Abstract
Neutrophils are essential phagocytes of the innate immune system. They are rapidly recruited to sites of infection and engage pathogens via degranulation, phagocytosis and the release of extracellular web-like structures called neutrophil extracellular traps (NETs). Traditionally, neutrophils were thought to implement these strategies indiscriminately. In addition their regulatory roles during inflammation are largely unknown. Our work suggests that neutrophils selectively implement their antimicrobial strategies to fight infection more effectively and employ novel mechanisms to regulate inflammation. In particular, the immune mechanisms that combat large pathogens had been poorly understood. NETs are composed of decondensed chromatin and antimicrobial proteins that trap and kill microbes extracellularly but their significance for immune defense remained unclear. We showed that neutrophils sense microbe size and selectively release neutrophil extracellular traps (NETs) to combat large pathogens, such as fungal filaments. These observations explain why NET-deficient human patients are only susceptible to fungal infection. Disruption of this decision-making mechanism leads to aberrant NET release and NET-mediated tissue damage during infection. Therefore, once at the site of infection, neutrophils fine-tune their antimicrobial strategies to effectively clear large microbes while minimizing NET-mediated pathology when microbes are small enough to be killed intracellularly. In addition, NETosis plays important regulatory roles during sterile inflammation. NETs are triggered by endogenous danger signals such as atherosclerosis-promoting cholesterol crystals and cause pathology by licensing macrophages for proinflammatory cytokine release.
Bio
I did my undergraduate studies at Rutgers University in New Jersey working with Ken Irvine on the mechanisms that establish tissue barriers during drosophila development. This work defined the role of fringe genes as modulators of the Notch signaling pathway. Subsequently, I moved to San Francisco to pursue a PhD at UCSF with Wendell Lim, studying the mechanisms that allow small fluctuations in phopsholipid signals to promote switch-like regulation of actin dynamics. Intrigued by the discovery of neutrophil extracellular traps (NETs), I headed to Berlin for post-doctoral work with Arturo Zychlinsky at the Max Planck Institute for Infection Biology working on the molecular mechanisms of neutrophil extracellular trap formation and their implication in cystic fibrosis. In 2012, I started a research team at the MRC National Institute for Medical Research in London. Our lab studies the role and regulation of the antimicrobial responses of the innate immune system during infection and disease.