Journal Article

Pro-lymphangiogenic VEGFR-3 signaling modulates memory T cell responses in allergic airway inflammation

Sperling, Anne I., Swartz, Melody A., Hrusch, Cara L., Medellin, Jorge E.G., Alitalo, Kari, Maisel, Katharina, Camacho, Daniel F., Chapel, David B., Potin, Lambert, Nurmi, Harri, Gleyzer, Rachel

2021

Overview

In allergic airway inflammation, VEGFR-3-mediated lymphangiogenesis occurs in humans and mouse models, yet its immunological roles, particularly in adaptive immunity, are poorly understood. Here, we explored how pro-lymphangiogenic signaling affects the allergic response to house dust mite (HDM). In the acute inflammatory phase, the lungs of mice treated with blocking antibodies against VEGFR-3 (mF4-31C1) displayed less inflammation overall, with dramatically reduced innate and T-cell numbers and reduced inflammatory chemokine levels. However, when inflammation was allowed to resolve and memory recall was induced 2 months later, mice treated with mF4-31C1 as well as VEGF-C/-D knockout models showed exacerbated type 2 memory response to HDM, with increased Th2 cells, eosinophils, type 2 chemokines, and pathological inflammation scores. This was associated with lower CCL21 and decreased TRegs in the lymph nodes. Together, our data imply that VEGFR-3 activation in allergic airways helps to both initiate the acute inflammatory response and regulate the adaptive (memory) response, possibly in part by shifting the TReg/Th2 balance. This introduces new immunomodulatory roles for pro-lymphangiogenic VEGFR-3 signaling in allergic airway inflammation and suggests that airway lymphatics may be a novel target for treating allergic responses.

• Publisher: Elsevier Inc,Nature Publishing Group US,Elsevier Limited
• Subject: Adaptive immunity / Allergens / Allergology / Animal models / Animals / Antibodies / Biomarkers / Biomedical and Life Sciences / Biomedicine / Blocking antibodies / CCL21 protein / Chemokines / Disease Susceptibility / Gastroenterology / Helper cells / Hypersensitivity / Immunologic Memory / Immunological memory / Immunology / Immunomodulation / Immunophenotyping / Inflammation / Leukocytes (eosinophilic) / Lymph nodes / Lymphangiogenesis - genetics / Lymphocytes T / Memory cells / Mice / Pyroglyphidae - immunology / Respiratory Hypersensitivity - etiology / Respiratory Hypersensitivity - metabolism / Respiratory Hypersensitivity - pathology / Respiratory tract / Respiratory tract diseases / Signal Transduction / T-Lymphocyte Subsets - immunology / T-Lymphocyte Subsets - metabolism / Vascular endothelial growth factor / Vascular Endothelial Growth Factor C - genetics / Vascular Endothelial Growth Factor C - metabolism / Vascular Endothelial Growth Factor Receptor-3 - genetics / Vascular Endothelial Growth Factor Receptor-3 - metabolism / Vascular endothelial growth factor receptors