DOP072 The IL1-dependent transcription factor MEOX1 as a driver of differentiation programs in ACKR1+ endothelial cells of inflammatory bowel disease granulation tissue
Bibliographic record
Abstract
Abstract Background Activated endothelial cells (ECs) are expanded in IBD tissue and express ACKR11, a chemokine receptor known to mark venular endothelium and enable immune cell trafficking. ACKR1+ ECs have been reported in diseases associated with inflammation and/or fibrosis2, although their role in stromal differentiation is unclear. We investigated the relationship between IL1 and inflammation in IBD and identified an IL1-dependent transcription factor (TF), MEOX1, known to regulate fibrosis in cardiac ischemia3 that is associated with IBD ulcers and expressed in ACKR1+ ECs. Methods We assessed IL-1 bioactivity and performed matched RNA-seq on a cohort of Crohn’s disease (n=23), ulcerative colitis (n=18) and non-IBD (n=17) patients. We performed scRNA-seq of n=208 very early onset (VEO)IBD and control intestinal patient samples. RNA-scope was performed in IBD tissue with/without ulcers. Primary colonic ECs and human umbilical vein (HUV)ECs were stimulated with IL1B +/- TGFB +/- JQ1 (a BRD4 inhibitor that knocked down IL1/MEOX1 driven cardiac fibrosis) followed by qPCR, bulk/scRNA-seq. Results In the paired IL1 proteomic and RNA-seq analyses of IBD tissue, we identified an IL1 and ulcer-specific gene signature which included the TF MEOX1. In scRNA seq analysis, MEOX1 was expressed exclusively in ECs (most robustly in ACKR1+ ECs, which co-expressed the IL1 receptor IL1R1) (Fig 1A). ACKR1+MEOX1+IL1R1+ ECs were significantly expanded in inflamed VEOIBD, especially in those with deep ulcers and IL10R deficiency, and exhibited hallmarks of cell cycle arrest, e.g. expression of CDKN1A (Fig 1B and data not shown). RNA-scope revealed abundant ACKR1+MEOX1+IL1R1+ EC structures specifically in granulation tissue (Fig 1C). In primary colonic ECs, IL1B stimulation induced CDKN1A, unlike TGFB which induced a proliferation/apoptosis phenotype (Fig 1D). In HUVECs, IL1B induced a spindle-shape/fibroblastic EC morphology and ACKR1/MEOX1 expression (data not shown). scRNA-seq revealed an IL1-induced cluster defined by ACKR1, CDKN1A and chemotactic/collagen-producing gene programs, eliminated upon addition of JQ1 (Fig 1E; data not shown). Conclusion ACKR1+ ECs define IBD granulation tissue and co-express IL1R1 as well as the TF MEOX1, which may prove to be a driver of differentiation programs downstream of IL1 signaling at the EC niche that may lead to fibrosis. In silico and in vitro data suggest IL1-driven EC programs are characterized by cell cycle arrest signatures. We hypothesize that the IL1/MEOX1 pathway in ACKR1+ ECs may represent a novel molecular mechanism related to ulcer biology and wound repair in IBD with potential therapeutic implications. References 1. Martin JC, Chang C, Boschetti G, et al. Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy. Cell. Sep 5 2019;178(6):1493-1508 e20. doi:10.1016/j.cell.2019.08.0082. 2. Ramachandran P, Dobie R, Wilson-Kanamori JR, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature. Nov 2019;575(7783):512-518. doi:10.1038/s41586-019-1631-33. 3. Alexanian M, Padmanabhan A, Nishino T, et al. Chromatin remodelling drives immune cell-fibroblast communication in heart failure. Nature. Nov 2024;635(8038):434-443. doi:10.1038/s41586-024-08085-6
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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 | 0.000 | 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 | 0.000 |
| 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".