Mechanisms of IL-1B secretion during microbial infection

Stanford University, Stanford CA

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Interleukin-1? (IL-1?) is a proinflammatory cytokine that has been the focus of much interest due to its importance in controlling inflammation during microbial infection and chronic inflammatory disease. During microbial infections, secretion of IL-1? is an essential step for the innate immune defense and modulation of adaptive immune responses. After secretion into the extracellular milieu, IL-1? can bind to interleukin-1 receptor (IL-1R) and induce a signaling cascade important for the release of other proinflammatory cytokines and induction of a Th17 bias in the adaptive immune response. All of these events are integral for rapid clearance of infection and host susceptibility to infection. Despite intensive study on the production and processing of IL-1?, the mechanism of active IL-1? secretion from innate immune cells still remains unsolved. Many proinflammatory cytokines are secreted through classical protein secretory pathway; however, IL-1? lacks the proper signal to be trafficked through this pathway. Thus, it has been hypothesized that IL-1? is secreted via a non-classical secretory pathway. Recent studies have suggested that IL-1? release in response to intracellular bacteria may rely on a variety of non-classical secretory pathways, including: lysosomal exocytosis, microvesicles, and exosomal exocytosis. However, none of these studies have been conclusive. The intracellular bacterial pathogen Salmonella typhimurium induces robust IL-1? secretion after inflammasome activation in macrophages. The release of IL-1? from infected cells is imperative for control and clearance of the infection; however, the mechanism of secretion is not known. Thus, we aim to identify new host factors involved in secretion of IL-1? in response to S. typhimurium infection. We hypothesize that multiple unidentified proteins are required for non-classical secretion of IL-1? during microbial infection. This work will lead to a better understanding of how IL-1? secretion and trafficking is regulated during microbial infections and other chronic inflammatory diseases. Additionally, the results of these studies will work towards identifying ideal therapeutic targets for future anti-inflammatory drug development.