The role of TLR8 in lupus nephritis
Kidney inflammation occurs in up to 60% of SLE patients and is a significant cause of damage and death in lupus patients. The goal of our experiments is to study the function of a particular molecule called TLR8 in a subset of immune cells that expand in the inflamed kidneys during kidney flares. These cells, called macrophages, function as sentinels in the immune response and can mediate inflammation as well as repair. In lupus kidney flares these cells become activated and take up damaged material that needs to be processed and recycled. Due to the continuous inflammatory process these cells are abnormally regulated and can promote kidney damage and scarring. TLR8 is located inside macrophages and recognizes nucleic acids that are taken up by dead cells. This can activate the cells and cause them to release inflammatory mediators. Because TLR8 is on the X chromosome, females make more TLR8 than males and this can worsen lupus in females.
We have found in mouse models that there is a large increase in TLR8 inside kidney macrophages during kidney inflammation. Because mouse and human TLR8 are different from each other we will use a mouse model of lupus in which human TLR8 is present to study the function of TLR8 inside macrophages and other related cells. We will determine how one or two copies of the human TLR8 gene alter the inflammatory process that causes lupus and the progression of kidney inflammation. We will then determine how the presence of human TLR8 alters the function of kidney macrophages and related cells. Our experiments should give new information about the role of TLR8 in lupus kidney disease. Because drugs targeting TLRs are being developed to treat lupus it is important to understand the function of TLR8 so that it can be targeted appropriately.