Sepsis is a biphasic disease characterized by an acute inflammatory response, followed by a prolonged immunosuppressive phase. Therapies aimed at controlling inflammation help to reduce the time sepsis patients spend in intensive care units, but they do not lead to a reduction in overall mortality. Recent focus has been on addressing the immunosuppressive phase, often caused by apoptosis of immune cells. However, molecular triggers of these events are not yet known. Using a whole genome CRISPR screen in mice we identified Trigger Receptor Expressed in Myeloid-Like 4 (TREML4) as a key receptor that regulates inflammation and immune cell death in sepsis. Genetic ablation of Treml4 in mice demonstrated that TREML4 regulates calcium homeostasis, the inflammatory cytokine response, myeloperoxidase activation, the ER stress response and apoptotic cell death in innate immune cells, leading to an overall increase in survival rate, both during the acute and the chronic phases of polymicrobial sepsis including Pseudomonas aeruginosa pneumonia and invasive candidiasis.