Immunomodulation of the Innate Host Response by Mesenchymal-Derived Versican during Influenza A Virus Infection.

Authors

Jourdan E Brune, Mary Y Chang, Fengying Tang, Cecilia Lopez-Martinez, Stephen R Reeves, Christina K Chan, Peter Waldron, David F Boyd, Sina A Gharib, Paul G Thomas, William A Altemeier, Charles W Frevert

Published in

American journal of physiology. Lung cellular and molecular physiology. Sep 16, 2026. Epub Sep 16, 2026.

Abstract

Viral and bacterial lung infections place a significant burden on public health. Versican, an extracellular matrix (ECM) chondroitin sulfate proteoglycan, coordinates the innate immune response in multiple experimental models. Versican's potential as an immunomodulatory molecule makes it a promising therapeutic target for controlling the host's immune response to lung infection. However, versican's contribution to lung inflammation, injury, and immune cell activity during influenza A virus (IAV) infection represents a critical knowledge gap. To address our central hypothesis that mesenchymal-derived versican is pro-inflammatory and enhances the innate immune response to IAV infection, we generated a tamoxifen-inducible mouse deficient in mesenchymal-derived versican (B6. Col1a2-Cre^ERT+/-/Vcan^tm1.1Cwf, Col1a2/Vcan^-/-). We report that mesenchymal-derived versican plays a critical role in neutrophil, monocyte, and dendritic cell migration into the lungs and airways early in IAV infection. Intriguingly, mesenchymal-derived versican deficiency had the most substantial negative impact on neutrophil emigration into the lungs. We found that neutrophils were less adhesive to the ECM of Col1a2/Vcan^-/- mouse lung fibroblasts (mLFs), which had a significant decrease in versican compared to wild-type mLFs. Additionally, Col1a2/Vcan^-/- mLFs treated with poly(I:C) in vitro have reduced cell-associated hyaluronan. These findings suggest that fibroblast-derived versican is necessary for adhesion to lung fibroblasts by neutrophils as they transit into the lung interstitium and airways from the pulmonary vasculature. Our findings demonstrate that mesenchymal-derived versican is a key regulator of the early host immune responses to IAV.

PMID:
42747347
Bibliographic data and abstract were imported from PubMed on 16 Sep 2026.

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