Impaired Function of Dendritic Cells Deficient in Angiotensin II Type 1 Receptors

Abstract

Dendritic cells (DC) are highly specialized antigen-presenting cells with a unique ability to activate resting T lymphocytes and initiate primary immune responses. Angiotensin II (AII) is involved in key events of the inflammatory response. Because our previous work implicated an effect of AII on differentiation and function of murine and human DC, we investigated the impact of AII type 1 receptor (AT1) deficiency on the phenotypical and functional properties of mouse DC in vitro and in vivo. Bone marrow (BM) cells isolated from mice lacking AII subtype 1a receptor (AT1a), AII subtype 1b receptor (AT1b), or both receptor isoforms and control littermates [wild type (WT)] were cultured for 7 days in the presence of recombinant mouse granulocyte/macrophage colony-stimulating factor to generate myeloid DC in vitro. Generation of CD11c+ cells was less efficient in both AT1a- and AT1b-deficient BM cells than in WT BM cell cultures. Moreover, DC generated from AT1-deficient progenitors showed lower levels of expression of major histocompatibility complex II (MHC-II) and CD11c (p < 0.01) and a marked reduction in their allostimulatory activity (p < 0.01 or 0.001). Although AT1-deficient DC released comparable levels of interleukin (IL)-10 and IL-12p70 to WT DC, they produced significantly lower levels of tumor necrosis factor α (TNF-α) (p < 0.05). Remarkably, CD11c+ cells isolated from the spleen of AT1 knockout mice challenged with lipopolysaccharide in vivo up-regulated MHC-II, CD40, and CD80 as did WT, but released significantly lower levels of TNF-α (p < 0.01). These data provide clear evidence that AT1 controls differentiation and functionality of DC and thus may have a crucial impact on inflammatory processes where local angiotensinergic systems are known to be activated.