The impact of risk-associated genes on a novel injury-associated monocyte subset in lupus nephritis 

Lupus nephritis (LN) is a severe kidney disease that develops in many people with systemic lupus erythematosus (SLE). Monocytes (a type of immune cell) in the kidneys are linked to kidney injury and fibrosis (thickening and scarring of tissue), yet there are currently no treatments that target these cells.

Dr. Hoover recently analyzed kidney biopsy samples from people with active LN and identified a group of monocytes, called injury-associated monocytes, which were strongly linked to kidney disease severity and produced genes involved in inflammation. He aims to understand how these injury-associated monocytes contribute to kidney disease in lupus nephritis so they can be therapeutically targeted.

Large global genetic studies have identified many genes, called risk genes, which raise a person’s risk for SLE and LN. Dr. Hoover will use cutting-edge technologies, including CRISPR (a tool that can cut and edit DNA at specific spots), to learn how SLE/LN risk genes alter the function of injury-associated monocytes to contribute to the disease.

He will first use a mouse model of lupus that has injury-associated monocytes to quickly and efficiently screen a specific type of risk genes, called transcription factors, to see how they affect the number of injury-associated monocytes and the genes they produce. He will then study these risk transcription factors in human cells, testing whether these genes impact cell processes that are often altered in LN and SLE, like phagocytosis (the process of engulfing particles) and cellular migration (movement to new locations such as the kidney). This study will uncover the functional impact of risk transcription factors on injury-associated monocytes.

What this means for people with lupus
Existing therapies can cause harmful side effects and there are currently no therapies that target this new subset of monocytes associated with kidney injury. Findings from this study could lead to the development of therapeutic strategies to target injury-associated monocytes for the first time using a precision-based approach.

Lupus nephritis (LN) is a heterogeneous kidney disease that develops in ~50% of patients with systemic lupus erythematosus (SLE), and many progress to end-stage kidney disease. Myeloid cells play an important pathogenic role in LN, but no treatments directly target these cells. We discovered an intrarenal injury-associated monocyte that is strongly associated with kidney injury in human LN, supporting a role in pathogenesis and thus identifying a potential treatment target. Further, we identified an analogous injury associated monocyte in kidneys from 4 lupus mouse models with severe disease, providing a system to study this cell type in vivo. LN and SLE have a strong genetic component based on familial clustering, heritability, and GWAS identification of susceptibility genes. We hypothesize that transcription factors (TF) associated with lupus susceptibility alleles (“risk-TFs”) differentially regulate the functions and differentiation of injury-associated monocytes, and are an important source of disease heterogeneity. We will determine the contribution of SLE/LN risk-TFs on the differentiation and functions of an injury-associated monocyte. Results will link human genetic findings with physiologically relevant cellular phenotypes in myeloid cells and help to stratify patients based on active disease mechanisms. Aim 1. Determine the gene programs and differentiation states regulated by conserved SLE/LN risk-TFs in myeloid cells within the mouse kidney environment. We will use a lupus mouse model to study the contribution of 15 risk-TFs on transcriptional programs within injury-associated monocytes employing an established in vivo method, the Chimeric Immune Editing (PMID: 30971695), that will teach us the full effect of the immune and kidney tissue environment on the TF-directed gene programs. Findings will provide a basis for creating transgenic mice with alterations in identified TFs to determine impact on disease. Aim 2. Identify the SLE/LN risk-associated TFs that induce differentiation and functions of monocytes in vitro. We will determine the effects of risk-TFs on the in vitro differentiation and cellular functions of human injury-associated monocytes. This approach allows us to study a broader spectrum of risk TFs since we are no longer limited to conserved TFs that are expressed in mouse monocytes, and to use both overexpression and knockdown approaches that can be manipulated in vitro (whereas only knockdown is possible in vivo). We expect to identify the full contribution and functional heterogeneity of SLE risk-TFs on injury-associated monocyte functions, including phagocytosis, cytokine production, migration, ROS production and T cell activation. Results could identify therapeutic strategies to exploit pathways of monocyte differentiation and function based on genetics that could potentially be tested in a precision based way. This would be a significant step as no current drugs for LN directly target myeloid cells.