GPR55 in B cells limits atherosclerosis development and regulates plasma cell maturation

Guillamat-Prats, R.; Hering, D.; Rami, M.; Haerdtner, C.; Sanovito, D.; Rinne, P.; Bindila, L.; Hristov, M.; Pagano, S.; Vuilleumier, N.; Schmid, S.; Janjic, A.; Enard, W.; Weber, C.; Maegdefessel, L.; Faussner, A.; Hilgendorf, I.; Steffens, S.

doi:10.1101/2021.12.20.473518

bioRxiv · 10.1101/2021.12.20.473518

GPR55 in B cells limits atherosclerosis development and regulates plasma cell maturation

Guillamat-Prats, R.·Hering, D.·Rami, M.·Haerdtner, C.·Sanovito, D.·Rinne, P.·Bindila, L.·Hristov, M.·Pagano, S.·Vuilleumier, N.·Schmid, S.·Janjic, A.·Enard, W.·Weber, C.·Maegdefessel, L.·Faussner, A.·Hilgendorf, I.·Steffens, S.

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Abstract

Identifying novel pathways regulating the adaptive immune response in chronic inflammatory diseases such as atherosclerosis is of particular interest in view of developing new therapeutic drugs. Here we report that the lipid receptor GPR55 is highly expressed by splenic B cells and inversely correlates with atheroma plaque size in mice. In human carotid endarterectomy specimen, GPR55 transcript levels were significantly lower in unstable compared to stable carotid plaques. To study the impact of GPR55 deficiency in atherosclerosis, we crossed Gpr55 knockout mice with apolipoprotein E (ApoE) knockout mice and subjected the mice to Western diet for 4 to 16 weeks. Compared to ApoE-/- controls, ApoE-/-Gpr55-/- mice developed larger plaques with increased necrotic core size, associated with elevated circulating and aortic leukocyte counts. Flow cytometry, immunofluorescence and RNA-sequencing analysis of splenic B cells in these mice revealed a hyperactivated B cell phenotype with disturbed plasma cell maturation and immunoglobulin (Ig)G antibody overproduction. The specific contribution of B cell GPR55 in atherosclerosis was further studied in mixed Gpr55-/-/{micro}MT bone marrow chimeras on low density receptor deficiency (Ldlr-/-) background, revealing that B-cell specific depletion of Gpr55 was sufficient to promote plaque development. Conversely, adoptive transfer of wildtype B cells into ApoE-/-Gpr55-/- mice blunted the proatherogenic phenotype. In vitro stimulation of splenocytes with the endogenous GPR55 ligand LPI promoted plasma cell proliferation and enhanced B cell activation marker expression, which was inhibited by the GPR55 antagonist CID16020046. Collectively, these discoveries provide new evidence for GPR55 as key modulator of the adaptive immune response in atherosclerosis. Targeting GPR55 could be useful to limit inflammation and plaque progression in patients suffering from atherosclerosis.

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Guillamat-Prats, R., Hering, D., Rami, M., Haerdtner, C., Sanovito, D., Rinne, P., Bindila, L., Hristov, M., Pagano, S., Vuilleumier, N., Schmid, S., Janjic, A., Enard, W., Weber, C., Maegdefessel, L., Faussner, A., Hilgendorf, I., Steffens, S.. 2021-12-21. GPR55 in B cells limits atherosclerosis development and regulates plasma cell maturation. https://doi.org/10.1101/2021.12.20.473518

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