Abstract
Viral infection is an exacerbating factor contributing to chronic airway diseases, such as asthma, via mechanisms that are still unclear. Polyinosine-polycytidylic acid (poly(I:C)), a Toll-like receptor 3 (TLR3) agonist used as a mimetic to study viral infection, has been shown to elicit inflammatory responses in lungs and to exacerbate pulmonary allergic reactions in animal models. Previously, we have shown that poly(I:C) stimulates lung fibroblasts to accumulate an extracellular matrix (ECM), enriched in hyaluronan (HA) and its binding partner versican, which promotes monocyte adhesion. In the current study, we aimed to determine the in vivo role of versican in mediating inflammatory responses in poly(I:C)-induced lung inflammation using a tamoxifen-inducible versican-deficient mouse model (Vcan-/- mice). In C57Bl/6 mice, poly(I:C) instillation significantly increased accumulation of versican and HA, especially in the perivascular and peribronchial regions, which were enriched in infiltrating leukocytes. In contrast, versican-deficient (Vcan-/-) lungs did not exhibit increases in versican or HA in these regions and had strikingly reduced numbers of leukocytes in the bronchoalveolar lavage fluid and lower expression of inflammatory chemokines and cytokines. Poly(I:C) stimulation of lung fibroblasts isolated from control mice generated HA-enriched cable structures in the ECM, providing a substrate for monocytic cells in vitro, whereas lung fibroblasts from Vcan-/- mice did not. Moreover, increases in proinflammatory cytokine expression were also greatly attenuated in the Vcan-/- lung fibroblasts. These findings provide strong evidence that versican is a critical inflammatory mediator during poly(I:C)-induced acute lung injury and, in association with HA, generates an ECM that promotes leukocyte infiltration and adhesion.
Highlights
Cytokine expression were greatly attenuated in the Vcan؊/؊ lung fibroblasts
These in vivo observations support our previously published in vitro findings that poly(I:C) treatment of lung fibroblasts promotes the formation of an HA- and versican-rich extracellular matrix (ECM), which enhances monocyte binding (30 –32)
Poly(I:C)-induced HA Cable Formation and HA-dependent Monocyte Adhesion was Significantly Reduced in Cultures of Lung Fibroblasts from VcanϪ/Ϫ Mice—Because we observed a relationship between HA, versican, and leukocyte accumulation in poly(I:C)-treated mouse lungs, we examined the formation of HA cables induced by poly(I:C) stimulation of lung fibroblasts in vitro, which promote leukocyte adhesion, as we have previously shown (30 –32, 34)
Summary
Cytokine expression were greatly attenuated in the Vcan؊/؊ lung fibroblasts These findings provide strong evidence that versican is a critical inflammatory mediator during poly(I:C)induced acute lung injury and, in association with HA, generates an ECM that promotes leukocyte infiltration and adhesion. Extracellular matrix (ECM) around blood vessels and airways remodels to allow for infiltration of leukocytes. A number of studies by our group have demonstrated that lung fibroblasts synthesize and deposit HA- and versican-enriched ECM in response to poly(I:C). We examine the formation of HA- and versican-enriched ECM in lungs of conditionally versican-deficient mice, developed recently in our laboratory, in response to poly(I:C) as a surrogate for viral infection. We report that global deficiency of versican perturbs both the accumulation of HA and the accumulation and infiltration of leukocytes, demonstrating that versican is a critical ECM component mediating HA-dependent leukocyte accumulation in the lungs and a potential therapeutic target
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