The interplay between hormonal vitamin D and lipopolysaccharide signaling on human neutrophil transcriptional responses
Bibliographic record
Abstract
Introduction Biologically active vitamin D (1,25-dihydroxyvitamin D or 1,25D) has emerged as a key regulator of human innate immunity. 1,25D signaling in macrophages strongly induces the expression of neutrophil chemoattractants, such as IL-8/CXCL8. Meta-analysis of vitamin D-regulated expression profiles has suggested that 1,25D may regulate granule formation in granulocytic cells. Here, we have examined the effects of 1,25D signaling on human neutrophil gene expression, alone and in combination with the inflammatory signal lipopolysaccharide (LPS). These studies are of interest because, whereas 1,25D signaling boosts innate immunity, it is anti-inflammatory. Methods and results We determined the effects of 1,25D alone and in combination with LPS on gene expression of primary human neutrophils by RNAseq. LPS did not affect or slightly enhanced the expression of several well-characterized 1,25D-target genes, but strongly suppressed that encoding the 1,25D catabolic enzyme CYP24A1. Chromatin immunoprecipitation (ChIP) assays revealed that 1,25D-dependent vitamin D receptor (VDR) binding to the major CYP24A1 enhancer was eliminated in neutrophils treated with LPS, whereas binding to other 1,25D-target genes was unaffected. Notably, LPS induced binding of transcriptional repressors MAFF and BACH1 to the major CYP24A1 enhancer region. In other studies, pathway analyses revealed that 1,25D suppressed LPS-induced genes encoding inflammatory proteins. In addition, RNAseq and confirmatory RT/qPCR studies revealed that 1,25D, both on its own and in combination with LPS, increased mRNA expression of genes encoding antimicrobial components of secretory granules, including that encoding cathelicidin antimicrobial peptide (CAMP). Consistently, exposure of neutrophils to 1,25D enhanced bacterial killing, as revealed by a 20-25% reduction in E. coli colonies incubated with 1,25D-treated neutrophil conditioned media. The increased bacterial killing by 1,25D is mediated by 1,25D-induced secretion of cathelicidin, as an antibody against LL-37, the active form of cathelicidin, blocked antimicrobial activity. Discussion Collectively, the data suggest that LPS prolongs vitamin D signaling by suppressing expression of the 1,25D catabolic enzyme CYP24A1. 1,25D signaling in the presence of LPS attenuates the expression of several genes associated with LPS inflammatory responses, whereas 1,25D in the absence or presence of LPS enhances the release of antibacterial proteins secreted by neutrophils in response to infection.
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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 | 0.000 |
| 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".