Glycobiology and Extracellular Matrices
Versican Deficiency Significantly Reduces Lung Inflammatory Response Induced by Polyinosine-Polycytidylic Acid Stimulation*
Role of Versican in Lung Inflammation

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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.

double-stranded RNA (dsRNA)
extracellular matrix
hyaluronan
leukocyte
versican (VCAN)
Lung inflammation
Poly(I:C)

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*

This work was supported, in whole or in part, by National Institutes of Health Grants P01 HL098067 (to S. F. Z., C. W. F., and T. N. W.), R01 AI068731 and U19 AI125378 (to S. F. Z.), and R21 RR030249 (to C. W. F) and the University of Auckland Faculty Development Fund (to M. J. M.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

This article contains supplemental Figs. 1–4 and Table 1.

1

Both authors contributed equally to this work.

2

Supported by the Ann Ramsay-Jenkins and William M. Jenkins Fellowship for Matrix Biology.

3

Present address: Dept. of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195.

4

Present address: Dept. of Medicine, Stanford University, Stanford, CA 94305.