithelial barrier integrity. A wound healing assay was conducted using CaCo2 epithelial cells and conditioned medium (CM,1:2 dilution) from the different treatments. Prostaglandin D2 production was evaluated by ELISA and cyclooxygenase (COX)-1 and -2 activity inhibited using SC560 and indomethacin. Results Compared to non-treated macrophages (M(0)), M(IL4)s from HD had increased RAMP1 and CLR mRNA. M(IL4)s treated with CGRP showed enhanced expression of CD206, CCL26, RAMP1 and CCL18. When delivered systemically to oxazolone-treated rag1-/- mice, M(IL4,CGRP) had an anti-colitic effect superior to M(IL4)s from the same healthy blood donor. Use of the the human colon CaCo2 cell in vitro wounding model revealed that CM from M(IL4,CGRP) had increased amounts of TGFb and increased wound-healing capacity compared to matched M(IL4)-CM. Moreover, M(IL4,CGRP)s displayed increased COX-1 and PGD2. CM from M(IL4,CGRP)s treated with indomethacin or SC-560 to inhibit COX1 activity failed to promote repair of wounded CaCo2 cell monolayers. Conclusions Neuronal input is revealed as an important local modifier capable of boosting the anti-colitic effect of autologous M(IL4) transfer to treat enteric inflammation. Funding Agencies CCCHelmsley Charity
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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 | 0.001 | 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 | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".