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Am J Physiol Lung Cell Mol Physiol. 2017 Dec 1;313(6):L1069-L1086. doi: 10.1152/ajplung.00353.2017. Epub 2017 Sep 14.

Versican is produced by Trif- and type I interferon-dependent signaling in macrophages and contributes to fine control of innate immunity in lungs.

Author information

1
Comparative Pathology Program, Department of Comparative Medicine, University of Washington School of Medicine, Seattle, Washington.
2
Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington.
3
Department of Immunology, University of Washington School of Medicine, Seattle, Washington.
4
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington; and.
5
Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, California.
6
Comparative Pathology Program, Department of Comparative Medicine, University of Washington School of Medicine, Seattle, Washington; cfrevert@uw.edu.

Abstract

Growing evidence suggests that versican is important in the innate immune response to lung infection. Our goal was to understand the regulation of macrophage-derived versican and the role it plays in innate immunity. We first defined the signaling events that regulate versican expression, using bone marrow-derived macrophages (BMDMs) from mice lacking specific Toll-like receptors (TLRs), TLR adaptor molecules, or the type I interferon receptor (IFNAR1). We show that LPS and polyinosinic-polycytidylic acid [poly(I:C)] trigger a signaling cascade involving TLR3 or TLR4, the Trif adaptor, type I interferons, and IFNAR1, leading to increased expression of versican by macrophages and implicating versican as an interferon-stimulated gene. The signaling events regulating versican are distinct from those for hyaluronan synthase 1 (HAS1) and syndecan-4 in macrophages. HAS1 expression requires TLR2 and MyD88. Syndecan-4 requires TLR2, TLR3, or TLR4 and both MyD88 and Trif. Neither HAS1 nor syndecan-4 is dependent on type I interferons. The importance of macrophage-derived versican in lungs was determined with LysM/Vcan-/- mice. These studies show increased recovery of inflammatory cells in the bronchoalveolar lavage fluid of poly(I:C)-treated LysM/Vcan-/- mice compared with control mice. IFN-β and IL-10, two important anti-inflammatory molecules, are significantly decreased in both poly(I:C)-treated BMDMs from LysM/Vcan-/- mice and bronchoalveolar lavage fluid from poly(I:C)-treated LysM/Vcan-/- mice compared with control mice. In short, type I interferon signaling regulates versican expression, and versican is necessary for type I interferon production. These findings suggest that macrophage-derived versican is an immunomodulatory molecule with anti-inflammatory properties in acute pulmonary inflammation.

KEYWORDS:

hyaluronan synthase 1; inflammation; type I interferons; versican, syndecan-4

PMID:
28912382
PMCID:
PMC5814701
[Available on 2018-12-01]
DOI:
10.1152/ajplung.00353.2017
[Indexed for MEDLINE]

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