Amsterdam institute for Immunology and Infectious diseases

Cytokine signaling in macrophages: beyond JAK-STAT (CYTOMAC)

Assistant professor Marten Hoeksema (Department of Medical Biochemistry, ACS/AII) will use his prestigious ERC grant to study how cytokines, small secreted signaling molecules with immune-modulatory functions, shape the phenotype of macrophages, thereby affecting disease state.

Dysregulated macrophage function underlies many inflammatory diseases. Cytokines, small secreted signaling molecules with immune-modulatory functions, shape the macrophage’s phenotype, thereby affecting disease states. Puzzlingly, many cytokines with opposing functions, utilize highly similar JAK-STAT signaling cascades, leaving it unclear how cytokine-specific responses can occur. By exploiting genetic variation across mouse strains, CYTOMAC aims to identify cytokine-specific transcription factors (beyond JAK-STAT) that direct appropriate cell responses. These newly identified transcription factors will subsequently be studied in various inflammatory disease models.

Inhibitors targeting JAK-STAT show high potential in clinically treating inflammatory diseases, including rheumatoid arthritis. However, as they affect generic pathways of many cytokines they come with considerable side-effects, limiting their applicability. CYTOMAC will reveal novel, cytokine-specific transcription factors, which will aid in developing better tailored intervention strategies.

ENDOMET-STEER

Assistant professor Jeffrey Kroon (Department of Experimental Vascular Medicine, ACS) will use his prestigious ERC grant to develop approach to reduce the atherogenic milieu in the bone marrow and plaque, utillizing endothelial metabolism.

Inflammation is an important driver of atherosclerosis, the primary cause of global morbidity and mortality in emerging and developed countries. New strategies to reduce atherosclerotic cardiovascular disease (CVD) risk are therefore eagerly needed. We recently found that atherogenic inflammatory stimuli rewire cellular metabolism in endothelial cells (ECs) and thereby contribute to atherosclerosis progression. Defining the intricate link between EC inflammation, metabolic rewiring and functional consequences for the vasculature will open new avenues for therapeutic strategies in CVD. Our recent work shows that CVD-associated metabolic changes in ECs can affect their secretome. In turn, the endothelial secretome disrupts both stem cell function in the bone marrow niche and macrophage activation in the plaque microenvironment, two highly vascularized tissue compartments that drive atherosclerosis progression. With this ERC Starting Grant, our group will unravel how EC metabolism is affected in atherosclerosis, what the impact of this altered EC metabolism is for stem cell function in the bone marrow niche and for macrophage activation in the plaque. Our ultimate goal is to define how interventions in EC metabolism improve tissue function and halt CVD development.