Orphan Receptor GPR55: A New Therapeutic Target for Atherosclerosis? Blog post by Nina Culum, MSc Cardiovascular disease is the leading cause of death worldwide, representing 32% of all global deaths in 2019 [1]. One of the major contributors to this epidemic is atherosclerosis, the chronic inflammation of the arterial wall [2, 3]. Increasing evidence supports the role of T cells as drivers and modifiers of the pathogenesis of atherosclerosis [2], while clinical studies have shown that therapies that target inflammatory pathways hold potential in preventing and treating this condition [3]. Advances in analytical methodologies have led to a deeper understanding of the cellular heterogeneity of atherosclerotic lesions, which now supports the relevance of B cells in their pathophysiology [4]. Depending on their subset and activation state, B cells can exert both pro- and anti-atherogenic effects, which are mediated by their three main functions (i.e., antibody production, cytokine release, and antigen presentation) (Figure 1) [5]. Recently, antagonism of GPR55, a G protein-coupled orphan receptor that is highly expressed in splenic plasma cells and (to a lesser extent) marginal zone B cells, has been reported to have atheroprotective effects in human aortic endothelial cells [6] and has been found to increase neutrophil activation in a murine atherogenesis model [7]. https://insidescientific.com/wp-content/uploads/2022/11/B-cell-functions-in-atherosclerosis.jpg

Figure 1: Illustration of B cell functions in atherosclerosis. 2021 Ma et al. , licensed under CC BY 4.0 .

Since the role of GPR55 in adaptive B cell response regulation has not yet been reported in the context of atherosclerosis, Guillamat-Prats et al. have investigated how GPR55 in B cells affects atherosclerosis development [4]. In this blog post, we highlight the main findings from this study, which was published this month in Nature Cardiovascular Research.

GPR55 expression and functionality in murine and human B cells

In the first experiments described, the authors investigated the regulation and function of GPR55 signaling in atherosclerosis by feeding apolipoprotein E-deficient ( Apoe-/- ) mice Western diet (WD) for 4 or 16 weeks, and compared the effects to a global Gpr55 knockout ( Apoe-/-Gpr55-/- ) mouse model. At 4 weeks, Apoe-/-Gpr55-/- mice exhibited larger aortic plaques than Apoe-/- controls, suggesting that GPR55 signaling may counterbalance plaque development at the early disease stage. Although the difference in aortic lesion area was no longer observed at 16 weeks, the plaque burden was still found to be higher in the descending aorta of Apoe-/-Gpr55-/- mice. The authors note that these effects of Gpr55 deficiency on advanced plaque phenotype could be relevant to the complications that are observed in human atherosclerosis. The authors also determined that Gpr55 expression was highest in B cells, followed by T cells, neutrophils, and monocytes. Additionally, the highest expression of Gpr55 was found in plasma cells, which was localized to the follicular and germinal center areas. To assess the functional GPR55 signaling response in B cells, the authors measured intracellular calcium levels in response to stimulation with the endogenous GPR55 ligand lysophosphatidylinositol (LPI). With a normal diet, increased intracellular calcium was only observed after LPI stimulation in Apoe-/- cells expressing Gpr55 . Moreover, a dose-dependent calcium response to LPI was found in human peripheral blood B cells, indicating a functional LPI-GPR55 signaling pathway. [fusion_builder_column_inner type="1_3" layout="1_3" align_self="auto" content_layout="column" align_content="flex-start" valign_content="flex-start" content_wrap="wrap" spacing="" center_content="no" column_tag="div" link="" target="_self" link_description="" min_height="" hide_on_mobile="small-visibility,medium-visibility,large-visibility" sticky_display="normal,sticky" class="" id="" background_image_id="" type_medium="" type_small="" order_medium="0" order_small="0" spacing_left_medium="" spacing_right_medium="" spacing_left_small="" spacing_right_small="" spacing_left="" spacing_right="" margin_top_medium="" margin_bottom_medium="" margin_top_small="" margin_bottom_small="" margin_top="" margin_bottom="" padding_top_medium="" padding_right_medium="" padding_bottom_medium="" padding_left_medium="" padding_top_small="" padding_right_small="" padding_bottom_small="" padding_left_small="" padding_top="" padding_right="" padding_bottom="" padding_left="" hover_type="none" border_sizes_top="" border_sizes_right="" border_sizes_bottom="" border_sizes_left="" border_color=""