Inflammation & autophagy
Cells frequently experience ER-stress and oxidative stress with increased levels of reactive oxygen species (ROS). Activation of pattern recognition receptors (PRRs) induces the production of ROS via phagosomal NADPH oxidase complexes and by recruiting mitochondria, and ROS may contribute in activation of the NLR inflammasomes.
Oxidative stress also induces autophagy, an evolutionary conserved catabolic process in which damaged organelles, protein aggregates or intracellular pathogens are enclosed into an autophagosome and degraded after fusion to lysosomes. Autophagy is essential for cellular homeostasis, and defects lead to disorders like degenerative diseases, cancers, infections and cardiovascular diseases. Autophagy may directly regulate inflammation via ubiquitination and delivery of inflammasomes into the lysosomes. Several types of PRR ligands can trigger autophagy and autophagy-related proteins have been shown to fine-tune inflammatory signalling from PRRs. Improved understanding of how these processes are interconnected may point to novel therapeutic targets.
We will explore how PRR-initiated inflammatory responses and autophagy are interconnected and regulated. In particular we hope to identify new relations between pathways that are central in regulating intracellular survival of mycobacteria: Phagocytosis by C-type lectins, inflammatory signalling through Toll-like receptors, and autophagy instrumented by autophagy-related proteins.