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

Area of Science:

• Immunology
• Pulmonary Medicine
• Cell Biology

Background:

• Idiopathic pulmonary fibrosis (IPF) involves Interleukin 17A (IL-17A) and complement (C') activation.
• Previous research indicated IL-17A-induced epithelial injury and C' cascade interactions in lung fibrosis.
• C' receptor blockade was shown to mitigate lung fibrosis.

Purpose of the Study:

• To investigate the role of IL-17A in regulating complement activation in lung fibrosis.
• To determine if IL-17A influences C' component expression and activity in lung epithelial cells.
• To evaluate the therapeutic potential of targeting IL-17A in mitigating lung fibrosis.

Main Methods:

• Microarray analysis of human small airway epithelial cells treated with IL-17A.
• IL-17A treatment of primary human alveolar type II epithelial cells (AECs).
• Bleomycin (BLEO)-induced lung fibrosis model in wild-type and IL-17A knockout (il17a) mice, including IL-17A neutralization studies and RNAi-mediated gene silencing.

Main Results:

• IL-17A upregulated C' components, cytokines, and chemokines in human airway epithelial cells and AECs.
• IL-17A deficiency or neutralization protected mice against BLEO-induced lung fibrosis, collagen deposition, and epithelial injury markers.
• IL-17A blockade prevented C' activation (C3a, C5a, C5b-9) and preserved epithelial C' inhibitors, reducing apoptosis and fibrosis progression.

Conclusions:

• IL-17A drives complement activation and contributes to lung fibrosis pathogenesis.
• Neutralizing IL-17A or its deficiency mitigates lung fibrosis by limiting complement activation.
• Targeting IL-17A represents a potential therapeutic strategy for idiopathic pulmonary fibrosis.