The Function of Renal Macrophages in Lupus Nephritis
Abstract
This proposal addresses the topic area Systemic Lupus Erythematosus (SLE - lupus). Inflammation of the kidneys is a common and severe complication of SLE, for which current therapies are insufficiently effective and result in multiple side effects. It is currently not possible to predict the outcome of disease or whether a patient will respond to a particular drug based on looking at the kidney biopsy. Unfortunately, only half of patients with kidney lupus respond to therapies and about one-third of patients go on to develop permanent kidney damage. Immune cells enter the kidneys during lupus nephritis and may damage the kidneys either by releasing inflammatory mediators or by causing tissue scarring. We are particularly interested in the role played by macrophages that become activated during kidney inflammation in lupus patients. The presence of these cells in kidney biopsies is associated with a poorer outcome in lupus nephritis patients. In this proposal, we will investigate the function of kidney macrophages using disease models. Macrophages are interesting because they can assume many different functions depending on their location and the environment to which they are exposed. For example, when they enter damaged tissues they promote inflammation, but they can then switch their function to rebuild the tissues without permanent damage or scarring. However, macrophages can become harmful during disease. In lupus kidneys, we have found that the macrophages that normally reside in the kidney become activated and promote tissue damage and scarring. We now wish to know more about these cells in order to determine whether we can target specific cell functions to improve the outcome of lupus kidney disease. The first goal of our study is to isolate single macrophages from the kidneys of lupus-prone mice. We will apply new state-of-the-art genetic technologies and systems approaches to determine all the potential functions of these cells and to understand how they become dysfunctional during the course of disease. Importantly, we are part of a consortium that is obtaining similar information from single cells from human lupus kidney biopsies, and this will allow us to quickly identify which pathways are relevant to human disease and need to be prioritized for further study of their potential as therapeutic targets. The next goal of our proposal is to specifically examine two processes that are central to abnormal macrophage functions and that we already know are shared between the mouse models and human disease. The first of these is autophagy, a process by which unwanted cell contents are disposed of in a safe manner. We have shown that there is excessive autophagy in kidney macrophages and will investigate what happens when either of two distinct forms of autophagy are missing. The second process we will study is macrophage metabolism. How a cell gets and uses its fuel determines the function of that cell and under conditions of stress the metabolism of the cell changes. We will determine whether macrophages are using glucose, glutamine, or fatty acids to power the cell and how this might impact cell function. We will also study how deficiency in autophagy alters the metabolism of the cell. Finally, we will study a molecule called PGC1 alpha, which is a master regulator of the macrophage energy supply. We have found that levels of this protein are very low in lupus kidney macrophages and this may impair their ability to alter their metabolism such that they cannot respond appropriately to stress. We will determine whether specifically altering these cells so that they produce high levels of PGC1 alpha improves their function and the outcome of kidney inflammation. Findings from these studies should help us gain a better understanding of lupus kidney disease, which will help us improve therapies for lupus patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710657
Entities
People
- Anne Davidson
Organizations
- The Feinstein Institute for Medical Research
- United States Army