Our published work and preliminary data using mouse models and in vitro cell cultures show that extracellular matrix (ECM) molecules such as versican accumulate in lungs following exposure to viruses and bacteria. The creation of a specialized versican-enriched ECM coincides with invasion and retention of leukocytes in lungs during the immune response to influenza virus. We have found that two cellular sources synthesize versican in response to Toll-like receptor (TLR) agonists: macrophages and fibroblasts. Studies identify two distinct signaling pathways directing versican synthesis in these two cell types - the ?-catenin/T-cell factor (TCF) pathway in stromal cells such as smooth muscle cells and fibroblasts and the TLR/Trif/Type I interferon (IFN) receptor pathway in macrophages. However, the cellular specificity of these signaling pathways is not known. Using two novel strains of genetically engineered mice in which the versican gene is deleted in a cell- and time-specific manner, our published and preliminary data shows that versican has a dramatic effect on leukocyte phenotype. When treated with polyinosinic:polycytidylic acid (poly(I:C)), mice with a global deficiency in versican have decreased recovery of leukocytes in bronchoalveolar (BAL) fluid suggesting that versican is pro-inflammatory and required for leukocyte migration into lungs. In contrast, mice lacking versican in macrophages have increased recovery of leukocytes in BAL fluid suggesting that macrophage-derived versican is anti- inflammatory and suppresses leukocyte migration into lungs. Both strains of versican-deficient mice had significantly decreased recovery of Type I IFNs and IL-10 in lung tissue or BAL fluid when compared to controls. Our in vitro studies attribute this to decreased production of these anti-inflammatory cytokines by versican-deficient macrophages. The differences observed in these novel versican-deficient mice are the basis of our central hypothesis that the formation of a versican-enriched ECM by macrophages and stromal cells provides critical contextual cues and extracellular-control of the innate immune response to viral lung infection. We propose three aims to test this hypothesis.
Aim 1 defines the role of versican derived from macrophages and/or Type I IFN signaling in providing extracellular-control of the innate immune response in lungs of mice exposed to influenza virus.
Aim 2 determines if stromal cells and/or ?- catenin/TCF signaling promote the generation of a versican-enriched ECM that provides fine-control of the innate immune response to influenza virus.
Aim 3 identifies the mechanisms and signaling pathways whereby macrophage- versus fibroblast-derived versican provide contextual extracellular-control of the innate immune response. Understanding the contextual settings in which versican provides fine-control of the innate immune response to influenza virus is critical for the design of therapeutic strategies for improving the immune response to viral lung infection.
This proposal addresses the context-dependent manner by which versican, a component of the extracellular matrix, modulates the innate immune response to influenza virus. Studies to date indicate that versican can have either pro- or anti-inflammatory roles depending on its cellular source or the signaling pathway by which it is produced. Better understanding of these dual roles of versican will enable development of unique targeting strategies for improving the immune response to viral lung infection.
|Hull, Rebecca L; Gibson, Ronald L; McNamara, Sharon et al. (2018) Islet Interleukin-1? Immunoreactivity Is an Early Feature of Cystic Fibrosis That May Contribute to ?-Cell Failure. Diabetes Care 41:823-830|
|Kang, Inkyung; Chang, Mary Y; Wight, Thomas N et al. (2018) Proteoglycans as Immunomodulators of the Innate Immune Response to Lung Infection. J Histochem Cytochem 66:241-259|
|Frevert, Charles W; Felgenhauer, Jessica; Wygrecka, Malgorzata et al. (2018) Danger-Associated Molecular Patterns Derived From the Extracellular Matrix Provide Temporal Control of Innate Immunity. J Histochem Cytochem 66:213-227|
|Manuel, Sharrón L; Johnson, Brian W; Frevert, Charles W et al. (2018) Revisiting the scientific method to improve rigor and reproducibility of immunohistochemistry in reproductive science. Biol Reprod 99:673-677|
|Chang, Mary Y; Kang, Inkyung; Gale Jr, Michael et al. (2017) Versican is produced by Trif- and type I interferon-dependent signaling in macrophages and contributes to fine control of innate immunity in lungs. Am J Physiol Lung Cell Mol Physiol 313:L1069-L1086|
|Nolin, James D; Lai, Ying; Ogden, Herbert Luke et al. (2017) Secreted PLA2 group X orchestrates innate and adaptive immune responses to inhaled allergen. JCI Insight 2:|