Inflammation is our body’s response to infection and injury. It is generally beneficial promoting resistance, repair and recovery. However, when the process of inflammation is not controlled properly it becomes damaging. This is the case during chronic diseases such as atherosclerosis, diabetes, Alzheimer’s disease, and after acute injuries such as stroke. There are many aspects of the inflammatory response that are not known. Through increased understanding of inflammation we may identify new drug targets that could ultimately reduce the severity of many diseases. My lab aims to understand the molecular and cellular mechanisms that contribute to inflammation.
Processing and secretion of interleukin-1
Interleukin-1ß (IL-1ß) is a key pro-inflammatory cytokine that contributes to the damaging inflammatory component of nearly every major human disease. Thus understanding the mechanisms of its cellular release may help to identify new therapeutic targets for inflammatory disease. The cellular release of IL-1ß also poses a considerable biological problem since it does not harness any of the conventional / classical mechanisms of protein export. It is produced by macropghages as an inactive precursor called pro-IL-1ß in response to an inflammatory challenge. When the cell encounters an additional stimulus, this inactive precursor is cleaved by the enzyme caspase-1 to a mature, active form that is then secreted. The stimuli coordinating these events are many and varied, specific to particular disease or injury, and depend upon Pattern Recognition Receptors (PRR) on the host cell. For example, bacterial endotoxin (lipopolysacharide, LPS), which is an outer wall component of Gram-negative bacteria, is the Pathogen Associated Molecular Pattern (PAMP) that induces pro-IL-1ß expression via the plasma membrane PRR TLR4. The PRR's involved in the activation of caspase-1 directly are cytosolic and are of the NOD Like Receptor (NLR) family. These cytosolic receptors are activated by many stimuli, one of which is extracellular ATP acting through the cell surface P2X7 receptor. We are currently investigating the mechanisms that lead to the activation and secretion of IL-1ß.
Intracellular actions of interleukin-1
There are a small number of cytokines for which an intracellular role has been defined. These are termed dual function cytokines. There is evidence that IL-1 family members can act intracellularly in addition to their secreted extracellular actions. Intracellular IL-1 is reported to influence inflammatory gene expression and RNA splicing. We are currently investigating mechanisms of IL-1 trafficking to the nucleus and its mechanisms of action.