title: IRAK-M promotes alternative macrophage activation and fibroproliferation in bleomycin-induced lung injury.
abstract: Idiopathic pulmonary fibrosis is a devastating lung disease characterized by inflammation and the development of excessive extracellular matrix deposition. Currently, there are only limited therapeutic intervenes to offer patients diagnosed with pulmonary fibrosis. Although previous studies focused on structural cells in promoting fibrosis, our study assessed the contribution of macrophages. Recently, TLR signaling has been identified as a regulator of pulmonary fibrosis. IL-1R-associated kinase-M (IRAK-M), a MyD88-dependent inhibitor of TLR signaling, suppresses deleterious inflammation, but may paradoxically promote fibrogenesis. Mice deficient in IRAK-M (IRAK-M(-/-)) were protected against bleomycin-induced fibrosis and displayed diminished collagen deposition in association with reduced production of IL-13 compared with wild-type (WT) control mice. Bone marrow chimera experiments indicated that IRAK-M expression by bone marrow-derived cells, rather than structural cells, promoted fibrosis. After bleomycin, WT macrophages displayed an alternatively activated phenotype, whereas IRAK-M(-/-) macrophages displayed higher expression of classically activated macrophage markers. Using an in vitro coculture system, macrophages isolated from in vivo bleomycin-challenged WT, but not IRAK-M(-/-), mice promoted increased collagen and α-smooth muscle actin expression from lung fibroblasts in an IL-13-dependent fashion. Finally, IRAK-M expression is upregulated in peripheral blood cells from idiopathic pulmonary fibrosis patients and correlated with markers of alternative macrophage activation. These data indicate expression of IRAK-M skews lung macrophages toward an alternatively activated profibrotic phenotype, which promotes collagen production, leading to the progression of experimental pulmonary fibrosis.
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210; megan.ballinger@osumc.edu.
authors.forename: Megan N
authors.initials: MN
authors.lastname: Ballinger
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109;
authors.forename: Michael W
authors.initials: MW
authors.lastname: Newstead
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109;
authors.forename: Xianying
authors.initials: X
authors.lastname: Zeng
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109;
authors.forename: Urvashi
authors.initials: U
authors.lastname: Bhan
authors.affiliation: Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH 43221;
authors.forename: Xiaokui M
authors.initials: XM
authors.lastname: Mo
authors.affiliation: Department of Pathology, University of Michigan Medical Center, Ann Arbor, MI 48109; and.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109;
authors.forename: Bethany B
authors.identifier: http://orcid.org/0000-0003-3051-745X
authors.initials: BB
authors.lastname: Moore
authors.affiliation: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520.
authors.forename: Richard
authors.initials: R
authors.lastname: Flavell
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210;
authors.forename: John W
authors.initials: JW
authors.lastname: Christman
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109;
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D015153:Blotting, Western; D002469:Cell Separation; D018920:Coculture Techniques; D003094:Collagen; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D008262:Macrophage Activation / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D000903:Antibiotics, Antineoplastic; D001761:Bleomycin; D003094:Collagen; C507771:IRAK3 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse