2022 Recipient of the Lupus Canada Catalyst Award
Éric Boilard, PhD
Platelets are tiny cell fragments in blood circulation in charge of the prevention of bleedings. However, in systemic lupus erythematosus (lupus), our studies and that of others demonstrate that platelets can aggravate the disease. They produce molecules that promote inflammation and they can plug blood vessels, a process known as thrombosis. As there is no cure for lupus, we propose to examine whether we can treat this disease by the identification of targetable molecules relevant to platelet biology.
Platelets are made by megakaryocytes, a giant cell located in bones and lungs, making them hard to study. Each megakaryocyte can generate up to 5,000 platelets. In this project, we propose to study megakaryocytes in lupus to determine whether there are defects in these cells that promote them to generate dangerous platelets.
We will use mouse models that we have generated and will study megakaryocytes in bones and lungs. We will examine how these cells produce the energy they require for their functions and for their platelet progeny, and will determine whether these pathways are dysregulated in lupus. We will then target these pathways and will examine the effects on disease development.
Our findings could bring a paradigm shift in how we think of lupus classification and treatment
through the implication of a new underappreciated immune cell: the megakaryocyte. New therapies that specifically target platelet/megakaryocyte immune functions could offer relief to patients without making them more vulnerable to bleedings. As megakaryocytes produce billions of platelets each day, we may reveal how to target the pathogenic megakaryocyte progeny, platelets, directly at their source.
Our laboratory examines the role of platelets and their mother cell, the megakaryocyte (MK), in systemic lupus erythematosus (SLE).
The accumulation of autoantibodies and autoantigens in blood, the formation of immune complexes (ICs) and their deposition in organs play a central role in this pathogenesis. Up-regulation of the type I interferon (IFN), leading to expression of IFN-regulated genes, also characterizes SLE. We found that autoantibodies target mitochondrial antigens in SLE. In response to ICs in SLE, we found that platelets release naked mitochondria. Moreover, we found that Fc receptor IIA for IgG (FcγRIIA), a receptor for ICs, accelerates platelet activation, nephritis and mortality in a mouse model of SLE. We further demonstrated that dependently of the expression of FcγRIIA, platelets displayed an altered transcriptome presenting IFN-regulated genes and dysregulated mitochondrial pathways in SLE. As platelets are anucleate, these data indicate that MK, the cells that produce platelets and afford them their RNA content, are altered in SLE. We will integrate these intriguing findings by examining MKs in SLE with emphasis on MK bioenergetics.
An SLE-prone environment reprograms MKs into a pro-inflammatory phenotype that plays a significant role in driving SLE pathology.
AIM 1 Evaluate MK responses to SLE-relevant stimuli
AIM 2 Evaluate the phenotype of endogenous MK subpopulations in SLE
We will evaluate MKs in healthy conditions and SLE with special attention to mitochondrial energetics. To do this, we will evaluate whether certain subpopulations of MKs are preferentially affected in SLE using spatial omics. Studies will implicate mouse models of SLE that we have developed.
These findings will be utilized for larger grant applications meant to understand how MKs contribute to SLE. Platelets are now recognized as active players of both inflammation and thrombosis. MKs continuously fuel the fire with new platelets with pro-inflammatory and pro-thrombotic phenotype.
Whether and how MKs are impacted by SLE is unknown. As MKs produce billions of platelets each day, we may reveal how to target the pathogenic MK progeny, platelets, directly at their source.
The Lupus Foundation of America supports basic, clinical, epidemiological, behavioral, and translational lupus research in areas where there are gaps in scientific knowledge or in areas that have not received adequate funding.See the Research We Fund