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

Methods GPR55 expression was quantified by flow cytometry in 63 untreated RA patients, 11 arthralgia individuals 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 leukocyte populations. GPR55 expression was associated with proinflammatory cytokines, and proteomic signatures related to vascular remodelling and B-cell responses in RA. These associations were dependent on the atherosclerosis status. LPS 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 to understand the crosstalk between immune circuits and maladaptive responses in atherosclerosis.

The authors have declared no competing interest.

This work was supported by 'Accion Estrategica en Salud' under PI (references PI21/00054 and PI24/00819), and PFIS (reference FI22/00148) programmes from 'Instituto de Salud Carlos III (ISCIII)', co-founded by the European Union (FEDER/FSE+ funds).

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The study was approved by the local institutional review board (Comite de Etica de Investigacion con Medicamentos del Principado de Asturias) in compliance with the Declaration of Helsinki (reference CEImPA 2021.126). All study subjects gave written informed consent.

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