Metabolic networks and unbiased genetic screens to identify targets for SLE

Immune cells known as T cells can be harmful or helpful in lupus. The T cells that promote inflammation and tissue damage differ metabolically from the beneficial T cells that can rein in the immune system. We have found that the harmful T cells require the metabolic enzymes glutaminase and methylene tetrahydrofolate dehydrogenase 2. Two drugs that block these enzymes are being developed as potential cancer treatments. We plan to test whether the drugs protect mice with lupus against kidney inflammation, a common complication in lupus, and reduce the number of damaging immune system proteins known as antibodies that the animals produce. We also plan to use the CRISPR technology for disabling genes to identify other possible metabolic molecules that could be targeted with drugs.

What this study means for people with lupus:

“The Achilles heel of the harmful immune cells in lupus may be their metabolism. We will test two drugs being developed for cancer that target cells’ metabolism to find out if they reduce lupus symptoms in mice. If the drugs are beneficial, clinical trials could test them in patients with lupus.”

T cells are now recognized to play a major role to drive inflammation and pathogenesis in Systemic Lupus Erythematosus (SLE). We were the first to show that inflammatory effector T cells (Teff) require distinct metabolic programs from regulatory T cells (Treg) to elicit their functions and we have worked to identify and exploit these differential metabolic dependencies. T cells have long been shown to have altered metabolic profiles in SLE and we showed increased glucose metabolism can promote SLE-like disease. Here we propose to explore T cell metabolism as a fertile area to identify new therapeutic targets for this devastating disease. Our initial metabolomics studies and metabolic network analyses of Teff and Treg have identified glutamine and one carbon metabolism pathways to be highly induced on inflammatory T cells. Based on regulated gene expression and metabolomics, we have focused our studies on Glutaminase (GLS) in glutaminolysis and Methylene Tetrahydrofolate Dehydrogenase 2 (MTHFD2) in the folate cycle of mitochondrial one carbon metabolism. MTHFD2 was found to be highly regulated and increased in SLE and other inflammatory diseases and was expressed in the most pathogenic Th17 cells when measured by single cell RNAseq. We show here that inhibition of GLS or MTHFD2 can inhibit mTORC1 signaling in Teff to promote Treg and reduce inflammatory pathology in a variety of models. To identify additional metabolic genes that may provide new classes of potential targets to treat SLE, we have also developed an unbiased in vivo forward genetic CRISPR screening strategy based on metabolic networks and expression of nutrient transporters. A preliminary screen shows this approach is robust to rank-order new targets for further validation and study. We will test the hypothesis that inflammatory T cell subsets have specific metabolic dependencies including GLS and MTHFD2 that can be inhibited to protect against SLE and that in vivo genetic screens will identify additional metabolic targets to selectively modulate immunity and provide potential new SLE therapies. We will further explore T cell metabolism to understand disease mechanisms and as a source of SLE therapeutic targets to (1) Test GLS and MTHFD2 as candidate targets to suppress SLE inflammation and autoantibody production in mouse models and SLE patient samples and (2) Use pooled CRISPR gene targeting in primary cells in SLE models for pathway-based and nutrient transporter screening to identify the relative roles of metabolic enzymes in T cell-mediated inflammation. Hits from these screens will be validated in both mouse and human SLE samples. Our study will identify new mechanisms of immunometabolic regulation and has the potential to repurpose two new agents developed as anti-cancer metabolism drugs to instead treat SLE as well as to identify new classes of enzymes and transporters that may provide additional targets for development in future study and exploitation as SLE therapeutics.