Decreased GPR55 expression links B-cell activation and vascular remodelling in atherosclerosis in patients with early rheumatoid arthritis.

Abstract

Objective: Inflammation and repair responses may be involved in atherosclerosis in rheumatoid arthritis (RA), although mechanisms are unknown. GPR55, a cannabinoid receptor expressed in haematopoietic and stromal tissues, has been implicated in atherosclerosis in mouse models, but evidence in humans is lacking. Our aim was to evaluate GPR55 expression in leucocyte populations in RA and their potential role in atherosclerosis.

Methods: GPR55 expression was quantified by flow cytometry in 63 treatment-naïve patients with RA, 11 individuals with arthralgia and 36 controls. Atherosclerosis was assessed by Doppler ultrasound. Cytokines were measured by immunoassays, and serum proteomics were performed by a high-throughput targeted panel. In vitro cultures were performed with mononuclear cells from healthy donors.

Results: Decreased GPR55 expression in B-cells and monocytes was found in RA, whereas no differences were observed in arthralgia. Public datasets validated these findings. B-cell GPR55 expression was unrelated to clinical features, risk factors and atherosclerosis in RA, but exhibited divergent associations with leucocyte populations. GPR55 expression was associated with proinflammatory cytokines, immunoglobulin and antibody levels, metabolomic markers of inflammation and proteomic signatures related to vascular remodelling and B-cell responses in RA. These associations were dependent on the atherosclerosis status. Lipopolysaccharide exposure in vitro decreased GPR55 expression in B-cells in a dose-dependent manner, which overlapped increasing CB86 expression.

Conclusions: Reduced GPR55 expression hallmarked B-cells and monocyte subsets in early RA. GPR55 expression was linked to B-cell activation-related pathways, presumably via T-cell independent mechanisms and vascular remodelling. GPR55 may be a novel hub between immune circuits and maladaptive responses in atherosclerosis.