Distinct Roles of Vascular Endothelial Growth Factor Receptor-1– and Receptor-2–Mediated Signaling in T Cell Priming and Th17 Polarization to Lipopolysaccharide-Containing Allergens in the Lung

Abstract

Vascular endothelial growth factor (VEGF) is a key mediator in the development of airway immune dysfunction to inhaled allergens. However, the exact role of its receptors-mediated signaling is controversial. In this study, we evaluated the role of VEGF receptor (VEGFR)-1– and VEGFR-2–mediated signaling in T cell priming and polarization in the context of inhalation of LPS-containing allergens. A murine asthma model of mixed Th1 and Th17 cell responses was generated using intranasal sensitization with LPS-containing allergens. Pharmacologic intervention was performed during sensitization. In vivo production of VEGF and Th1- and Th17-polarizing cytokines (IL-12p70 and IL-6, respectively) were upregulated by airway exposure to LPS. Pharmacological intervention with a VEGFR-2–neutralizing Ab (anti-Flk1 mAb) abolished the production of IL-6 (but not IL-12p70) and the subsequent development of allergen-specific Th17 cell response. On the other hand, blocking VEGFR-1 signaling with a VEGFR-1 antagonist (anti-Flt1 hexapeptide) did not affect the production of IL-12p70 and IL-6. However, blocking VEGFR-1 signaling resulted in T cell tolerance rather than priming, mainly by inhibiting the maturation of lung dendritic cells, and their migration into lung-draining lymph nodes. These results suggest that T cell priming to LPS-containing allergens depends on VEGFR-1–mediated signaling, and the subsequent Th17 polarization depends on VEGFR-2 signaling.

Airway Activation of Formyl Peptide Receptors Inhibits Th1 and Th17 Cell Responses via Inhibition of Mediator Release from Immune and Inflammatory Cells and Maturation of Dendritic Cells

“…With respect to T cell polarization, polarizing cytokines, such as IL-12 and IL-6, released from DCs enhanced by VEGF are essential for the polarization of naive T cells into Th1 and Th17 cells, respectively (24,25). The present study showed that airway activation of FPRs downregulated Th1 and Th17 cell responses in the lung.…”

“…Previous evidence showed that noneosinophilic inflammation induced by sensitization with LPS-containing allergens was caused by both Th1 and Th17 cell responses (6,24,25). To evaluate the effects of airway activation of FPRs on the development of Th1 and Th17 cell responses, W-peptide (200 mg/kg) was administered intranasally during sensitization, and immune responses were evaluated 6 h after the last allergen challenge (Fig.…”

“…In our previous study, we demonstrated that vascular endothelial growth factor (VEGF) produced by LPS plays a key role in priming T cells and that IL-12p70 and IL-6 are essential for Th1 and Th17 polarization, respectively (24,25). To further investigate the molecular mechanisms underlying the effect of W-peptide on T cell polarization, the expression of polarizing mediators was evaluated 24 h after the third sensitization on day 2 (Fig.…”

Mode of dendritic cell activation: The decisive hand in Th2/Th17 cell differentiation. Implications in asthma severity?

“…High dose LPS exposure specifically induces VEGF secretion by the airway epithelium. VEGF induces DC maturation and secretion of Th17 promoting cytokines like IL-6 ( Kim et al 2010). Up to 50% of asthma exacerbations are associated with viral infections (Grünberg et al 1997).…”

What is hypoxia-inducible factor-1 doing in the allergic lung?

“…For example, the expression of several HIF-1 target genes is increased in the airway in asthma including vascular endothelial growth factor (VEGF) (11,12). In addition to promoting vascular remodeling and lymphangiogenesis, VEGF contributes to T-cell activation in response to inhaled allergens through distinct effects on dendritic and T cells (13,14). A nonbiased proteomic analysis revealed that several hypoxia-inducible, HIF-1-regulated proteins are upregulated in the lung in a mouse model of asthma, including several enzymes involved in glycolysis (15).…”