Ferroptosis as a novel driver of inflammation in lupus nephritis
Lupus nephritis occurs because the kidneys become inflamed. In the process, cells of the kidneys can die and look abnormal to the immune system. Instead of efficiently clearing these dead cells away, the immune system can then react causing inflammation and potentially making the kidney damage even worse. Cells can die in several ways, and researchers need to pinpoint what triggers their demise to determine if the cause of death impacts the immune system’s reaction. Our project investigates whether a newly recognized type of cell death called ferroptosis contributes to kidney damage in lupus. Ferroptosis differs from other kinds of cell death because it is caused by iron, which is naturally present in small amounts in the body but can cause damage too. To learn if ferroptosis has a role in lupus, Dr. Boesen and colleagues will see if a chemical that blocks it, liproxstatin-1, reduces kidney damage in mice with lupus. Their project will also ask whether ferroptosis causes additional harm to the kidneys by promoting inflammation. This study will improve understanding of how kidney injury occurs in lupus and could provide the impetus for developing new therapies that block ferroptosis.
What this study means for people with lupus
About half of people with lupus suffer from lupus nephritis, or damage caused when the immune system attacks the kidneys. Dr. Boesen’s study investigates a new possible reason why kidney cells die in lupus, which could lead to new drugs that prevent kidney damage in lupus patients.
Inflammation and damage of the kidneys (lupus nephritis) is a serious complication of systemic lupus erythematosus (SLE), affecting approximately 50% of SLE patients. Current treatments have significant side effects, and despite treatment, renal impairment still occurs in ~40% of lupus nephritis patients. Key underlying pathological mechanisms in SLE include a loss of immune tolerance to “self” antigens and development of autoantibodies directed against nuclear and other intracellular material such as the mitochondrial lipid cardiolipin. Dead cell debris is poorly-cleared in SLE patients, further fueling the autoimmune response. Understanding the pathways that generate antigenic material and provoke the inflammatory response in SLE, particularly in target organs such as the kidney, may lead to new therapeutic approaches to block organ injury. The current proposal investigates whether a newly-described form of iron-mediated necrotic cell death, called “ferroptosis”, contributes to renal injury and provokes an inflammatory response in lupus. This highly novel work builds on our recently-published data that iron accumulation occurs in and contributes to renal injury in a mouse model of lupus, the NZBWF1 mouse, and preliminary data in this model showing an increase in a putative biomarker for ferroptosis. Ferroptosis has recently been shown to contribute to acute kidney injury, but whether it contributes to renal injury in lupus or any other form of chronic kidney disease has not yet been investigated. Experiments in Aim 1 will test the hypothesis that ferroptosis contributes to renal injury in lupus. We will treat NZBWF1 mice with a ferroptosis inhibitor to test whether this can prevent the development of renal injury, or block the further progression of renal injury if treatment commences once injury has already occurred. Aim 2 tests the hypothesis that ferroptosis promotes inflammation in lupus nephritis. We will test whether ferroptotic cell debris attracts macrophages and activates T and B cells from NZBWF1 mice. The ability of ferroptosis inhibitors to block immune complex deposition, immune cell infiltration and production of inflammatory cytokines in the kidney of NZBWF1 mice will also be tested. Achieving these Aims will provide new insights into the processes and mechanisms underlying renal injury and inflammation in lupus, and offer a novel therapeutic approach to blocking renal injury in this disease.