A60 THE NEURAL SIGNAL, CALCITONIN GENE-RELATED PEPTIDE (CGRG) ENHANCES A REGULATORY PHENOTYPE IN THE HUMAN IL-4 TREATED HUMAN MACROPHAGE
Bibliographic record
Abstract
Abstract Background Recent studies in pre-clinical models of disease have revealed the ability of murine and human IL-4-treated macrophages (M(IL4)) to promote wound recovery and reduce the severity of colitis. An unbiased RNA-sequence analysis of human blood-derived macrophages revealed increased expression of the RAMP1 chain of the CGRP receptor in IL-4 treated cells, raising the intriguing possibility of neural control of regulatory macrophages in the context of neuroimmune interaction in colitis. Thus, we sought to address if this mRNA signal translated into increased RAMP1 protein, if/how CGPR affected M(IL4) function, and if this applied to macrophages from patients with IBD as well as those from healthy donors. Aims To determine if CRGP-RAMP1 signalling in human IL-4 treated macrophages enhances a regulatory phenotype. Methods Peripheral blood mononuclear cells from healthy volunteers and individuals with IBD 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 20 ng/mL) and assessed by qPCR and immunocytochemistry. In other cells, CGRP (10 nM) was added 24h after IL-4 and (1) cAMP (2) cytokines and (3) phagocytosis of inert FITC-beads measured, and (4) the capacity of supernatant from the cells to promote healing in wounded Caco2 epithelial monolayers tested. Results Compared to non-treated macrophages (M(0)), M(IL4)s from healthy individuals had increased mRNA for both chains of the CGRP-receptor (i.e. RAMP1 and CLR), and increased surface expression of the receptor as shown by immunostaining and CGRP-evoked cAMP. The IL-4 evoked RAMP1 mRNA was only detected in macrophages from 50% of the patients with active IBD. M(IL4)s treated with CGRP showed enhanced expression of the mannose receptor (CD206, allows detection of bacteria), increase phagocytosis of inert beads/macrophages. Moreover, CGRP increases VEGF and CCL18 expression in M(IL4), and soluble mediators from these cells promoted in vitro epithelial wound repair. Conclusions Reduced expression of CGRP and its receptor has been shown in IBD. The findings herein, demonstrating how CGRP-RAMP1 signalling can reinforce and enhance a regulatory, reparatory phenotype in human macrophages reveals another aspect of IBD pathophysiology. We speculate that loss of this neuroimmune axis (i.e. CGRP/Nerve-M(IL4) interaction) has the potential to significantly impair mucosal healing in IBD. Funding Agencies CCCAlberta Innovates in Health Innovation
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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 | 0.002 | 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 | 0.001 | 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) | 0.001 | 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".