Molecular control of pathogenic neutrophil responses in inflammation

Neutrophils cause immunopathology by overproducing anti-microbial activities that may lead to tissue damage in inflammatory and autoimmune diseases, including rheumatoid arthritis, vasculitis, and lupus. Recent data highlight the existence of neutrophil subsets with different pathogenic properties. However the molecular control of pathogenic neutrophil responses is largely unknown. We will identify the intrinsic transcriptional circuitry that controls neutrophil functional reprogramming and provide insights into neutrophil heterogeneity and pathogenic phenotypes at sites of inflammation. Our recent studies highlighted a number of candidate transcription factors that will be functionally validated during the course of this project. Our work and the results of others have shown that neutrophil accumulation in tissues during sterile inflammation is controlled by macrophages. We will characterise how protein and lipid signals produced by monocytes and macrophages in the tissue at the different stages of inflammation affect neutrophil accumulation and activation and whether these are under a unified transcriptional control. Understanding the control of pathogenic neutrophil responses and identification of key regulators of immunopathogenic phenotypes will help to redefine these understudied cells in chronic inflammatory disorders and may lead to new treatments reducing the burden of human chronic inflammatory disease.