title: Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment.
abstract: Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1(-/-) mice received intratracheal LPS. Fibroproliferation was characterized by histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1(-/-) mice received CD4(+)CD25(+) (Tregs) or CD4(+)CD25(-) Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1(-/-) mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1(-/-) mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1(-/-) mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. bgariba1@jhmi.edu
authors.forename: Brian T
authors.initials: BT
authors.lastname: Garibaldi
authors.forename: Franco R
authors.initials: FR
authors.lastname: D'Alessio
authors.forename: Jason R
authors.initials: JR
authors.lastname: Mock
authors.forename: D Clark
authors.initials: DC
authors.lastname: Files
authors.forename: Eric
authors.initials: E
authors.lastname: Chau
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Eto
authors.forename: M Bradley
authors.initials: MB
authors.lastname: Drummond
authors.forename: Neil R
authors.initials: NR
authors.lastname: Aggarwal
authors.forename: Venkataramana
authors.initials: V
authors.lastname: Sidhaye
authors.forename: Landon S
authors.initials: LS
authors.lastname: King
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology* / Q000473:pathology*; D019264:Adoptive Transfer; D000818:Animals; D001596:Benzylamines; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000276:immunology / Q000473:pathology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology
chemical_list: D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D018398:Homeodomain Proteins; D008070:Lipopolysaccharides; D019718:Receptors, CXCR4; C064658:RAG-1 protein; C088327:plerixafor