title: CD4+CD25+FoxP3+ Regulatory Tregs inhibit fibrocyte recruitment and fibrosis via suppression of FGF-9 production in the TGF-β1 exposed murine lung.
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.
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine New Haven, CT, USA.
authors.forename: Xueyan
authors.initials: X
authors.lastname: Peng
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine New Haven, CT, USA.
authors.forename: Meagan W
authors.initials: MW
authors.lastname: Moore
authors.affiliation: Department of Respiratory Medicine, The Second Xiangya Hospital of Central-South University Changsha, Hunan, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine New Haven, CT, USA.
authors.forename: Huanxing
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine New Haven, CT, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Gan
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine New Haven, CT, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Homer
authors.affiliation: Department of Internal Medicine, Section of Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine New Haven, CT, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Herzog
keywords: FGF-9; Fibrosis; TGF-β1; fibrocytes; regulatory T cells