Abstract
Efferocytosis is the process by which phagocytes recognize, engulf, and digest (or clear) apoptotic cells during development. Impaired efferocytosis is associated with developmental defects and autoimmune diseases. In Drosophila melanogaster, recognition of apoptotic cells requires phagocyte surface receptors, including the scavenger receptor CD36-related protein, Croquemort (Crq, encoded by crq). In fact, Crq expression is upregulated in the presence of apoptotic cells, as well as in response to excessive apoptosis. Here, we identified a novel gene bfc (booster for croquemort), which plays a role in efferocytosis, specifically the regulation of the crq expression. We found that Bfc protein interacts with the zinc finger domain of the GATA transcription factor Serpent (Srp), to enhance its direct binding to the crq promoter; thus, they function together in regulating crq expression and efferocytosis. Overall, we show that Bfc serves as a Srp co-factor to upregulate the transcription of the crq encoded receptor, and consequently boosts macrophage efferocytosis in response to excessive apoptosis. Therefore, this study clarifies how phagocytes integrate apoptotic cell signals to mediate efferocytosis.
Highlights
Apoptosis is a developmentally programmed cell death process in multicellular organisms essential for the removal of excessive or harmful cells [1]; whereby apoptotic cells (ACs) are swiftly removed by phagocytes to prevent the release of toxins and induction of inflammation [2], a process crucial for organ formation, tissue development, homeostasis, and normal immunoregulation
Defects in the removal of dying cells, a process known as the clearance of apoptotic cells (ACs), can contribute to the development of autoimmune disorders such as systemic Lupus erythematosus (SLE) and neurodegenerative diseases like Alzheimer’s disease
Via transcriptomic analysis and RNAi screening, we discovered 12 genes required for the clearance of ACs in macrophage-like S2 cells in Drosophila
Summary
Apoptosis is a developmentally programmed cell death process in multicellular organisms essential for the removal of excessive or harmful cells [1]; whereby apoptotic cells (ACs) are swiftly removed by phagocytes to prevent the release of toxins and induction of inflammation [2], a process crucial for organ formation, tissue development, homeostasis, and normal immunoregulation. Franc and colleagues first characterized Croquemort (Crq), a Drosophila CD36-related receptor required by macrophages to engulf ACs [8,15]. SIMU, a Nimrod family cell surface receptor [22], functions upstream of Drpr to mediate the recognition and clearance of ACs as well as of non-apoptotic cells at wound sites [10,23] through the recognition of phosphatidylserine (PS). The transcriptional factor Serpent (Srp), a GATA factor homolog [24,25], was recently found to be required for the efficient phagocytosis of ACs in the context of Drosophila embryonic macrophages and acted via the regulation of SIMU [10], Drpr, and Crq [26]
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