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.