Upregulation of FcγRIIB by resveratrol via NF-κB activation reduces B-cell numbers and ameliorates lupus

Abstract

Resveratrol, an anti-inflammatory agent, can inhibit pro-inflammatory mediators by activating Sirt1, which is a class III histone deacetylase. However, whether resveratrol can regulate inhibitory or anti-inflammatory molecules has been less studied. FcγRIIB, a receptor for IgG, is an essential inhibitory receptor of B cells for blocking B-cell receptor-mediated activation and for directly inducing apoptosis of B cells. Because mice deficient in either Sirt1 or FcγRIIB develop lupus-like diseases, we investigated whether resveratrol can alleviate lupus through FcγRIIB. We found that resveratrol enhanced the expression of FcγRIIB in B cells, resulting in a marked depletion of plasma cells in the spleen and notably in the bone marrow, thereby decreasing serum autoantibody titers in MRL/lpr mice. The upregulation of FcγRIIB by resveratrol involved an increase of Sirt1 protein and deacetylation of p65 NF-κB (K310). Moreover, increased binding of phosphor-p65 NF-κB (S536) but decreased association of acetylated p65 NF-κB (K310) and phosphor-p65 NF-κB (S468) to the −480 promoter region of Fcgr2b gene was responsible for the resveratrol-mediated enhancement of FcγRIIB gene transcription. Consequently, B cells, especially plasma cells, were considerably reduced in MRL/lpr mice, leading to improvement of nephritis and prolonged survival. Taken together, we provide evidence that pharmacological upregulation of FcγRIIB expression in B cells via resveratrol can selectively reduce B cells, decrease serum autoantibodies and ameliorate lupus nephritis. Our findings lead us to propose FcγRIIB as a new target for therapeutic exploitation, particularly for lupus patients whose FcγRIIB expression levels in B cells are downregulated. Compounds that selectively inactivate key immune cells could safely reduce inflammatory damage in lupus. This disease is associated with a hyperactive immune system, which targets patients' own tissues, producing symptoms that include painful joint inflammation and kidney damage. National Taiwan University researcher Shiang-Jong Tzeng and colleagues have found that resveratrol, an anti-inflammatory molecule produced by various fruits, can limit this autoimmune activity. They showed that resveratrol reduces immune activation and tissue damage in a mouse model of lupus, extending survival. Resveratrol stimulates production of a protein called FcγRIIB, which acts as a safeguard against excess immune activity. This FcγRIIB activation greatly reduced production of B cells, which secrete damaging antibodies in lupus, without affecting other immune cells. Compounds that initiate such targeted immune suppression could offer a safe means of controlling lupus.