Molecular responses of macrophages to microbial and host products

Inflammation is a critical part of the immune response that normally protects the host from traumatic, infectious, toxic or autoimmune injury. However, while a successful inflammatory reaction promotes the resolution of injury or infection, uncontrolled inflammatory responses can also lead to many human diseases such as systemic inflammatory response syndrome (SIRS), inflammatory bowel disease (IBD) and many neurodegenerative diseases. Macrophages, a major component of innate immune system, are an essential component of this inflammatory response. My research goal is to understand the mechanisms involved in the regulation of macrophage activation. Analysis of the response of macrophages to LPS led to the discovery of LPS-mimetic actions of taxol and the identification of heat shock protein 90 (Hsp 90) as a shared cellular target of taxol and LPS. Comparison of genes that are differentially expressed between LPS responder and non-responder macrophages led to the identification of secretory leukocyte protease inhibitor (SLPI) as an LPS-inducible macrophage product with LPS-antagonistic activity. Examination of SLPI's anti-inflammatory actions led to the discovery that SLPI/elastase regulates the conversion of progranulin (proepithelin) to granulin (epithelin) to control host defense and wound repair. Study of the interferon-gamma mediated macrophage activation identified a MyD88/MLK3-dependent pathway that stabilizes ARE-containg mRNA. Current work focuses on identifying novel molecules that can affect proinflammatory mediator mRNA stability, as well as for the molecular events involved in regulating inflammatory responses focusing on two mouse models with homologous delections of either MyD88-5 (sarm) or progranulin (pgrn) gene.