Introduction:
Sepsis is a serious life-threatening condition (death rates up to 50%) characterised by an acute inflammatory response to an infection. Current treatment options focus on controlling this initial inflammatory response. Although these treatments alleviate the acute disease symptoms, they have not lowered the overall mortality rates. Recently it has been shown that this is due to a prolonged immunosuppressive phase that follows the acute phase of sepsis. Little is known about this secondary phase except for the apoptosis of immune cells.
Aims:
We sought to uncover the molecular details that trigger and control the immunosuppressive phase of sepsis.
Methodology:
We used a combination of whole-genome CRISPR screening, mice knockouts and studies using immune cells.
Results:
The CRISPR screening revealed a (TREM) family receptor TREML4 on myeloid cells as the molecular switch that triggered and regulated inflammation and immune cell death during sepsis. Importantly, genetic ablation of Treml4 in mice led to an overall increase in survival rate, both during the acute and chronic phases of sepsis. Adaptations to neutrophils in TREML4 ablated mice during sepsis were found to be the basis for increased survival during sepsis.
Conclusions:
We show for the first time that the receptor TREML4 is responsible for the high mortality rates during sepsis and that targeting this receptor represents a valid strategy for the design of new treatments for sepsis.