Project 3- Role of Leukocyte-Platelet Interactions in Inflammation and Thrombosis

PROJECT SUMMARY/ABSTRACT This translational project will focus on systemic lupus erythematosus (SLE) as a unique disease model of inflammation and thrombosis. SLE is a complex autoimmune disease. The prevalence of SLE ranges from 20 to 150 cases per 100,000 population. SLE affects primarily women and there is a significant impact

of health disparities in patients with Lupus. SLE is 2-3 times more prevalent among African American and Hispanic than among Caucasian women. Patients with SLE can experience significant symptoms, such as chronic pain, extreme fatigue, hair loss, cognitive issues, and physical impairments that affect every facet

of their lives. Many suffer from cardiovascular disease, strokes, disfiguring rashes, and painful arthritis. The 10-year survival rate is about 70%. Historically, SLE has been considered as an adaptive immune system disorder characterized by the presence in patient serum of autoantibodies raised against nuclear

components which deposit in blood vessels, skin, kidney, lung, joints and brain causing tissue damage and clinical manifestations. New advances in the understanding of SLE pathogenesis have focused on the innate immune system, with a particular focus on leukocytes (i.e., neutrophils, monocytes) as key players

in perpetuating and amplifying this systemic disease. Currently, there is no prevention or cure for SLE, and the mainstay of treatment is non-specific immunosuppressive and cytotoxic agents. Thus, there is significant unmet clinical need in SLE and compelling demand for more effective therapeutic approaches.

Leukocyte-platelet interactions induce bidirectional signals that amplify pro-inflammatory and pro- thrombotic cellular responses. We have focused on the leukocyte integrin Mac-1 (αMβ2), identifying this adhesive receptor as a critical molecular determinant of leukocyte recruitment and signaling. Our

laboratory first reported the interaction between Mac-1 and its platelet counter-receptor GPIbα and determined the molecular basis of GPIb recognition. We established that Mac-1:GPIbα broadly regulates inflammation in models of vasculitis, glomerulonephritis, and multiple sclerosis as well as arterial

thrombosis. The central hypothesis of this proposal is that the Mac-1:GPIbα interaction is broadly required for inflammation and initiates pro-inflammatory and prothrombotic signals that promote diverse disease processes. The specific aims of the project are: 1) To determine the effect of disrupting Mac-1:GPIbα on

the progression and complications of SLE using mouse models; 2) To define the physical determinants of Mac-1:GPIbα binding and the nature of “outside-in” signals generated by this interaction; and 3) To provide evidence that clinical SLE disease activity is correlated with biomarkers of the Mac-1:GPIbα interaction.

Because leukocyte-platelet interactions broadly regulate inflammation and thrombosis, understanding the molecular machinery of this cellular complex will provide important insights for developing new therapies directed at reducing end-organ damage in SLE and other inflammatory/thrombotic disorders.