Olfr2 Promotes Recruitment of Monocytes via CX3CR1 in Abdominal Aortic Aneurysm

Patrik Schelemei^{1

2

3}, Felix S R Picard^{1

2

3}, Yein Park^{1

2

3}, Philipp Wollnitzke⁴, Harshal Nemade^{1

2

3}, Sebastian K Lechner^{1

2

3}, Dennis Mehrkens^{1

2

3}, Per Arkenberg^{1

2

3}, Anna C Köbele^{1

2

3}, Jan Wrobel^{1

2

3}, Kristel Martinez Lagunas^{1

2

3}, Elena Wagner^{1

2

3}, Henning Guthoff^{1

2

3}, Alexander Hof^{1

2

3}, Khalia Cummings⁵, Muntadher Al Zaidi⁶, Sebastian Zimmer⁶, Joy Roy^{7

8}, Moritz Lindquist Liljeqvist^{7

8}, Dennis Wolf^{9

10}, Thomas Riffelmacher^{1

2

3}, Wiebke Ibing^{11

12}, Markus U Wagenhäuser^{11

12}, Hubert Schelzig^{11

12}, Bodo Levkau^{4

13}, Ulrich Flögel¹⁴, Norbert Gerdes^{15

13}, Mohammad Karimpour^{2

16}, Axel M Hillmer^{2

16}, Gerhard Sengle^{2

17

18

19}, Remco T A Megens^{20

21}, Christian Weber²⁰, Marco Orecchioni⁵, Stephan Baldus^{1

2

3}, Martin Mollenhauer^{1

2

3}, Holger Winkels^{1

2

3}

Affiliations

¹ Department of Cardiology, Heart Center (P.S., F.S.R.P., Y.P., H.N., S.K.L., D.M., P.A., A.C.K., J.W., K.M.L., E.W., H.G., A.H., T.R., S.B., M.M., H.W.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
² Center for Molecular Medicine Cologne (P.S., F.S.R.P., Y.P., H.N., S.K.L., D.M., P.A., A.C.K., J.W., K.M.L., E.W., H.G., A.H., T.R., M.K., A.M.H., G.S., S.B., M.M., H.W.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³ Center for Cardiovascular Medicine Aachen-Bonn-Cologne-Düsseldorf, Germany (P.S., F.S.R.P., Y.P., H.N., S.K.L., D.M., P.A., A.C.K., J.W., K.M.L., E.W., H.G., A.H., T.R., S.B., M.M., H.W.).
⁴ Institute of Molecular Medicine III, (P.W., B.L.), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
⁵ Immunology Center of Georgia, Augusta University, Augusta, GA (K.C., M.O.).
⁶ Department of Internal Medicine II-Cardiology, University Hospital Bonn, Bonn, Germany (M.A.Z., S.Z.).
⁷ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden (J.R., M.L.L.).
⁸ Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden (J.R., M.L.L.).
⁹ Cardiology and Angiology, Medical Center (D.W.), University of Freiburg, Freiburg, Germany.
¹⁰ Faculty of Medicine (D.W.), University of Freiburg, Freiburg, Germany.
¹¹ Department of Vascular and Endovascular Surgery (W.I., M.U.W. H.S.), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹² Department of Vascular and Endovascular Surgery, Medical Faculty and University Hospital Düsseldorf, Germany (W.I., M.U.W., H.S.).
¹³ Cardiovascular Research Institute Düsseldorf (N.G., B.L.), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹⁴ Experimental Cardiovascular Imaging, Institute for Molecular Cardiology (U.F.), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹⁵ Department of Cardiology, Pulmonology and Vascular Medicine (N.G.), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹⁶ Institute of Pathology, (M.K., A.M.H.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁷ Center for Biochemistry (G.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁸ Department of Pediatrics and Adolescent Medicine (G.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁹ Cologne Center for Musculoskeletal Biomechanics (G.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
²⁰ Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Munich, Germany (R.T.A.M., C.W.).
²¹ Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (R.T.A.M.).

PMID: 41473953
DOI: 10.1161/CIRCRESAHA.125.326591

Olfr2 Promotes Recruitment of Monocytes via CX3CR1 in Abdominal Aortic Aneurysm

Patrik Schelemei et al. Circ Res. 2026.

. 2026 Jan 30;138(3):e326591.

doi: 10.1161/CIRCRESAHA.125.326591. Epub 2025 Dec 31.

Authors

Affiliations

¹ Department of Cardiology, Heart Center (P.S., F.S.R.P., Y.P., H.N., S.K.L., D.M., P.A., A.C.K., J.W., K.M.L., E.W., H.G., A.H., T.R., S.B., M.M., H.W.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
² Center for Molecular Medicine Cologne (P.S., F.S.R.P., Y.P., H.N., S.K.L., D.M., P.A., A.C.K., J.W., K.M.L., E.W., H.G., A.H., T.R., M.K., A.M.H., G.S., S.B., M.M., H.W.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³ Center for Cardiovascular Medicine Aachen-Bonn-Cologne-Düsseldorf, Germany (P.S., F.S.R.P., Y.P., H.N., S.K.L., D.M., P.A., A.C.K., J.W., K.M.L., E.W., H.G., A.H., T.R., S.B., M.M., H.W.).
⁴ Institute of Molecular Medicine III, (P.W., B.L.), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
⁵ Immunology Center of Georgia, Augusta University, Augusta, GA (K.C., M.O.).
⁶ Department of Internal Medicine II-Cardiology, University Hospital Bonn, Bonn, Germany (M.A.Z., S.Z.).
⁷ Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden (J.R., M.L.L.).
⁸ Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden (J.R., M.L.L.).
⁹ Cardiology and Angiology, Medical Center (D.W.), University of Freiburg, Freiburg, Germany.
¹⁰ Faculty of Medicine (D.W.), University of Freiburg, Freiburg, Germany.
¹¹ Department of Vascular and Endovascular Surgery (W.I., M.U.W. H.S.), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹² Department of Vascular and Endovascular Surgery, Medical Faculty and University Hospital Düsseldorf, Germany (W.I., M.U.W., H.S.).
¹³ Cardiovascular Research Institute Düsseldorf (N.G., B.L.), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹⁴ Experimental Cardiovascular Imaging, Institute for Molecular Cardiology (U.F.), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹⁵ Department of Cardiology, Pulmonology and Vascular Medicine (N.G.), Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
¹⁶ Institute of Pathology, (M.K., A.M.H.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁷ Center for Biochemistry (G.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁸ Department of Pediatrics and Adolescent Medicine (G.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁹ Cologne Center for Musculoskeletal Biomechanics (G.S.), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
²⁰ Institute for Cardiovascular Prevention (IPEK), Ludwig Maximilian University of Munich, Munich, Germany (R.T.A.M., C.W.).
²¹ Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands (R.T.A.M.).

PMID: 41473953
DOI: 10.1161/CIRCRESAHA.125.326591

Abstract

Background: Abdominal aortic aneurysms (AAAs) are characterized by ECM (extracellular matrix) degradation and chronic vascular inflammation, with macrophages playing a key role. The mechanisms regulating macrophage activation in AAA remain incompletely understood. Vascular macrophages express Olfr2 (olfactory receptor 2), a GPCR (G-protein-coupled receptor) implicated in inflammation, but its role in AAA development is unknown.

Methods: We investigated the role of Olfr2 in AAA using PPE (porcine pancreatic elastase) infusion in Olfr2-deficient (Olfr2^-/-), Ang II (angiotensin II) infusion in Apoe^-/- Olfr2^-/-mice, bone marrow transplantation, and pharmacological modulation experiments. Echocardiography and histology were complemented by spectral flow cytometry, transcriptional profiling, and functional in vivo and ex vivo assays.

Results: Microarray analysis revealed increased expression of the human Olfr2 orthologue OR6A2 (olfactory receptor family 6 subfamily A member 2) in AAA tissue. Flow cytometry showed OR6A2 upregulation in monocytes from patients with large versus small AAAs. In both human and murine tissues, up to 30% of vascular macrophages expressed OR6A2/Olfr2, which peaked in MHCII^high CCR2^low monocytes/macrophages on day 7 of experimental AAA. Both whole-body and hematopoietic Olfr2 deficiency protected mice from AAA formation, with reduced ECM degradation, decreased macrophage infiltration, and preserved smooth muscle cell content. Treatment with the Olfr2 agonist octanal exacerbated, while the antagonist citral reduced AAA and inflammation. In Olfr2^-/- mice, inflammatory gene expression and aortic leukocyte accumulation were diminished. Despite a similar total leukocyte count, Ly6C^high monocytes displayed reduced CX3CR1 (CX3C motif chemokine receptor 1) expression and impaired migration toward CX3CL1 in vitro. Competitive transfer confirmed reduced migratory capacity of Olfr2^-/- monocytes, while pharmacological CX3CR1 inhibition mitigated the proinflammatory effects of octanal in AAA.

Conclusions: Olfr2 regulates monocyte recruitment and macrophage-driven inflammation during AAA. Its genetic deletion or pharmacological inhibition protects against AAA, whereas receptor activation worsens the disease. Olfr2 represents a critical modulator of vascular inflammation and a potential therapeutic target in AAA.

Keywords: aortic aneurysm, abdominal; inflammation; monocytes; receptors, odorant.

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Conflict of interest statement

None.

Comment in

When Smell Drives Swell: Olfr2 Fuels Inflammation in AAA.
Stuttgen GM, Chang M, Williams JW. Stuttgen GM, et al. Circ Res. 2026 Jan 30;138(3):e327969. doi: 10.1161/CIRCRESAHA.125.327969. Epub 2026 Jan 29. Circ Res. 2026. PMID: 41610191 Free PMC article. No abstract available.

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Olfr2 Promotes Recruitment of Monocytes via CX3CR1 in Abdominal Aortic Aneurysm

Affiliations

Olfr2 Promotes Recruitment of Monocytes via CX3CR1 in Abdominal Aortic Aneurysm

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

MeSH terms

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Full Text Sources

Research Materials

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