LL-37 modulates IL-17A/F-mediated airway inflammation by selectively suppressing Lipocalin-2
Bibliographic record
Abstract
ABSTRACT Background Levels of the human cationic host defence peptide (CHDP) LL-37 is enhanced in the lungs during neutrophilic airway inflammation. LL-37 drives Th17 differentiation, and Th17 cells produce IL-17A and IL-17F which forms the biologically active heterodimer IL-17A/F. While IL-17 is a critical mediator of neutrophilic airway inflammation, LL-37 exhibits contradictory functions; LL-37 can both promote and mitigate neutrophil recruitment depending on the inflammatory milieu. The impact of LL-37 on IL-17-induced responses in the context of airway inflammation remains largely unknown. Therefore, we examined signaling intermediates and downstream responses mediated by the interplay of IL-17A/F and LL-37, in human bronchial epithelial cells (HBEC). As LL-37 can get citrullinated during airway inflammation, we also examined LL-37-mediated downstream response compared to that with citrullinated LL-37 (citLL- 37), in HBEC. Results Using an aptamer-based proteomics approach, we identified proteins that are altered in response to IL-17A/F in HBEC. Proteins enhanced in response to IL-17A/F were primarily neutrophil chemoattractants, including chemokines and proteins associated with neutrophil migration such as lipocalin-2 (LCN-2) and Elafin. We showed that selective depletion of LCN-2 mitigated neutrophil migration, thus functionally demonstrating LCN-2 as a critical neutrophil chemoattractant. We further demonstrated that LL-37 and citLL-37 selectively suppresses IL- 17A/F-induced LCN-2 production, in bronchial epithelial cells. Mechanistic studies revealed that LL-37 and citLL-37 suppressed IL-17A/F-mediated C/EBPβ, a transcription factor required for LCN-2 production. In contrast, LL-37 and citLL-37 enhanced the ribonuclease Regnase-1, which is a negative regulator of IL-17 and LCN-2. In an animal model of neutrophilic airway inflammation with elevated IL-17A/F in the lungs, we demonstrated that CRAMP (mouse ortholog of LL-37) negatively correlates with LCN-2. Conclusions Overall, our findings showed that LL-37 and citLL-37 can selectively suppress the abundance of IL-17A/F-mediated LCN-2, a protein that is critical for neutrophil migration, in bronchial epithelial cells. These results suggest that LL-37, and its modified citrullinated form, has the potential to negatively regulate IL-17-mediated neutrophil migration to control airway inflammation. To our knowledge, this is the first study to report that the immunomodulatory function of LL-37 engages an RNA binding protein, Regnase-1, indicating post-transcriptional regulation of airway inflammation by the peptide.
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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) | 0.002 | 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".