Regulation and Function of Atypical Chemokine Receptor-1 (ACKR1/DARC) in Primary Endothelial Cells
Bibliographic record
Abstract
Atypical chemokine receptor-1 (ACKR1), previously known as the Duffy antigen receptor for chemokines, is a widely conserved cell surface protein that is expressed on erythrocytes and the endothelium of post-capillary venules. In addition to being the receptor for the parasites causing malaria, ACKR1 has been postulated to regulate innate immunity by displaying and trafficking chemokines. Intriguingly, a common mutation in its promoter leads to loss of the erythrocyte protein but leaves endothelial expression unaffected. The study of endothelial ACKR1 has been limited by the rapid downregulation of both transcript and protein when endothelial cells are extracted and cultured from tissue. Thus, to date the study of endothelial ACKR1 has been limited to heterologous over-expression models or the use of transgenic mice. To overcome this technical difficulty and further investigate the regulation and function of endothelial ACKR1 in humans, we established an in vitro ACKR1 induction model on human pulmonary microvascular endothelial cells (HPMECs). By exposing endothelial cells to whole blood, we observed the induction of ACKR1 mRNA and protein expression in cultured primary human pulmonary microvascular endothelial cells. We also found that contact with neutrophils is required for this effect and that this contact confers susceptibility of endothelial cells to recombinant staphylococcal leukocidin, indicating cell-surface expression of ACKR1. We show that NF-κBiii regulates ACKR1 expression and that upon removal of blood, the protein is rapidly secreted by extracellular vesicles concordant with loss of susceptibility of the endothelial cells to eukocidin. Finally, we confirm that endogenous ACKR1 does not signal upon stimulation with IL-8 or CXCL1. Together, the findings from my PhD project define a simple method for inducing endogenous endothelial ACKR1 protein and demonstrate the mechanisms of ACKR1 regulation in cultured primary endothelial cells. Other than ACKR1, numerous endothelial proteins are downregulated in cell culture environment due to phenotypic instability of endothelium. Our observations offer a new sight of reversing protein loss in vitro and further facilitate functional studies of unknown endothelial proteins.
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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) | 0.001 | 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".