Crosstalk between PI3K Signalling & SIGN-R1 in Autoimmunity

Apoptosis is a form of programmed cell death by which organisms remove unwanted cells, which post apoptosis need to be further cleared from our bodies. Apoptotic cell clearance which is primarily mediated by immune cells called macrophages is crucial for maintaining bodily homeostasis by preventing harmful inflammation. Defects in apoptotic cell clearance can lead to autoimmune diseases, where our own immune system attacks the cells and organs of our body. The macrophages of the spleen, so called splenic marginal zone macrophages are specialized in removing apoptotic cells as they contain special receptors that allow them to recognize dying cells, including a receptor called SIGN-R1. Our preliminary data suggests that SIGN-R1 levels are controlled by PI3K signalling and marginal zone macrophages with hyperactive PI3K activity can efficiently clean up aged or dying red blood cells through SIGN-R1 and thereby modulate iron levels in the body. However, we still require a more detailed understanding of how PI3K signalling is both intertwined with SIGN-R1 activity and how these effects are exerted. We will address the mechanisms further using cutting edge approaches including mouse models and systems biology. We expect these studies to provide significant insight into how apoptotic cell clearance within the spleen is fine-tuned and linked to iron metabolism. They may further have implications for autoimmune diseases such as Systemic Lupus Erythematosus, which is associated with defects in apoptotic cell clearance and wide spread inflammation.