Olfactory receptor 2 drives abdominal aortic aneurysm by promoting CX3CR1-mediated monocyte recruitment

Schelemei, P.; Picard, f.; Park, Y.; Wollnitzke, P.; Nemade, H.; Mehrkens, D.; Arkenberg, P.; Rappenecker, A.; Wrobel, J.; Martinez Lagunas, K.; Wagner, E.; Guthoff, H.; Roy, J.; Lindquist Liljeqvist, M.; Ibing, W.; Wagenhäuser, M. U.; Schelzig, H.; Levkau, B.; Flögel, U.; Gerdes, N.; Karimpour, M.; Hillmer, A.; Sengle, G.; Megens, R. T.; Weber, C.; Orecchioni, M.; Baldus, S.; Mollenhauer, M.; Winkels, H.

doi:10.1101/2025.02.28.640923

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bioRxiv · 10.1101/2025.02.28.640923

Olfactory receptor 2 drives abdominal aortic aneurysm by promoting CX3CR1-mediated monocyte recruitment

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Abstract

BackgroundAbdominal aortic aneurysms (AAA) are characterized by an intricate interplay of extracellular matrix degradation and inflammation. Macrophages are centrally involved in these processes. The mechanisms underlying macrophage activation in AAA remain incompletely understood. Vascular macrophages have been shown to express olfactory receptor 2 (Olfr2), a G-protein coupled receptor involved in mediating the sense of smelling and regulating inflammatory activity in macrophages. Whether Olfr2 plays a role in modulating macrophage responses in AAA formation remains unknown. Methods & ResultsIn silico micro-array analysis showed increased expression of the human Olfr2 orthologue OR6A2 in AAA tissue compared to healthy aorta. Flow cytometric analysis revealed increased expression of OR6A2 on classical, non-classical, and intermediate monocytes of patients with a large AAA (> 5cm) in comparison to patients with smaller AAA (< 5cm). Up to 30% of vascular macrophages expressed OR6A2 in human AAA and Olfr2 in mouse AAA tissue. Olfr2 expression peaked on major histocompatibility complex II-high (MHCIIhigh) and C-C chemokine receptor type 2-low (CCR2low) aortic monocytes and macrophages on day 7 following experimental AAA initiation and decreased to baseline expression on day 28. Olfr2 gene (Olfr2-/-) deficiency protected mice from AAA formation, which was accompanied by lowered ECM degradation, reduced macrophage infiltration and increased smooth muscle cell content. Conversely, treatment with the Olfr2 agonist octanal exacerbated AAA formation and inflammation, while the antagonist citral reduced AAA formation in comparison to vehicle treated mice. Bulk transcriptome analysis of aortic tissue revealed reduced inflammatory gene expression in Olfr2-/- mice at day 7 following AAA initiation. Spectral flow cytometry resolved 20 aortic immune cell populations, which were largely reduced in quantity by Olfr2-deficiency at day 7 and day 28 post experimental AAA formation, while circulating leukocyte counts and monocyte subset distribution were not altered between Olfr2+/+ and Olfr2-/- mice. Circulating Ly6Chigh-monocytes exhibited reduced expression of the CX3C motif chemokine receptor 1 (CX3CR1) and CCR2 during AAA formation. Transcriptional analysis of monocytes confirmed downregulation of pathways associated with cell adhesion, motility and migration. In vitro, Olfr2-/- monocytes showed impaired migration towards the CX3CR1 ligand CX3CL1. Competitive transfer of Olfr2+/+ and Olfr2-/- monocytes confirmed reduced migratory capacity of Olfr2-/- monocytes into the developing AAA. ConclusionWe demonstrate a critical relevance for Olfr2 in the modulation of the inflammatory response underlying AAA, which is mediated by enhanced monocyte recruitment.

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Schelemei, P., Picard, f., Park, Y., Wollnitzke, P., Nemade, H., Mehrkens, D., Arkenberg, P., Rappenecker, A., Wrobel, J., Martinez Lagunas, K., Wagner, E., Guthoff, H., Roy, J., Lindquist Liljeqvist, M., Ibing, W., Wagenhäuser, M. U., Schelzig, H., Levkau, B., Flögel, U., Gerdes, N., Karimpour, M., Hillmer, A., Sengle, G., Megens, R. T., Weber, C., Orecchioni, M., Baldus, S., Mollenhauer, M., Winkels, H.. 2025-03-11. Olfactory receptor 2 drives abdominal aortic aneurysm by promoting CX3CR1-mediated monocyte recruitment. https://doi.org/10.1101/2025.02.28.640923

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