ESR 16: Metabolic reprogramming of human myeloid immune cells during chronic inflammation – POSITION FILLED

PhD research

Host:

Dr. Jeroen den Dunnen

PI | Assistant Professor | PhD

Amsterdam Rheumatology and immunology Center (ARC)

Rheumatology & Clinical Immunology

Experimental Immunology

Location AMC | K0-105 | Meibergdreef 9 1105 AZ Amsterdam

T: +31205668043  |  E: j.dendunnen@amsterdamumc.nl

Duration: 48 months

Background

Inflammatory disorders such as rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) are characterized by chronic inflammation of the joints and the intestine, respectively. Although the cause of both diseases is still unknown, myeloid immune cells are considered to be important players in the pathogenesis, since they are the main producers of pro-inflammatory cytokines such as TNF that promote inflammation. However, the exact combination of factors responsible for excessive inflammation in RA and IBD is still largely unclear. While C-reactive protein (CRP) is currently only used as a general marker of inflammation in RA and IBD patients, our findings have demonstrated that this protein is able to directly induce inflammation, via stimulation of Fc receptors on immune cells. This project aims to dissect at the molecular level how interaction of CRP with Fc receptors stimulates pro-inflammatory cytokine production by macrophages to promote excessive inflammation in RA and IBD patients. Identification of the underlying mechanisms will give rise to new potential new targets for therapy, which will be tested in vitro, and ultimately in vivo.

Approach 

To identify the molecular mechanisms that underlie CRP-induced inflammation, we will combine various techniques, such as RNA interference, flow cytometry, RNAseq, ChIPseq, Seahorse analysis, and fluxomics (a metabolomics technique). The project is divided in three key objectives, that will be performed on two diseases (RA and IBD). First, in depth identification of CRP-induced metabolic reprogramming of immune cells. Second, identification how metabolic reprogramming interconnects with CRP-induced cell signaling. And third, targeting of CRP-induced metabolic reprogramming and signaling, in order to identify new therapeutic avenues to counteract inflammation in the context of RA and IBD.

Our research team

The research team is a collaboration between two PI groups of the Amsterdam UMC (location AMC) in Amsterdam. One group led by dr. Jeroen den Dunnen of the Department of Rheumatology, who is an expert in the field of molecular immunology, particularly on signaling by Fc receptors on human immune cells. The other group led by prof. Riekelt Houtkooper of the Department of Metabolic Diseases, who is an expert in the field of cellular metabolism. Expertise on RA is provided by embedding of the project in the Amsterdam Rheumatology and immunology Center (ARC), while expertise on IBD and patient samples is provided by prof. Marjolein van Egmond (Amsterdam UMC, location VUmc) and dr. Manon Wildenberg (Amsterdam UMC, location AMC). The complementary expertise of the different groups in this project will allow us to perform cutting-edge research at the cross-roads of immunology and metabolism.