Suppression of Notch Signaling during Efferocytosis Prevents Macrophage Pro-Inflammatory Polarization 2817

Abstract Description The clearance of dying cells in human body via phagocytes-mediated efferocytosis is essential for tissue homeostasis maintenance and actively repression of inflammatory responses. However, the anti-inflammatory feature of efferocytosis promotes immunosurveillance evasion in tumor microenvironment, which makes it interesting therapeutic target for cancer treatment. Here we reveal that Notch is actively suppressed in macrophages, one of the most potent phagocytes, during efferocytosis through phosphatidylserine (PS) and cognate receptor, TIM4, interaction which induces the activation of integrin to form barrier thereby excluding Notch receptor from where efferocytosis occurs. This active integrin barrier formation requires Rubicon-VPS34 complex which recruits phospholipase D (PLD) to regulate integrin activation. Immunoblotting and transcriptomic analysis show that disruption of active integrin barrier formation via Rubicon ablation and PLD inhibitor treatment increase Notch activation during efferocytosis. Activation of Notch, either by genetically overexpression of NICD in macrophages or by treatment of PLD inhibitors, promotes pro-inflammatory polarization of macrophages and enhances anti-tumor effect. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)