VEGFR3-driven pulmonary lymphangiogenesis exacerbates induction of bronchus-associated lymphoid tissue in allergic airway disease

Abstract

Abstract Asthmatic lung samples present with both a higher density of pulmonary lymphatic vessels and a higher incidence of bronchus associated lymphoid tissue (BALT). Here, we asked whether lymphangiogenesis, stimulated by the VEGF-C/VEGFR-3 signaling axis in lymphatic endothelial cells (LECs), plays a role in promoting BALT in mouse models of allergy. First, we determined that chronic intratracheal instillation of house dust mite (HDM), a clinically relevant allergen, recapitulates both lymphangiogenesis and BALT induction. Intratracheal stimulation of VEGFR-3 in LECs exacerbated BALT, while blocking VEGFR-3 signaling reduced BALT. Furthermore, in transgenic mice with an expanded pulmonary lymphatic network (induced prior to allergen challenge), we found an exacerbated BALT response upon chronic HDM inhalation. Recent studies have determined that LEC-derived CXCL13 plays an important role in secondary lymphoid structure organogenesis, and thus we pondered whether LEC-derived CXCL13 could play a role in the development of tertiary lymphoid structures. Indeed, we observed an increase in lung infiltration by CXCR5+ cells when we used VEGF-C to modulate the chronic allergic response. Finally, we found that the VEGF-C exacerbated BALT phenomenon was indeed CXCL13 dependent. Altogether, these results suggest a causative role for pulmonary lymphatics in mediating BALT induction in chronic allergic airway inflammation.