Center for Molecular Medicine Cologne

Winkels, Holger | Mollenhauer, Martin - B 12

Olfr2-mediated macrophage activation in obesity induced endothelial dysfunction

Introduction

Obesity is a major risk factor for cardiovascular diseases (CVD), the leading cause of global mortality. Endothelial dysfunction, a feature of obesity, has been identified as an early driver for CVD development. Low-grade, chronic inflammation due to obesity-induced subintimal lipid deposition plays an important role in the onset of obesity-associated CVD. Particularly macrophages accumulate in dysfunctional adipose tissue and vessels of obese patients and exert proinflammatory actions through e.g. release of cytokines. Yet, the interplay between macrophages, adipocytes, and endothelial dysfunction in CVD development is not well understood. We recently identified ectopic olfactory receptor 2 (Olfr2) expression in vascular and adipose tissue macrophages (ATM), which was increased in obese mice. Of note, genetic deficiency for Olfr2 reduced atherosclerosis and macrophage inflammation. The aim of this project is to uncover the role of Olfr2 in ATM-mediated inflammation in the context of obesity-induced endothelial dysfunction. We will address if Olfr2 affects adipose tissue inflammation and metabolism. Furthermore, we will assess vascular dysfunction in obese Olfr2-deficient and control mice by sonography and organ bath investigations.

Summary figure:

Clinical Relevance

Obesity greatly impacts overall health and can lead to the development of chronic diseases including CVD. Inflammation is a key mechanism rewiring adipose tissue, metabolic and vascular function. Yet, no clinical therapies targeting inflammation in obesity are available and novel pathways that curb adipose tissue inflammation while preserving host immunity are needed.

Approach

  • Preliminary data from our group confirms macrophage expansion in adipose tissue of obese mice. These macrophages upregulate surface Olfr2 expression (Figure 1).
Figure 1

In collaboration with Prof. Marco Orecchioni at Augusta University, we will address in this project:

  • Which PVAT-residing cell types express Olfr2 by histology and flow cytometry
  • Identify the impact of Olfr2 activation on metabolic alterations in obese wildtype and Olfr2-deficient mice
  • Assess the function of Olfr2 on macrophage activation and vascular function in the context of obesity by ultrasound and organ bath investigations
  • How Olfr2 affects the macrophage-adipocyte cross-talk
  • Orecchioni M, Kobiyama K, Winkels H, Ghosheh Y, McArdle S, Mikulski Z, Kiosses WB, Fan Z, Wen L, Jung Y, Roy P, Ali AJ, Miyamoto Y, Mangan M, Makings J, Wang Z, Denn A, Vallejo J, Owens M, Durant CP, Braumann S, Mader N, Li L, Matsunami H, Eckmann L, Latz E, Wang Z, Hazen SL, Ley K. Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production. Science. 2022 Jan 14;375(6577):214-221. doi: 10.1126/science.abg3067. Epub 2022 Jan 13. PMID: 35025664; PMCID: PMC9744443.
  • Chen Q, Lai SM, Xu S, Tan Y, Leong K, Liu D, Tan JC, Naik RR, Barron AM, Adav SS, Chen J, Chong SZ, Ng LG, Ruedl C. Resident macrophages restrain pathological adipose tissue remodeling and protect vascular integrity in obese mice. EMBO Rep. 2021 Aug 4;22(8):e52835. doi: 10.15252/embr.202152835. Epub 2021 Jul 1. PMID: 34196465; PMCID: PMC8339675.
  • Scheja L, Heeren J. The endocrine function of adipose tissues in health and cardiometabolic disease. Nat Rev Endocrinol. 2019 Sep;15(9):507-524. doi: 10.1038/s41574-019-0230-6. Epub 2019 Jul 11. PMID: 31296970.
  • McArdle S, Buscher K, Ghosheh Y, Pramod AB, Miller J, Winkels H, Wolf D, Ley K. Migratory and Dancing Macrophage Subsets in Atherosclerotic Lesions. Circ Res. 2019 Dec 6;125(12):1038-1051. doi: 10.1161/CIRCRESAHA.119.315175. Epub 2019 Oct 9. PMID: 31594470; PMCID: PMC7201888.
Prof. Dr. Holger Winkels CMMC Cologne
Prof. Dr. Holger Winkels

Clinic III of Internal Medicine - Experimental Cardiology

CMMC - PI - B 12

+49 221 478 40897

Clinic III of Internal Medicine - Experimental Cardiology

Kerpener Str. 62

50937 Cologne

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Holger Winkels

Link to PubMed

Dr. Martin Mollenhauer CMMC Cologne
Dr. Martin Mollenhauer

Clinic III of Internal Medicine

CMMC - Co-PI - B 12

+49 221 478 87402

+49 221 478 87372

Clinic III of Internal Medicine

Kerpener Str. 62

50937 Cologne

https://kardiologie.uk-koeln.de/forschung/inflammation-im-rahmen-der-herzinsuffizienz/

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - Martin Mollenhauer

Link to PubMed

Group Members

PostDoc: Dr. rer. nat. Felix Picard
PhD students: Elena Wagner, Lauren De Vore
Master student: Yein Park (start summer 23)
Medical student: Patrik Schelemei
Technician: Katharina Tinaz