Sepsis is a biphasic disease characterised by acute inflammation, leading into extended immune suppression. Many clinical trials sought to modulate inflammation, but this had no effect on patient mortality. Recently, focus has shifted to addressing the immunosuppressive phase and allow the host’s immune system to return to a functional state. Previous work by Nedeva et al., 2020 identified triggering receptor expressed on myeloid cells (TREM) family receptor, TREML4 as the key regulator immune cell death and inflammation, following polymicrobial sepsis. Genetic ablation of TREML4 in mice using CRISPR demonstrated its role in regulating many cellular responses, especially apoptosis of innate immune cells, leading to a higher rate of survival in the acute and chronic phases of sepsis. This improved survival is due, in part, to long lasting epigenetic changes in the effector innate immune cells of TREML4 ablated mice. Neutrophils play an essential role in the early stages of many infections and recently been shown to play a major role in TREML4 ablated mice survival advantage. Therefore, epigenetic changes to the histones of neutrophils during the early stages of polymicrobial sepsis results in an innate immune memory that protects TREML4 ablated mice from secondary infections during the chronic phase of sepsis.