CYTOMAC · Cytokine signaling in macrophages: beyond JAK-STAT

Dysregulated macrophage function underlies many inflammatory diseases. Cytokines, small secreted signaling molecules with immune-modulatory functions, shape the macrophages 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.In my previous work, I studied enhancer activation in mouse macrophages from genetically different strains. By studying genetic variation, I found that transcription factor (TF) motifs crucial for enhancer activation can be identified. I further developed the bio-informatic tool MAGGIE to study TF motif mutations in different strains of mice, which subsequently enabled me to discover a novel TF important for enhancer activation by the cytokine interleukin-4. Based on my findings, I hypothesize that cytokines require specific, yet unidentified TFs that cooperate with JAK-STAT signaling to mount cytokine-specific effects. CYTOMAC aims to identify these cytokine-specific TFs downstream of JAK-STAT that direct appropriate cell responses. I will exploit the genetic variation across mouse strains and study enhancer activation in macrophages from these strains in response to different disease-related cytokines. Specifically, I will: (1) use genetic diversity between mouse strains to identify specific TFs regulating cytokine-specific responses; to then target these novel TFs in (2) mouse and (3) human macrophages and (4) translate my findings to human disease and 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 applicability. CYTOMAC will reveal novel, cytokine-specific TFs, which will aid in developing better tailored intervention strategies.