Abstract
Pulmonary fibrosis is a difficult to treat, often fatal disease whose pathogenesis involves dysregulated TGF-β1 signaling. CD4+CD25+FoxP3+ Regulatory T cells (“Tregs”) exert important effects on host tolerance and arise from naïve CD4+ lymphocytes in response to TGF-β1. However, the precise contribution of Tregs to experimentally induced murine lung fibrosis remains unclear. We sought to better understand the role of Tregs in this context. Using a model of fibrosis caused by lung specific, doxycycline inducible overexpression of the bioactive form of the human TGF-β1 gene we find that Tregs accumulate in the lung parenchyma within 5 days of transgene activation and that this enhancement persists to at least 14 days. Anti-CD25 Antibody mediated depletion of Tregs causes increased accumulation of soluble collagen and of intrapulmonary CD45+Col Iα1 fibrocytes. These effects are accompanied by enhanced local concentrations of the classical inflammatory mediators CD40L, TNF-α, and IL-1α, along with the neuroimmune molecule fibroblast growth factor 9 (FGF-9, also known as “glial activating factor”). FGF-9 expression localizes to parenchymal cells and alveolar macrophages in this model and antibody mediated neutralization of FGF-9 results in attenuated detection of intrapulmonary collagen and fibrocytes without affecting Treg quantities. These data indicate that CD4+CD25+FoxP3+ Tregs attenuate TGF-β1 induced lung fibrosis and fibrocyte accumulation in part via suppression of FGF-9.
Highlights
Pulmonary fibrosis is a difficult to treat and life-threatening disease that is characterized by the dysregulated accumulation of extracellular matrix components in the parenchyma of the lung (Murray et al, 2012)
In order to determine whether Tregs accumulate in the lungs of mice subject to TGFβ1-induced lung fibrosis, TGF-β1 transgene positive (Tg+) and transgene negative (Tg−, i.e., wild type) mice were given doxycycline in their drinking water, sacrificed at early (48 h), intermediate (5 days), and late timepoints (14 days) and Tregs were quantified using standard FACS-based assessment of CD4+CD25+FoxP3+ cells on lung digests (Figure 1A)
Using this approach we found that the percentage of CD4+ cells meeting flow cytometric criteria for Tregs were unchanged at the early timepoint but that compared to Tg− mice, the lungs of Tg+ mice exposed to 5 days of doxycycline contained a 24.3% increase in the percentage of CD4+ cells that were Tregs (p = 0.0252, Figure 1B) that was further increased to 34.1% at 14 days (p = 0.0021, Figure 1B)
Summary
Pulmonary fibrosis is a difficult to treat and life-threatening disease that is characterized by the dysregulated accumulation of extracellular matrix components in the parenchyma of the lung (Murray et al, 2012). The development of pulmonary fibrosis is believed to involve a complex interplay between structural cell death responses and recruitment of inflammatory cells including collagen-producing fibrocytes. These events result in the activation of profibrotic growth factors such as TGF-β1 and culminate in myofibroblast transformation and ECM accumulation (Reilkoff et al, 2011). Examination of factors that might be used to regulate the pathogenic aspects of TGF-β1 signaling may facilitate better treatments for pulmonary fibrosis
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