IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis
dc.contributor.author | Cipolla, Ellyse | |
dc.contributor.author | Fisher, Amanda J. | |
dc.contributor.author | Gu, Hongmei | |
dc.contributor.author | Mickler, Elizabeth A. | |
dc.contributor.author | Agarwal, Manisha | |
dc.contributor.author | Wilke, Carol A. | |
dc.contributor.author | Kim, Kevin K. | |
dc.contributor.author | Moore, Bethany B. | |
dc.contributor.author | Vittal, Ragini | |
dc.contributor.department | Medicine, School of Medicine | en_US |
dc.date.accessioned | 2019-06-03T18:06:38Z | |
dc.date.available | 2019-06-03T18:06:38Z | |
dc.date.issued | 2017-12 | |
dc.description.abstract | Interleukin 17A (IL-17A) and complement (C') activation have each been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). We have reported that IL-17A induces epithelial injury via TGF-β in murine bronchiolitis obliterans; that TGF-β and the C' cascade present signaling interactions in mediating epithelial injury; and that the blockade of C' receptors mitigates lung fibrosis. In the present study, we investigated the role of IL-17A in regulating C' in lung fibrosis. Microarray analyses of mRNA isolated from primary normal human small airway epithelial cells indicated that IL-17A (100 ng/ml; 24 h; n = 5 donor lungs) induces C' components (C' factor B, C3, and GPCR kinase isoform 5), cytokines (IL8, -6, and -1B), and cytokine ligands (CXCL1, -2, -3, -5, -6, and -16). IL-17A induces protein and mRNA regulation of C' components and the synthesis of active C' 3a (C3a) in normal primary human alveolar type II epithelial cells (AECs). Wild-type mice subjected to IL-17A neutralization and IL-17A knockout (il17a-/- ) mice were protected against bleomycin (BLEO)-induced fibrosis and collagen deposition. Further, BLEO-injured il17a-/- mice had diminished levels of circulating Krebs Von Den Lungen 6 (alveolar epithelial injury marker), local caspase-3/7, and local endoplasmic reticular stress-related genes. BLEO-induced local C' activation [C3a, C5a, and terminal C' complex (C5b-9)] was attenuated in il17a-/- mice, and IL-17A neutralization prevented the loss of epithelial C' inhibitors (C' receptor-1 related isoform Y and decay accelerating factor), and an increase in local TUNEL levels. RNAi-mediated gene silencing of il17a in fibrotic mice arrested the progression of lung fibrosis, attenuated cellular apoptosis (caspase-3/7) and lung deposition of collagen and C' (C5b-9). Compared to normals, plasma from IPF patients showed significantly higher hemolytic activity. Our findings demonstrate that limiting complement activation by neutralizing IL-17A is a potential mechanism in ameliorating lung fibrosis.-Cipolla, E., Fisher, A. J., Gu, H., Mickler, E. A., Agarwal, M., Wilke, C. A., Kim, K. K., Moore, B. B., Vittal, R. IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis. | en_US |
dc.identifier.citation | Cipolla, E., Fisher, A. J., Gu, H., Mickler, E. A., Agarwal, M., Wilke, C. A., … Vittal, R. (2017). IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 31(12), 5543–5556. doi:10.1096/fj.201700289R | en_US |
dc.identifier.uri | https://hdl.handle.net/1805/19511 | |
dc.language.iso | en_US | en_US |
dc.publisher | Federation of American Societies for Experimental Biology | en_US |
dc.relation.isversionof | 10.1096/fj.201700289R | en_US |
dc.relation.journal | FASEB journal | en_US |
dc.rights | Publisher Policy | en_US |
dc.source | PMC | en_US |
dc.subject | C3a | en_US |
dc.subject | C5a | en_US |
dc.subject | C5b-9 | en_US |
dc.subject | DAF | en_US |
dc.subject | ER stress | en_US |
dc.title | IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis | en_US |
dc.type | Article | en_US |
ul.alternative.fulltext | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690386/ | en_US |
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