LL-37 and citrullinated-LL-37 modulate IL-17A/F-mediated responses and selectively suppress Lipocalin-2 in bronchial epithelial cells

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dc.contributor.authorAltieri, Anthony
dc.contributor.authorLloyd, Dylan
dc.contributor.authorRamotar, Padmanie
dc.contributor.authorvan der Does, Anne M.
dc.contributor.authorHemshekhar, Mahadevappa
dc.contributor.authorMookherjee, Neeloffer
dc.date.accessioned2025-06-06T14:45:21Z
dc.date.available2025-06-06T14:45:21Z
dc.date.issued2025-05-23
dc.date.updated2025-06-01T03:28:08Z
dc.description.abstractAbstract Background Levels of the human cationic antimicrobial host defence peptide LL-37 are enhanced in the lungs during neutrophilic airway inflammation. LL-37 drives Th17 differentiation, and Th17 cells produce IL-17A and IL-17F which form 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 become citrullinated during airway inflammation, we also examined LL-37-mediated downstream responses 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). We showed that selective depletion of LCN-2 mitigates neutrophil migration, functionally demonstrating LCN-2 as a critical neutrophil chemoattractant. We further demonstrated that LL-37 and citLL-37 selectively suppress IL-17A/F-induced LCN-2 abundance in HBEC. Mechanistic studies revealed that LL-37 and citLL-37 suppresses IL-17 A/F-mediated enhancement of C/EBPβ, a transcription factor required for LCN-2 production. In contrast, LL-37 and citLL-37 enhance the abundance of ribonuclease Regnase-1, which is a negative regulator of IL-17 and LCN-2 in HBEC. In an animal model of allergen-challenged airway inflammation with elevated IL-17A/F and neutrophil elastase in the lungs, we demonstrated that CRAMP (mouse orthologue 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 HBEC. These results suggest that LL-37, and its modified citrullinated form, have the potential to negatively regulate IL-17-mediated neutrophil migration during airway inflammation. To our knowledge, this is the first study to report that the immunomodulatory function of LL-37 enhances the RNA binding protein Regnase-1, suggesting that a post-transcriptional mechanism of action is mediated by the peptide.
dc.identifier.citationJournal of Inflammation. 2025 May 23;22(1):20
dc.identifier.doi10.1186/s12950-025-00446-w
dc.identifier.urihttp://hdl.handle.net/1993/39100
dc.language.isoeng
dc.language.rfc3066en
dc.publisherBMC
dc.rights.holderThe Author(s)
dc.subjectLL-37
dc.subjectIL-17
dc.subjectLung
dc.subjectLipocalin-2
dc.subjectRegnase-1
dc.titleLL-37 and citrullinated-LL-37 modulate IL-17A/F-mediated responses and selectively suppress Lipocalin-2 in bronchial epithelial cells
dc.typeresearch article
local.author.affiliationRady Faculty of Health Sciences::Max Rady College of Medicine::Department of Immunology
oaire.citation.startPage20
oaire.citation.titleJournal of Inflammation
oaire.citation.volume22
project.funder.identifierhttps://doi.org/10.13039/501100000038
project.funder.nameNatural Sciences and Engineering Research Council of Canada
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