IL-17A deficiency mitigates bleomycin-induced complement activation during lung fibrosis

FASEB J. 2017 Dec;31(12):5543-5556. doi: 10.1096/fj.201700289R. Epub 2017 Aug 17.


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.

Keywords: C3a; C5a; C5b-9; DAF; ER stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Animals
  • Bleomycin / pharmacology*
  • Blotting, Western
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cells, Cultured
  • Complement Activation / drug effects*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Fibrosis / genetics
  • Fibrosis / metabolism*
  • Fluorescent Antibody Technique
  • Hemolysis / genetics
  • Hemolysis / physiology
  • Humans
  • Interleukin-17 / deficiency*
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • Lung Diseases / genetics
  • Lung Diseases / metabolism*
  • Male
  • Mice
  • Middle Aged
  • Real-Time Polymerase Chain Reaction


  • Interleukin-17
  • Bleomycin
  • Caspase 3
  • Caspase 7