B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis

J Autoimmun. 2015 Jan;56:1-11. doi: 10.1016/j.jaut.2014.08.003. Epub 2014 Oct 23.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1(+) neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3(+) T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A.

Keywords: Autoimmunity; BAFF; IL-17; IL-1β; Pulmonary fibrosis; Systemic sclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / adverse effects*
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / pharmacology
  • B-Cell Activating Factor / antagonists & inhibitors
  • B-Cell Activating Factor / deficiency
  • B-Cell Activating Factor / genetics
  • B-Cell Activating Factor / metabolism*
  • Bleomycin / administration & dosage
  • Bleomycin / adverse effects*
  • Bronchoalveolar Lavage Fluid
  • Disease Models, Animal
  • Fibrosis
  • Gene Expression
  • Idiopathic Pulmonary Fibrosis / etiology*
  • Idiopathic Pulmonary Fibrosis / pathology
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • Interleukin-1beta / metabolism
  • Lung / drug effects
  • Lung / metabolism
  • Lung / pathology
  • Mice
  • Mice, Knockout
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Signal Transduction / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Antibodies, Monoclonal
  • B-Cell Activating Factor
  • Interleukin-17
  • Interleukin-1beta
  • Bleomycin