SAMSN1 causes sepsis immunosuppression by inducing macrophages to express coinhibitory molecules that causes T cell exhaustion via KEAP1-NRF2 signaling

Abstract

Immunosuppression has been found to be closely related to the pathogenesis of<br />sepsis, but the underlying mechanisms have not yet been fully elucidated. In this study,<br />we identified that SH3 domain and nuclear localization signals 1 (SAMSN1), a gene<br />encoding a putative adaptor protein, plays an important role in immunosuppression in<br />sepsis. The expression of SAMSN1 was significantly increased in patients with sepsis<br />and was positively correlated with sepsis mortality. When sepsis occurs, the number of<br />monocyte-macrophages increases significantly, among which SAMSN1 is highly<br />expressed. SAMSN1 binds to KEAP1, causing NRF2 to dissociate from the KEAP1-<br />NRF2 complex and translocate into the nucleus, promoting the transcription of co<br />inhibitory molecules CD48/CD86/CEACAM1, which bind to their corresponding<br />receptors 2B4/CTLA4/TIM3 on the surface of T cells, inducing T cell exhaustion.<br />SAMSN1 blockade alleviated organ injuries and improved survival of septic mice. Our<br />study reveals a novel mechanism that triggers immunosuppression in sepsis and may<br />provide a candidate molecular target for sepsis immunotherapy.