The Role of BET Proteins on M1/M2 Macrophage Polarization
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Date
2024-05
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The Ohio State University
Abstract
The main curative treatment for hematologic malignancies, such as leukemias, is an allogeneic hematopoietic stem cell transplantation. However, graft-versus-host disease (GVHD) is a leading cause of mortality in these patients. Previously, our lab has demonstrated that inhibition of epigenetic modifiers such as Bromodomain and extra terminal (BET) proteins alleviates GVHD pathology via dampening alloreactive T cell responses. However, emerging research indicates a role for macrophages in mediating GVHD. Macrophages have defensive functions such as phagocytosis, production of cytotoxic nitric oxide (NO), and secretion of pro-inflammatory cytokines like IFNγ which recruit other immune components to sites of inflammation. Macrophages are antigen presenting cells providing costimulatory signaling and cytokines necessary for T cell activation. Here, we aim to investigate the role of BET proteins in macrophage activation and function.
First, we sought to understand the role of BET proteins in M1 macrophage phenotype and function. M1 macrophages are important antigen presenting cells, directly contributing to T cell activation, thereby promoting a robust immune response against foreign pathogens. BET inhibition reduces surface expression of classical markers of M1 polarization such as MHCII and CD86 and gene expression of iNOS and IL-1b when compared to control untreated macrophages. This indicates a potent role for BET proteins to reduce classic proinflammatory pathways that have been implicated in T cell alloreactivity and tissue damage. We also investigated the impacts of BET proteins in In M2 macrophages, important homeostatic regulators of tissues. BETi reduces intracellular Arginase 1 and IRF4 expression, genes implicated in fibrosis. Lastly, we illustrated the effects of BETi on macrophage differentiation through CSF-1r expression and observed selective regulation of M1 macrophages while M2 macrophages remained unchanged.
We found that BET inhibition reduces the proinflammatory phenotype of M1 macrophages. Our data suggest that in addition to limiting T cell mediated responses, restraining macrophage activation, cytokine production, and antigen presentation could be an additional mechanism via which BET inhibition alleviates GVHD. In conjunction with M1 macrophages, the BET proteins also impact M2 macrophages and can potentially alleviate fibrotic pathways seen in GVHD. We also establish a selective reduction in CSF-1r expression in M1 macrophages, suggesting a potential synergistic treatment strategy with clinical CSF-1r inhibitors shown to have clinical benefit.
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Keywords
BET proteins, macrophages, cancer, bone marrow transplant