Cholangiocyte chemokine secretion and macrophage accumulation is mediated by osteopontin in murine liver models
Bibliographic record
Abstract
Background and aims Progression of chronic liver disease involves accumulation of inflammatory cells towards the peri-portal regions during a ductular inflammatory response. Osteopontin (OPN), an effector of Hh signalling, contributes to liver fibrogenesis and ductular inflammation via activation of hepatic stellate and progenitor cells. In tissue injury, OPN regulates macrophage functions via pro-inflammatory chemoattractant properties. In liver, however, the role of OPN in macrophage activation and recruitment remains unclear. We investigated the role of OPN in cholangiocyte chemokine secretion and macrophage recruitment using in vivo, in vitro, and in silico approaches. Methods In MCD and DDC murine models of liver fibrosis, total liver chemokine expression was measured by qRTPCR and macrophages detected by FACS (CD 11b, F4/80, CCR2, Ly6C). Lentiviral-mediated shRNA (shOPN) was used for OPN knockdown in murine 603B cholangiocytes, and secreted OPN neutralized by specific aptamers. Cholangiocyte chemokine secretion was measured by cytometric bead array and mRNA by qRTPCR. Macrophage migration was assessed in transwells using RAW264.7 cells. To obtain a global perspective of genes affected by OPN, next-generation RNA sequencing was used to compare control and shOPN cholan- giocytes. Transcripts were assessed in DESeq and gene ontologies and pathways by GOrilla, DAVID, and ReviGO software. Results Liver fibrosis in MCD and DDC was accompanied by upregulated total liver OPN, TGF-β, Ccl2, Ccl5, and Cxcll mRNA, and accumulation of liver CDl1b/F4/80(+) CCR2(hi) macrophages. Mice treated with OPN-aptamers had less fibrosis, reduced Ccl2, Ccl5, and Cxcll mRNA, and reduced accumulation of liver CD11b/F4/80(+) CCR2(hi) macrophages and the Ly6C(hi) inflammatory monocyte subset. In shOPN cholangiocytes, RNAseq detected 670 affected genes (Ben- jamini-Hochsberg padj <0.05). Ten chemokines were significantly downregulated: Cxcl16, Cxcl11, Cxcl10, Ccl5, Ccl2, Ccl9, Ccl7 Cxcl1, Cx3cl1 and Cxcl5 (by a range of log2fold between 2.70 and 0.99). Enriched gene ontologies clustered around immunity, chemotaxis and cytokine and chemokine production Altered pathways involved chemokine production and NfKB signalling. Consistent reductions in chemokine secretion and mRNA were verified in shOPN cholangiocytes Additionally, RAW264.7 macrophages cultured with OPN-deficient 603B conditioned media exhibited decreased migration. Conclusions In progressive liver disease OPN promotes chol- angiocyte production of chemokines and the accumulation of macrophages, including a proinflammatory monocyte subset. These data support neutralization of OPN as an anti-inflammatory and anti-fibrotic strategy.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 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 | 0.000 |
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 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".