title: Transcellular delivery of vesicular SOCS proteins from macrophages to epithelial cells blunts inflammatory signaling.
abstract: JAK-STAT signaling mediates the actions of numerous cytokines and growth factors, and its endogenous brake is the family of SOCS proteins. Consistent with their intracellular roles, SOCS proteins have never been identified in the extracellular space. Here we report that alveolar macrophages can secrete SOCS1 and -3 in exosomes and microparticles, respectively, for uptake by alveolar epithelial cells and subsequent inhibition of STAT activation. Secretion is tunable and occurs both in vitro and in vivo. SOCS secretion into lung lining fluid was diminished by cigarette smoking in humans and mice. Secretion and transcellular delivery of vesicular SOCS proteins thus represent a new model for the control of inflammatory signaling, which is subject to dysregulation during states of inflammation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109.
authors.forename: Emilie
authors.initials: E
authors.lastname: Bourdonnay
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Zasłona
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109.
authors.forename: Loka Raghu Kumar
authors.initials: LR
authors.lastname: Penke
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Speth
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schneider
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109.
authors.forename: Sally
authors.initials: S
authors.lastname: Przybranowski
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109.
authors.forename: Joel A
authors.initials: JA
authors.lastname: Swanson
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109.
authors.forename: Peter
authors.initials: P
authors.lastname: Mancuso
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109 Research Services and Medical Services, Department of Veterans Affairs Health Care System, Ann Arbor, MI 48105.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Freeman
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109 Research Services and Medical Services, Department of Veterans Affairs Health Care System, Ann Arbor, MI 48105.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Curtis
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine and Department of Microbiology and Immunology, University of Michigan Medical School; and Department of Environmental Health Sciences, School of Public Health; University of Michigan, Ann Arbor, MI 48109 petersm@umich.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D055252:Cell-Derived Microparticles / Q000276:immunology* / Q000473:pathology; D004847:Epithelial Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D053612:Janus Kinases / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D011650:Pulmonary Alveoli / Q000276:immunology* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D050791:STAT Transcription Factors / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology*
chemical_list: D050791:STAT Transcription Factors; D050826:Suppressor of Cytokine Signaling Proteins; D053612:Janus Kinases
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