Combination of IL-17A/F and TNF-α uniquely alters the bronchial epithelial cell proteome to enhance proteins that augment neutrophil migration
| dc.contributor.author | Altieri, Anthony | |
| dc.contributor.author | Piyadasa, Hadeesha | |
| dc.contributor.author | Hemshekhar, Mahadevappa | |
| dc.contributor.author | Osawa, Natasha | |
| dc.contributor.author | Recksiedler, Breann | |
| dc.contributor.author | Spicer, Victor | |
| dc.contributor.author | Hiemstra, Pieter S. | |
| dc.contributor.author | Halayko, Andrew J. | |
| dc.contributor.author | Mookherjee, Neeloffer | |
| dc.date.accessioned | 2023-01-01T04:54:20Z | |
| dc.date.issued | 2022-12-14 | |
| dc.date.updated | 2023-01-01T04:54:21Z | |
| dc.description.abstract | Abstract Background The heterodimer interleukin (IL)-17A/F is elevated in the lungs in chronic respiratory disease such as severe asthma, along with the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Although IL-17A/F and TNF-α are known to functionally cooperate to exacerbate airway inflammation, proteins altered by their interaction in the lungs are not fully elucidated. Results We used Slow Off-rate Modified Aptamer-based proteomic array to identify proteins that are uniquely and/or synergistically enhanced by concurrent stimulation with IL-17A/F and TNF-α in human bronchial epithelial cells (HBEC). The abundance of 38 proteins was significantly enhanced by the combination of IL-17A/F and TNF-α, compared to either cytokine alone. Four out of seven proteins that were increased > 2-fold were those that promote neutrophil migration; host defence peptides (HDP; Lipocalin-2 (LCN-2) and Elafin) and chemokines (IL-8, GROα). We independently confirmed the synergistic increase of these four proteins by western blots and ELISA. We also functionally confirmed that factors secreted by HBEC stimulated with the combination of IL-17A/F and TNF-α uniquely enhances neutrophil migration. We further showed that PI3K and PKC pathways selectively control IL-17A/F + TNF-α-mediated synergistic production of HDPs LCN-2 and Elafin, but not chemokines IL-8 and GROα. Using a murine model of airway inflammation, we demonstrated enhancement of IL-17A/F, TNF-α, LCN-2 and neutrophil chemokine KC in the lungs, thus corroborating our findings in-vivo. Conclusion This study identifies proteins and signaling mediated by concurrent IL-17A/F and TNF-α exposure in the lungs, relevant to respiratory diseases characterized by chronic inflammation, especially neutrophilic airway inflammation such as severe asthma. | |
| dc.identifier.citation | Journal of Inflammation. 2022 Dec 14;19(1):26 | |
| dc.identifier.uri | https://doi.org/10.1186/s12950-022-00323-w | |
| dc.identifier.uri | http://hdl.handle.net/1993/37036 | |
| dc.language.rfc3066 | en | |
| dc.rights | open access | en_US |
| dc.rights.holder | The Author(s) | |
| dc.title | Combination of IL-17A/F and TNF-α uniquely alters the bronchial epithelial cell proteome to enhance proteins that augment neutrophil migration | |
| dc.type | Journal Article |