Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells.

Angiotensin II (AngII) promotes hypertension, atherogenesis, vascular aneurysm and impairs post-ischemic cardiac remodeling through concerted roles on vascular cells, monocytes and T lymphocytes. However, the role of AngII in B lymphocyte responses is largely unexplored. Here, we show that chronic B cell depletion (Baffr deficiency) significantly reduces atherosclerosis in Apoe ^-/- mice infused with AngII. While adoptive transfer of B cells in Apoe ^-/- /Baffr ^-/- mice reversed atheroprotection in the absence of AngII, infusion of AngII in B cell replenished Apoe ^-/- /Baffr ^-/- mice unexpectedly prevented the progression of atherosclerosis. Atheroprotection observed in these mice was associated with a significant increase in regulatory CD1d^hiCD5⁺ B cells, which produced high levels of interleukin (IL)-10 (B10 cells). Replenishment of Apoe ^-/- /Baffr ^-/- mice with Il10 ^-/- B cells reversed AngII-induced B cell-dependent atheroprotection, thus highlighting a protective role of IL-10⁺ regulatory B cells in this setting. Transfer of AngII type 1A receptor deficient (Agtr1a ^-/-) B cells into Apoe ^-/- /Baffr ^-/- mice substantially reduced the production of IL-10 by B cells and prevented the AngII-dependent atheroprotective B cell phenotype. Consistent with the in vivo data, AngII synergized with BAFF to induce IL-10 production by B cells in vitro via AngII type 1A receptor. Our data demonstrate a previously unknown synergy between AngII and BAFF in inducing IL-10 production by B cells, resulting in atheroprotection.

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