Abstract 019: A20 in Dendritic Cells Protects Against Hypertension by Inhibiting Dendritic Cell-Mediated T Cell Activation

The ubiquitin-editor protein A20 in dendritic cells (DCs) suppresses NF-κB signaling and inhibits their capacity to activate T cells by limiting DC expression of co-stimulatory molecules. We previously reported that mice with spontaneous DC activation due to heterozygous deletion of A20 in DCs (CD11c-cre+ A20 flox/wt = DC ACT) have an exaggerated hypertensive response to low dose (300 ng/kg/min) chronic angiotensin (Ang) II infusion (143±2 vs. 131±4 mmHg; p=0.04) and augmented proportions of effector T cells in the kidney lymph node. Here, we explored the mechanism through which A20 in DCs limits blood pressure elevation. After 7 days of chronic Ang II infusion, flow cytometric analysis of kidney homogenates from wild-type (WT = CD11c-cre - A20 flox/wt ) and DC ACT mice revealed similar numbers of renal DCs in the 2 groups (2832±342 vs. 2531±435; p=NS). By contrast, numbers of CD11b + Ly6C hi inflammatory monocytes (9849±1108 vs. 6019±597; p=0.01) and CD8 + T cells (1757±101 vs. 908±155; p<0.03) were increased in the DC ACT kidneys compared to WT controls. Accordingly, the DC ACT kidneys showed upregulated mRNA expression for the pro-hypertensive cytokines TNF-α (1.6±0.2 vs. 1±0.2; p<0.02) and IL-17A (2.3±0.6 vs. 1±0.3; p=0.09) and the mononuclear cell chemokine CCL5 (1.9±0.27 vs. 1±0.11; p=0.01). Both monocytes and T cells have been implicated in the pathogenesis of hypertension. Therefore, to directly test whether enhanced T cell activation in the DC ACT cohort was responsible for their augmented hypertensive response, we chronically infused Ang II into lymphocyte-deficient DC ACT Rag1 -/- mice and WT (CD11c-cre- A20 flox/wt ) Rag1 -/- controls for 4 wks. In WT Rag1 -/- and DC ACT Rag1 -/- mice, radiotelemetry blood pressures (128±1 vs. 128±2 mmHg; p=NS) and heart to body weight ratios (6.0±0.1 vs. 6.4±0.2 mg/g body wt) were similar during Ang II, suggesting that T cells are required to mediate the augmented hypertensive response accruing from DC activation due to A20 deficiency. Thus, following stimulation of the renin angiotensin system, A20 suppresses DC activation and thereby mitigates T cell-dependent blood pressure elevation. These studies identify a novel target through which to limit the engagement of adaptive immunity during chronic hypertension.