Platelet-monocyte interactions in Systemic Lupus Erythematosus

• Applicant: Dr. Christina Charlotte Rolling
• Subject Area: Hematology, Oncology
• Term: from 2019 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 429657170

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disorder that can affect any organ and is associated with an increased risk of cardiovascular disease. Intriguingly, platelets isolated from SLE patients exhibit markers of enhanced platelet activity and engage with monocytes to form inflammatory cell clusters. Increased formation of monocyte-platelet aggregates (MPA) has been associated with atherosclerosis and thrombosis but its contribution to accelerated CVD in inflammatory diseases is still incompletely understood. The overall objective of this translational research project is to gain a deeper insight into platelet activation, platelet-monocyte interaction and their interplay with inflammation. SLE as a model disease of inflammation will be used to address the following questions: 1) Do monocyte-platelet aggregates correlate with disease severity in SLE? 2) What is the mechanistic link between the platelet and the monocyte transcriptome and inflammatory phenotype?, and 3) Which molecular mechanisms contribute to platelet and monocyte activation and interaction, and may thus lead to an increased cardiovascular disease risk in patients with SLE? The following analyses will help us to thoroughly characterize the role of platelet-monocyte interactions in inflammation: 1) Platelet activity and MPA will be assessed in patients with SLE and will be correlated with activity and different organ manifestations. 2) As a second step, the platelet and monocyte transcriptome will be differentially analyzed in patients with high MPA levels versus low MPA levels. Platelet RNA profiling will help to identify specific platelet transcripts associated with monocyte-platelet interaction. RNA sequencing of the corresponding monocytes will elucidate which signaling pathways within the monocyte transcriptome are regulated by platelet aggregation. 3) Platelets (and platelet releasates) from SLE patients with high and low MPA will be used for co-incubation assays with isolated human monocytes from healthy donors and monocytic cell lines. Changes in the inflammatory profile of monocytes and monocytic cell lines will be characterized to confirm the in vivo data. Findings from this project will help understand the contribution and interaction of platelet and monocyte activation in SLE as a model inflammatory disease with the ultimate goal of discovering therapeutic targets to influence the disease course

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Jeffrey Berger