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Jason S. Knight, MD, PhD

Assistant Professor

University of Michigan Medical School

https://www.uofmhealth.org/profile/2925/jason-scott-knight-md

Neutrophil Elastase as a Therapeutic Target in Lupus

Dr. Knight studies how a type of immune cell called a neutrophil contributes to lupus and its complications. In a model of lupus, he found that turning off elastase, a protein made in neutrophils, reduces autoimmunity, kidney disease, and blood clotting that can lead to strokes. Building on this intriguing discovery, Dr. Knight is now mapping out the molecular pathways that neutrophil elastase uses to damage the kidneys, heart, and blood vessels in lupus. This innovative research project will create a solid foundation for the development of drugs that target elastase as a potential lupus treatment.

What this study means for people with lupus

Dr. Knight has identified a new player in the development of lupus and its complications—neutrophil elastase. His Novel Research Grant will reveal whether elastase is a good target for the development of a new type of treatment for people with lupus.

Neutrophils are potential instigators of autoimmunity and perpetuators of organ damage in lupus. However, there is presently no consensus as to whether inhibition of neutrophil effector functions can be pursued as a therapeutic strategy in patients. For example, deletion of NADPH oxidase prevents neutrophil extracellular trap release (NETosis), but accelerates autoantibody formation and nephritis (likely by neutering homeostatic neutrophil subsets). Similarly, peptidylarginine deiminase inhibitors prevent NETosis and protect against vascular damage, but also raise the levels of key autoantibodies such as anti-double-stranded DNA. The serine protease neutrophil elastase is required for NETosis, but has been surprisingly little studied in lupus. Our preliminary data reveal that a selective neutrophil elastase inhibitor (GW311616A) mitigates in vitro NETosis in response to disease-relevant stimuli such as lupus serum. In NZW x BXSB F1 mice (a model characterized by immune-complex nephritis as well as a strong prothrombotic diathesis), daily oral GW311616A protects against numerous aspects of the lupus phenotype including the expansion of effector T cells, the emergence of certain autoantibodies, proteinuria, and both venous and arterial thrombosis. The Aims of this proposal will: (1) Determine the extent to which neutrophil elastase is required for lupus-mediated NETosis and can predict disease activity. Experiments will test the ability of neutrophil elastase inhibitors to protect against lupus-mediated NETosis in vitro, and will measure neutrophil elastase activity in the blood of patients with lupus and the related antiphospholipid syndrome. (2) Determine how inhibition of neutrophil elastase protects against autoantibody formation and glomerulonephritis in murine lupus. Experiments will expand inhibitor trials in NZW x BXSB F1 mice to include additional time points and the specific phenotyping of inflammatory and suppressive splenocyte subsets. (3) Elucidate mechanisms by which neutrophil elastase contributes to lupus-mediated thrombosis and endothelial dysfunction. Experiments will leverage unique mouse models to characterize the role of neutrophil elastase in venous thrombosis, dysfunction of the aortic endothelium, and cardiac thrombosis. In summary, these studies will be the first to comprehensively characterize the role of neutrophil elastase in both autoimmune and vascular complications of lupus. The prediction is that neutrophil elastase (which has no known role in suppressive neutrophil subsets) is a therapeutic target that can mitigate NETosis without exacerbating autoimmunity.

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