The Function of Renal Macrophages in Lupus Nephritis

This proposal addresses the Topic Area of Systemic Lupus Erythematosus (SLE or lupus), specifically lupus nephritis (LN). Lupus nephritis affects between 30-60% of adult SLE patients and is responsible for significant morbidity and mortality. Despite many advances in biologic drug therapy, effective new therapies for LN have been slow to emerge and the reason why so many patients fail therapy is not known. Novel molecular datasets are beginning to be generated from single cells isolated from human LN kidney biopsies. In the first aim, we successfully generated parallel datasets from the mouse models so that as pathways of interest are identified in the human samples they can quickly be modeled and their function clarified in the appropriate lupus prone mouse. There is striking overlap between the mouse and human datasets with heterogeneity in the humans that we can model in the mice. Our second aim addressed the role of autophagy and metabolism in renal macrophages.We have found that deficiency of Rubicon (LAP pathway) protects the lupus mice from LN and death due to altered B cell selection whereas deficiency of ATG14 (classical pathway) specifically in macrophages has no effect. ATG14 deficiency in B-cells also protects from disease indicating a role for autophagy in the generation of autoreactivity. We also investigated the role ofPGC-1alpha in metabolic programming of kidney macrophages in LN but were not able to demonstrate a significant role for this transcriptional regulator in macrophages of LN kidneys.