title: TREM-2 promotes macrophage survival and lung disease after respiratory viral infection.
abstract: Viral infections and type 2 immune responses are thought to be critical for the development of chronic respiratory disease, but the link between these events needs to be better defined. Here, we study a mouse model in which infection with a mouse parainfluenza virus known as Sendai virus (SeV) leads to long-term activation of innate immune cells that drive IL-13-dependent lung disease. We find that chronic postviral disease (signified by formation of excess airway mucus and accumulation of M2-differentiating lung macrophages) requires macrophage expression of triggering receptor expressed on myeloid cells-2 (TREM-2). Analysis of mechanism shows that viral replication increases lung macrophage levels of intracellular and cell surface TREM-2, and this action prevents macrophage apoptosis that would otherwise occur during the acute illness (5-12 d after inoculation). However, the largest increases in TREM-2 levels are found as the soluble form (sTREM-2) long after clearance of infection (49 d after inoculation). At this time, IL-13 and the adapter protein DAP12 promote TREM-2 cleavage to sTREM-2 that is unexpectedly active in preventing macrophage apoptosis. The results thereby define an unprecedented mechanism for a feed-forward expansion of lung macrophages (with IL-13 production and consequent M2 differentiation) that further explains how acute infection leads to chronic inflammatory disease.
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Kangyun
authors.initials: K
authors.lastname: Wu
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Derek E
authors.initials: DE
authors.lastname: Byers
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Jin
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Eugene
authors.initials: E
authors.lastname: Agapov
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Alexander-Brett
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110 Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Anand C
authors.initials: AC
authors.lastname: Patel
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Marina
authors.initials: M
authors.lastname: Cella
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Susan
authors.initials: S
authors.lastname: Gilfilan
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kober
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110 Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110 Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Tom J
authors.initials: TJ
authors.lastname: Brett
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110 Pulmonary and Critical Care Medicine, Department of Medicine, Department of Pediatrics, Department of Pathology and Immunology, Department of Biochemistry and Biophysics, and Department of Cell Biology, Washington University School of Medicine, St. Louis, MO 63110 holtzmanm@wustl.edu.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holtzman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D008171:Lung Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D010253:Respirovirus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D029082:Sendai virus / Q000502:physiology*; D014779:Virus Replication / Q000235:genetics / Q000276:immunology
chemical_list: D018793:Interleukin-13; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498716:Trem2 protein, mouse