B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary fibrosis
Introduction
Fibrosis is a devastating untreatable feature of numerous human diseases, including chronic heart, kidney or liver insufficiency, idiopathic pulmonary fibrosis (IPF) [1] and autoimmune diseases such as systemic sclerosis (SSc) [2] or primary Sjögren's syndrome (pSS) [3]. IPF is a progressive, chronic and irreversible interstitial lung disease of unknown etiology that is usually lethal [1]. A growing body of evidence suggests that the disease process is initiated through alveolar epithelial cell microinjuries that lead to a persistent immuno-inflammatory phase with production of cytokines, chemokines and growth factors responsible for the expansion of fibroblast and myofibroblast populations [4] leading to dysregulated tissue repair [5] and parenchyma destruction [6], [7]. These fibroblastic foci secrete exaggerated amounts of extracellular matrix components that destroy the lung parenchyma [6], [7]. Many forms of the disease are believed to be induced, at least initially by a strong inflammatory response [4] and recent workshops on research future directions in IPF recommended to promote studies, among six critical areas, on the role of inflammation and immunity in fibrotic diseases [8], [9]. To date, no therapy has been clearly shown to prolong IPF patient survival. In systemic sclerosis (SSc) fibrosis [10], [11], a skin fibrotic disease often associated with pulmonary fibrosis, levels of the tumor necrosis factor (TNF) family members B cell activating factor (BAFF; also known as TNFSF13B, BLyS or TALL1) correlate with disease progression [12], [13], [14]. Recently, Xue et al. showed that plasma concentrations of BAFF were significantly greater in IPF than control patients and that increased BAFF levels were associated with diminished survival [15]. Many important advances have been generated using mouse models of IPF. Using the bleomycin (BLM)-induced pulmonary fibrosis model, we previously reported that pulmonary inflammation and fibrosis are mediated by secretion of the pro-inflammatory and pro-fibrotic cytokine IL-1β through Nlrp3 inflammasome activation and IL-1R1/MyD88 signaling [16], [17], [18]. We also identified the existence of an early IL-1β-IL-23-IL-17A axis in pulmonary inflammation leading to late fibrosis in this model [19] and IL-17-producing Th17 cells were shown to be a critical mediator of BLM and/or IL-1β-mediated pulmonary fibrosis [7], [20], [21].
Here we hypothesized that BAFF and/or the proliferation-inducing ligand (APRIL, TNFSF13) could be involved in the physiopathology of pulmonary fibrosis. BAFF and APRIL are produced by innate immune cells [22] such as neutrophils [23], macrophages, monocytes, dendritic cells (DCs) or follicular DCs [24], but also T cells [25], B cells [26] or non-hematopoietic cells such as fibroblast-like synoviocytes from patients with rheumatoid arthritis [27] or salivary gland and conjunctival epithelial cells from patients with Sjögren's syndrome [28], [29]. Receptors for BAFF and APRIL are mainly expressed by B cells but also by T cells, monocytes or DCs, indicating that the role of BAFF and APRIL extends beyond that of B cell biology [22]. An excess of BAFF may lead to development of autoimmune disorders in mice and humans [30], [31], [32].
Here we report the first evidence of a critical role of BAFF in experimental pulmonary fibrosis in mice. Strong overexpression of BAFF was induced in both bronchoalveolar space and lung after bleomycin exposure in this model. Genetic ablation of BAFF or neutralization of BAFF by a soluble receptor significantly attenuated the experimental pulmonary fibrosis. We identified Gr1+ neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. We show that rIL-17A-induced fibrosis is dependent on BAFF and that BAFF amplifies IL-17-production by T cells from mouse fibrotic lungs. Finally, we report for the first time increased BAFF levels in the bronchoalveolar lavages of 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.
Section snippets
Mice
BAFF−/− [33], IL-1R1−/− [34], IL-17A−/− and IL-17RA−/− [35] backcrossed 10 times on the wild-type C57BL/6 genetic background were used. Mice were bred in our animal facility (CNRS, Orleans). Six to ten weeks used animals were kept in sterile isolated ventilated cages. All animal experiments complied with the French Government's ethical and animal experiment regulations.
Treatments
Bleomycin sulfate (5 mg/kg; Bellon Laboratories), rBAFF, rIL-1β or rIL-17A (1 μg/mice, once at day 0) in saline or saline
Bleomycin-treated mice have exacerbated BAFF expression in lungs and BALF
In order to investigate the contribution of BAFF in idiopathic pulmonary fibrosis (IPF), we used the bleomycin (BLM) model of lung injury and fibrosis in mice [16]. BLM instillation resulted in an increase of BAFF mRNA in the lungs compared with saline-treated littermates, which started after 1 day, peaked at day 7 and returned to basal levels at day 14 (Fig. 1a), while APRIL mRNA levels were not modified (Supplementary Fig. S1). At the protein level, a significant increase of BAFF in lung
Discussion
For the first time, our study presents evidence that BAFF is a critical mediator in experimental pulmonary fibrosis. We show that BAFF but not APRIL is strongly induced in bronchoalveolar spaces and lungs in the bleomycin-induced pulmonary fibrosis model, in an IL-1β- and IL-17A-dependent manner. BAFF expression was rapidly upregulated during acute inflammation and strongly increased during the development of fibrosis. Importantly, we report that BAFF deficiency or BAFF neutralization using
Conclusions
Our study demonstrates that BAFF is a critical mediator in experimental pulmonary fibrosis and supports a link between IL-1β, BAFF and IL-17A in the establishment of the disease in mice, with BAFF serving as an amplifier of IL-17-production by T lymphocytes from injured fibrotic lungs. The key role of BAFF in the experimental lung fibrotic model and the enhanced BAFF expression in the airways of IPF patients suggest the role of BAFF as a critical player in the establishment of human pulmonary
Acknowledgments
This work was supported by French Conseil Général du Loiret, French Région Centre and Agence Nationale de la Recherche MI2 and the Swiss National Science Foundation, Groupama pour la santé foundation, Association des Sclérodermiques de France, Société Française de Rhumatologie, INSERM and Strasbourg University. PS is supported by grants from the Swiss National Science Foundation.
We thank Dr Susan Kalled (BiogenIdec, Boston), Aubry Tardivel (University of Lausanne), Dr Anne Davidson (The
References (53)
- et al.
Geoepidemiology of COPD and idiopathic pulmonary fibrosis
J Autoimmun
(2010) - et al.
Diagnostic criteria of systemic sclerosis
J Autoimmun
(2014) - et al.
Sjögren's syndrome and the epithelial target: a comprehensive review
J Autoimmun
(2013) - et al.
Idiopathic pulmonary fibrosis
Lancet
(2011) - et al.
Pulmonary fibrosis: pathogenesis, etiology and regulation
Mucosal Immunol
(2009) - et al.
Systemic sclerosis: genetics and epigenetics
J Autoimmun
(2013) - et al.
The complexity of the BAFF TNF-family members: implications for autoimmunity
J Autoimmun
(2012) - et al.
B-cell activating factor genetic variants in lymphomagenesis associated with primary Sjogren's syndrome
J Autoimmun
(2014) - et al.
Proinflammatory mediators elicit secretion of the intracellular B-lymphocyte stimulator pool (BLyS) that is stored in activated neutrophils: implications for inflammatory diseases
Blood
(2005) - et al.
The role of the BAFF/APRIL system on T cell function
Semin Immunol
(2006)
Development of autoimmune nephritis in genetically asplenic and splenectomized BAFF transgenic mice
J Autoimmun
A novel method to compensate for different amplification efficiencies between patient DNA samples in quantitative real-time PCR
J Mol Diagn
Differential role of neutrophils and alveolar macrophages in hepatocyte growth factor production in pulmonary fibrosis
Lab Investig J Tech Methods Pathol
BAFF is elevated in serum of patients with Wegener's granulomatosis
J Autoimmun
TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts
Blood
MCAM-expressing CD4(+) T cells in peripheral blood secrete IL-17A and are significantly elevated in inflammatory autoimmune diseases
J Autoimmun
Integrating mechanisms of pulmonary fibrosis
J Exp Med
Pathogenesis of idiopathic pulmonary fibrosis
Annu Rev Pathol
Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report
Am J Respir Crit Care Med
Future research directions in idiopathic pulmonary fibrosis: summary of a National Heart, Lung, and Blood Institute working group
Am J Respir Crit Care Med
Fibrosis in systemic sclerosis: common and unique pathobiology
Fibrogenes Tissue Repair
Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes
Arthritis Rheum
Plasma B lymphocyte stimulator and B cell differentiation in idiopathic pulmonary fibrosis patients
J Immunol Balt Md
IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice
J Clin Invest
Uric acid is a danger signal activating NALP3 inflammasome in lung injury inflammation and fibrosis
Am J Respir Crit Care Med
Extracellular ATP is a danger signal activating P2X7 receptor in lung inflammation and fibrosis
Am J Respir Crit Care Med
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These authors contributed equally to the work.