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    Oral Communication

    Hemostatic Systems in Cancer, Inflammation and Immunity

    Basic Studies in Thromboinflammation and Sepsis

    OC 78.4 - Thrombocytopenia Independently Leads to Monocyte Immune Dysfunction in Sepsis

    Wednesday, June 28, 2023
    11:00 – 11:15 ET
    Room: 515
    Session Available As: On-Demand
    Background: Platelets are mediators of thrombosis, but platelets are also immune cells. Platelet activation promotes inflammation, however, resting platelets also maintain immune homeostasis in healthy/steady-state conditions. I have now discovered that thrombocytopenia independently leads to monocyte immune dysfunction. This is particularly relevant in conditions such as sepsis where thrombocytopenia is associated with exaggerated host inflammatory responses and increased mortality.

    Aims: Determine the mechanisms of platelet-mediated monocyte immune tolerance in healthy conditions and the functional consequence of thrombocytopenia on monocyte immune dysregulation.

    Methods: Inflammatory gene expression and LPS responses was determined in monocytes from WT and thrombocytopenic mice. Mouse sepsis was induced by LPS or cecal slurry model (Fig 1). In vitro, mouse monocytes were co-cultured with platelets overnight, platelets washed away and monocytes were LPS stimulated. RNA-Seq was performed on platelet incubated monocytes and ATAC-Seq was performed on monocytes from WT and thrombocytopenic mice.

    Results: We found that thrombocytopenia independently leads to monocyte dysfunction, in a manner that is dependent on direct platelet-monocyte CD47 interactions that regulate monocyte immunometabolism and gene expression (Fig 2). Compared to monocytes from mice with normal platelet counts, monocytes from thrombocytopenic mice had increased toll-like receptor (TLR) responses. Furthermore, ex vivo co-incubation of resting platelets with monocytes, induced monocyte metabolic programming and durable changes in TLR agonist responses. ATAC-Seq on monocytes from thrombocytopenic mice showed persistently open chromatin at LPS response genes. Using mouse models of thrombocytopenia and sepsis we found that normal platelet numbers are needed to limit immune dysregulation. IL6 and TNF expression in monocytes from human patients with sepsis also inversely correlated with patient platelet counts.

    Conclusion(s): Our studies demonstrate that in healthy conditions resting platelets maintain monocyte immune tolerance by regulating monocyte immunometabolic processes that lead to changes in gene expression. Thrombocytopenia may therefore independently lead to immune dysregulation in sepsis, exacerbating systemic inflammatory processes.

    Learning Objectives:

    • Understand the immune regulatory function of platelet and how platelets regulate monocyte immune function in both normal and disease conditions.
    • Understand how monocyte immune function is dysregulated during sepsis and contribute to sepsis outcome
    • Understand the mechanism of platelet-monocyte interaction and monocyte phenotype change after interaction with platelets