title: Bone Marrow CD11c+ Cell-Derived Amphiregulin Promotes Pulmonary Fibrosis.
abstract: Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in tissue repair and fibrosis, but its cellular source and role in regeneration versus fibrosis remain unclear. In this study, we hypothesize that AREG induced in bone marrow-derived CD11c(+) cells is essential for pulmonary fibrosis. Thus, the objectives were to evaluate the importance and role of AREG in pulmonary fibrosis, identify the cellular source of AREG induction, and analyze its regulation of fibroblast function and activation. The results showed that lung AREG expression was significantly induced in bleomycin-induced pulmonary fibrosis. AREG deficiency in knockout mice significantly diminished pulmonary fibrosis. Analysis of AREG expression in major lung cell types revealed induction in fibrotic lungs predominantly occurred in CD11c(+) cells. Moreover, depletion of bone marrow-derived CD11c(+) cells suppressed both induction of lung AREG expression and pulmonary fibrosis. Conversely, adoptive transfer of bone marrow-derived CD11c(+) cells from bleomycin-treated donor mice exacerbated pulmonary fibrosis, but not if the donor cells were made AREG deficient prior to transfer. CD11c(+) cell-conditioned media or coculture stimulated fibroblast proliferation, activation, and myofibroblast differentiation in an AREG-dependent manner. Furthermore, recombinant AREG induced telomerase reverse transcriptase, which appeared to be essential for the proliferative effect. Finally, AREG significantly enhanced fibroblast motility, which was associated with increased expression of α6 integrin. These findings suggested that induced AREG specifically in recruited bone marrow-derived CD11c(+) cells promoted bleomycin-induced pulmonary fibrosis by activation of fibroblast telomerase reverse transcriptase-dependent proliferation, motility, and indirectly, myofibroblast differentiation.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Lin
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Tianju
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Biao
authors.identifier: 0000-0002-4691-6490
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Taku
authors.identifier: 0000-0002-0035-674X
authors.initials: T
authors.lastname: Nakashima
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Matthew
authors.initials: M
authors.lastname: Ullenbruch
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Francina
authors.initials: F
authors.lastname: Gonzalez De Los Santos
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109 shphan@umich.edu.
authors.forename: Sem H
authors.initials: SH
authors.lastname: Phan
mesh_terms: D066258:Amphiregulin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication; D001854:Bone Marrow Cells / Q000276:immunology*; D039521:CD11c Antigen / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D045142:Cross-Priming; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000276:immunology*; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D050795:STAT2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D066258:Amphiregulin; D039521:CD11c Antigen; C508032:Ifnar1 protein, mouse; D008070:Lipopolysaccharides; D050795:STAT2 Transcription Factor; D051193:Toll-Like Receptors; D053633:Receptor, Interferon alpha-beta