HMGB1 drives T-cell activation in hypertensive males and females

We previously published that hypertensive males have greater renal necrosis and a more pro-inflammatory immune profile than females. Hypertension causes the release of damage-associated molecular patterns (DAMPs), which stimulate inflammation. The goal of the current study was to determine if high-mobility group box 1 (HMGB1), a well-characterized DAMP, contributes to greater T-cell activation in hypertensive males versus females and normotensive controls of both sexes. To test this hypothesis, initial studies measured renal and plasma HMGB1 levels in 13-wk-old male and female spontaneously hypertensive rats (SHRs) and Wistar Kyoto (WKY) rats by Western blot and ELISA. Total renal CD3⁺ T-cells and IL-6⁺ cells were measured by flow cytometry. The contribution of HMGB1 to T-cell activation was measured in isolated renal T-cells via mixed lymphocyte reaction (MLR) in the presence of control IgG or anti-HMGB1 neutralizing antibody. Plasma HMGB1 levels were greater in male SHRs compared with those in female SHR and WKY rats of both sexes. Renal HMGB1 levels were higher in SHR than in WKY and tended to be greater in males versus females in both strains. Consistent with this finding, T-cell activation and renal interleukin (IL)-6 were highest in male SHR. Interestingly, anti-HMGB1 antibody treatment decreased T-cell activation to the same extent in male and female SHRs, with negligible effects on WKY. These results indicate a role for HMGB1 in T-cell activation in SHR. However, despite male SHR having greater levels of HMGB1 than females, HMGB1 does not account for sex differences in T-cell activation.<b>NEW & NOTEWORTHY</b> There is growing evidence that T-cells contribute to both the development of hypertension and sex differences in blood pressure control. Our work establishes the damage-associated molecular pattern HMGB1 as an important contributor to T-cell activation in hypertension.