Cytokine signaling in macrophages: beyond JAK-STAT

Introduction

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.

Previous Work

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 bioinformatic 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.

Hypothesis

Based on my findings, I hypothesize that cytokines require specific, yet unidentified TFs that cooperate with JAK-STAT signaling to mount cytokine-specific effects.

Project Overview

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.
2. Target these novel TFs in mouse macrophages.
3. Target these novel TFs in human macrophages.
4. Translate my findings to human disease and inflammatory disease models.

Clinical Relevance

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.