Receptor-interacting protein 3 (RIP3) deficiency inhibits immune cell infiltration and attenuates organ injury in sepsis (INC6P.344)

Abstract

Abstract Sepsis is defined as a systemic inflammatory response syndrome (SIRS), leading to multiple organ dysfunction and lethality. RIP3-dependent necrosis is implicated in driving TNF-α- and sepsis-induced mortality in mice. However, it is unknown if RIP3 deficiency has any impact on immune cell trafficking, which attributes to organ damage in SIRS. To study this, male wild-type (WT) and RIP3-deficient (RIP3-KO) mice were subjected to cecal ligation and puncture (CLP), a sepsis model. Blood and tissue samples were collected at 20 h after CLP for analysis. In our severe sepsis model, the mean survival time of septic RIP3-KO mice was significantly extended from 41 h to 68 h, and their plasma levels of TNF-α, IL-6, AST, ALT and LDH were significantly decreased, compared to septic WT mice. In the lungs, septic RIP3-KO mice preserved a better integrity of microscopic structure with reduced apoptosis, and decreased the levels of IL-6, MIP2 and KC, compared to WT. In the liver, the levels of MIP2 and KC were also decreased in septic RIP3-KO mice. Particularly, the total number of neutrophils in the lungs and liver of septic RIP3-KO mice decreased by 64.6% and 52.2%, respectively, compared to septic WT mice. In addition, the number of natural killer (NK) and CD8T cells in the liver decreased by 63.9% and 50.3%, respectively, in septic RIP3-KO mice. Thus, targeting RIP3 may provide a therapeutic strategy in attenuating organ injury caused by excessive immune cell infiltration during sepsis.